This review will first start with an overview of the recent literature on the association between the retina with neurodegeneration and neuroinflammation. This will cover key findings from research in multiple sclerosis (MS) and optic neuritis (ON). In this context, neuroretinitis and a new easily overlooked, benign finding at the vitreoretinal interface (“mouche dormant”) are discussed, as well as glaucoma. Special focus is given to Alzheimer disease (AD). This is followed by other central nervous system (CNS) degenerative conditions including Parkinson disease (PD) and motor neuron disease (MND) or amyotrophic lateral sclerosis (ALS). There are patterns of retrograde trans-synaptic axonal degeneration (RTD) in epilepsy and stroke that suggest a window or opportunity for treatment. Taken together, the literature reveals patterns of optical coherence tomography (OCT) changes that can be readily recognized.
For didactic reasons, case vignettes will be used to discuss in great detail the OCT findings. The patterns discussed can be broken down into macular inner retinal layer atrophy resulting in 3 “red lines.” For illustration, “red lines” will be used in the Figures. For bedside teaching, I found an unconventional mnemonic approach helpful (Fig. 1). The “half moon” sign indicates need for potentially urgent brain imaging as primary neurological pathology is likely (Fig. 1A). The “sunset” sign is more common with opthalmologic pathology (Fig. 1B). Finally, the “rainbow” sign (Fig. 1C) aids to distinguish primary neurological from ophthalmologic pathology in case of a “sunset” or more complex patterns of inner retinal layer atrophy. The proposed system of 3 “red lines” is internally consistent.
OPTICAL COHERENCE TOMOGRAPHY PROTOCOLS
The OCT data in this review are from the macula and optic disc. Most commonly, a volume scan of the macula is combined with a peripapillary ring scan (1). Additional information can be obtained from an optic nerve head volume scan, B-scans placed through the region of interest (ROI) and autofluorescence. The reader should bear in mind that it can be very challenging to obtain reliable quantitative OCT data in patients who cannot easily sit still, are disabled, and/or cannot visually fixate. A simple trick to overcome at least the latter is to make use of proprioception. One always can move, for example, a patients finger and ask to look at where the patient thinks her/his finger tip is. This works reliably even in a blind person.
Retinal Layers and Neurodegeneration
The anatomy of the retina is hierarchical and already clearly described by Santiago Ramón y Cajal who also performed detailed investigations on the progression of anterograde and retrograde axonal degeneration through retinal layers (1). Retinal OCT does permit for an in vivo approximation of retinal layers as summarized in detail (2). For this review, relevant is the retinal nerve fiber layer (RNFL). This layer is clearly visible as a highly reflective band shown in Figure 2. Loss of axons in the RNFL impress as thinning of this layer also shown in Figure 2. All axons of the RNFL converge at the optic disc. After the axons pass through the cribirform plate, they become myelinated and form the optic nerve. Next, these axons synapse in the dorsolateral geniculate nucleus (LGN) to become the optic radiations (Meyer's loop), which reach the primary visual cortex in the occiput. Damage to the visual cortex, optic radiations or optic nerve sets off a process called retrograde trans-synaptic degeneration (RTD). The first case vignette discussed introduces the retinal layer anatomy (2) and abbreviations used in this review in great detail (Fig. 2A–Z).
There is direct RTD and trans-synaptic RTD (3). Direct RTD is because of damage of the axons originating from the retinal ganglion cell layer (GCL). Clinically, this is most frequently because of pathology of the optic nerve. As will be reviewed here, this is a rapid process. In contrast, trans-synaptic RTD is due to damage to the visual posterior pathways, that is after the LGN. It takes more time for neurodegeneration due to trans-synaptic RTD to cause atrophy in the retina than for direct RTD (3). Both processes cause atrophy of the RNFL as shown in Figures 2, 3, 5–7. Important for this review is to remember that the atrophy progresses to involve the inner plexiform layer (IPL) and the GCL. Generally, progression of atrophy due to RTD stops at level of the inner nuclear layer (INL) as illustrated Figure 3. Therefore, the first “red line” introduced in this review to help with pattern recognition of OCT in neurological disorders is at level of the INL.
Selection and Sequence of Diseases Selected for This Review
To illustrate the point made above on RTD further, the OCT findings of trans-synaptic RTD are reviewed in MS, followed by a review of direct RTD in ON. Because of the clinically relevant differential diagnosis in the postinfectious setting also OCT findings in neuroretinitis are discussed. Neither of these conditions permits to describe anterograde axonal degeneration for which reason an acquired large blind spot syndrome is reviewed. Bespoke “red line” at the INL is trespassed in this example. Clinically, another benign condition can be confused with ON, but is easily recognized by OCT.
The second section reviews primarily neurodegenerative conditions. Glaucoma was chosen not only because it is so frequent, but also because it permits to return to the “red line” at the level of the INL from a primarily ophthalmologic perspective. And importantly, introduce the second “red line” as a red flag for long-term monitoring of these patients. Next in the neurodegenerative section, Alzheimer disease was chosen because of frequency and the opportunity to make a point about the importance of high-quality OCT. This point is further enforced by a review of OCT data from 2 other neurodegenerative conditions, PD and ALS. In none of the neurodegenerative conditions there is validated progression of retinal layer atrophy beyond the INL, which is the first “red line.”
In contrast, the more easily timed events due to brain surgery and stroke were pivotal to introduce the concept of RTD to OCT and deserve their own, the third, section.
DEMYELINATION AND SELECTED DIFFERENTIAL DIAGNOSIS
Contemporary understanding is that the primary pathology in MS is demyelination with a neurodegenerative component due to axonal loss (4). High-frequency longitudinal quantification of axonal loss in vivo was challenging until OCT filled this void. Over the last 2 decades, OCT has become a surrogate marker of CNS neuroaxonal integrity in MS patients (5,6). Patterns of atrophy in MS can be seen in the inner retinal layers. The RNFL, GCL, and IPL are all reduced in thickness. The INL can be increased in thickness. The underlying mechanisms depend on location and age of the MS lesion. MS lesions located in the area of the visual cortex or Meyer's loop set off slow RTD (7). Much quicker in contrast is direct retrograde axonal degeneration due to MS lesions in the dorsolateral LGN, optic tract, or optic nerve (8). In general, retrograde axonal degeneration in the visual system of patients with MS stops at the INL (“rainbow,” Fig. 1C) (9).
Thickening of the INL in MS is not yet fully understood. There are indications that INL edema is related to increased inflammatory disease activity (10,11). Even more pronounced thickening can present as microcystic macular edema (MME) (12). Interestingly, recovery of INL edema has been observed in patients with MS who are treated successfully (13). The transient nature of INL edema and MME in many can be explained by inner retinal fluid transport through the retinal glymphatic system (14), which has just been shown to exist experimentally (15).
There is a large number of correlative studies underpinning and cross-validating the value of OCT as an outcome measure for neurodegeneration in MS. There is also potential for measures of retinal asymmetry in MS and MSON to be considered as a supportive diagnostic test (16–19).
Part of the success of OCT in MS is because of a network approach on early development of quality control criteria (20,21), which was followed by validation steps (22) and made it into reporting guidelines (23). The key point is that the amount of annual inner retinal layer atrophy rates (∼0.5 um/year) is below the spacial resolution of the OCTs used in clinical routine (∼3–7 um). Therefore, it is paramount to reduce measurement noise to permit for meaningful statistical analyses on a group level. Confidence in the group level data is justified by 2 meta-analyses covering 2 generations of OCT technologies (24,25).
Finally, swept-source OCTA now permits for imaging of the retinal and choroidal vasculature alike. This permits for a more detailed analysis of the increasingly recognized contribution of vascular pathology in MS. In addition to the documentation of reduced density of the microvasculature, this may serve to investigate the “virtual hypoxia hypothesis” as a cause for neurodegeneration (26).
The evidence to date indicates that peripapillary RNFL (pRNFL) damage in ON is substantial and that it takes about 3 months for pRNFL damage to manifest (27). The 3-month rule has informed the design of longitudinal cohort studies and clinical trials in ON (28). It was not until introduction of spectral domain OCT, that the much earlier degeneration of the macular GCIPL (mGCIPL) was recognized (29). There are data that suggest that mGCIPL atrophy can be detected within 8 to 11 days after onset of visual loss and can precede reliable detection of pRNFL atrophy (30,31). As with MS, RTD stops at the INL (“rainbow”) as illustrated in the second case vignette (Fig. 3A–I).
There is also scope for OCTA and functional assessment of outer retinal layers to contribute (32). It should be investigated if high-frequency OCT/OCTA imaging in a cohort of patients with acute ON permits to capture subgroups without optic disc swelling, mGCIPL atrophy preceding pRNFL atrophy, and electrodiagnostic features of early retinal ganglion cell dysfunction (33,34). Comprehensive analysis of the time course of these variables will help to advance our knowledge on the timing and progression of neurodegeneration in ON.
OCT provides an imaging correlate to the classic macular star in neuroretinitis (34,35). Reports on OCT findings in neuroretinitis remain anecdotal (36–38). In my own experience, I have seen the reported hyper-reflective dots migrate through the retina. The migrating hyper-reflective dots are clearly distinct to those hyper-reflective dots we come now to recognize as retinal capillaries using OCTA (32). The dynamic of this process in an own case is shown in a short video (See Supplemental Digital Content, Video S1, https://links.lww.com/WNO/A451). It is suggested that this represents a phenomenon related to migrating inflammatory pathology in the retina.
Acute Zonal Occult Outer Retinopathy Spectrum
The large blind spot syndromes include the Acute Zonal Occult Outer Retinopathy (AZOOR) (39). The OCT features in AZOOR are well-recognized and consist of disruption of the inner outer segment and changes on auto-fluorescence (40,41). For OCT research, AZOOR provides a model for the study of acquired anterior axonal degeneration in the retina that starts distal to the INL. This is relevant because, in contrast to RTD, which generally stops at the INL, anterior axonal degeneration seems to be more aggressive (42). Anatomically, this is believed to be related to convergence and divergence of the visual pathways. The more axons converge to one neuronal layer (e.g., the INL), the more likely this layer is affected by propagation of anterior trans-synaptic axonal degeneration.
Mouche Dormant—A Not Uncommon Pitfall
There are pitfalls to the interpretation of symptoms and sings in patients, which results in unnecessary referrals. One example is a mouche dormant (prefoveal floater). A tiny mouche dormant can readily be recognized on OCT, but not by slit lamp examination (43). For a patient to be symptomatic, there needs to be a shadow cast dense enough to cause a scotoma. If the scotoma reduces visual acuities, then this will also change the ERG and VEP signal. It is precisely because of this combination of VEP/ERG data with visual symptoms that a misdiagnosis of ON can be made.
The distinguishing feature of glaucoma to other optic neuropathies is the pattern of visual field loss associated with the characteristic image of the excavated optic nerve head (44).
With around 65 million people affected worldwide, glaucoma is likely the most prevalent neurodegenerative condition (44). The optic nerve head appearance is so characteristic that the first international consensus classification for global epidemiological studies incorporated this as the first criterion (see Box 33.1 in (44)). The 2 main risk factors for glaucoma are age and an increased intraocular pressure (IOP, i.e., > 21 mm Hg) (45,46). There is primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and a long list of secondary glaucoma, which includes treatment with corticosteroids, uveitis and other inflammatory conditions, tumors, trauma, and pigment dispersion. The most common for is POAG accounting for about 86% of all glaucoma cases (44). Glaucoma can also present with normal IOP, which opens up a discussion on the pressure gradient between the IOP and intracranial pressure (47). All types of glaucoma result in trans-synaptic axonal degeneration, which can be depicted by OCT and MRI. The signal changes of the optical pathways in the MRI brain scans from patients with glaucoma are generally a sign of anterior axonal degeneration. For quantification of structural disease progression in glaucoma, there is a role for OCT (48). There is also an emerging role for OCTA and AI in glaucoma (49). Because of the pattern of progression, an ROI approach has important advantages over more global OCT metrics (50). Because glaucoma is chronic, most patients are followed up lifelong accounting for an estimated 23% of all follow-up attendances in a United Kingdom hospital eye service (44). In a small proportion of these patients, a vertical “red line” will emerge in the macular OCT (Fig. 4). In these cases, a“half moon” shall always prompt for further investigations including prolactin levels and MRI brain imaging. This is an important role the neuro-ophthalmology services can fulfill working together with the glaucoma service.
An important differential diagnosis to glaucoma and ON are the ischemic optic neuropathies (51). Two of the “red lines” are helpful for pattern recognition in this context. Both, a branch retinal artery occlusion (BRAO, Fig. 5A–G) and an anterior ischemic optic neuropathy (NAION, Fig. 6 A–F) can produce the “sunset” sign. The difference between the 2 is that the INL is atrophied with a BRAO, but not NAION where pathology occurs at the optic disc.
The other addition in this age group relates to impaired higher visual function in patients in whom there is a substantial mismatch between the structural appearance of the optic nerve head and the visual fields due to dementia.
Alzheimer Disease and Disorders of Cognitive Impairment
In clinical practice, referrals to a neuro-ophthalmology service of people suspected to suffer from cognitive impairment are because of a mismatch between structure and function. There is a body of literature showing that difficulties with visual fields can be because of a neurodegenerative dementia. The text book example is posterior cortical atrophy (PCA) or Benson disease. Most people with PCA will develop Alzheimer disease in the long-term. Of course, Alzheimer disease can co-exist with glaucoma and indeed there is a genetic overlap in common genetic variants associated with an increased risk (44). The resulting overlap in care for these patients has contributed stimulating early research on OCT in AD (52).
One intriguing hypothesis is that of amyloid deposition in the retina of patients suffering from AD (53). In addition, and similar to what has been described in PD interest on OCT in AD has also been influenced by melanopsin-driven hypotheses on neurodegeneration (54). A critical appraisal of the early, mainly time domain dominated OCT literature and subsequent spectral domain OCT reveals however a publication bias (55). Because the effect size is very small, there is need for making use of big data. The large United Kingdom Biobank study suggests that it is likely that the association between progressive inner retinal layer atrophy and progression of cognitive decline is associated with a wider clinical spectrum than pure AD alone (56). In contrast to the research published in the field of MS which makes use of OCT quality control criteria (20), such a rigorous approach has yet to be adopted by OCT research in the dementia field. The degree of inner retinal layer atrophy in dementia (55) is much less than in MS (25,57) and high-quality scans even more important.
A stimulating discovery in the field was a novel opsin in the eye, melanopsin (58,59). Melanopsin is related to melanin, which is deficient in patients suffering from PD. Therefore, a hypothesis is that lack of melanopsin may be associated with retinal layer atrophy similar to the association between melanin and the substantia nigra (60). The effect size is small as demonstrated in a recent meta-analysis (61). There is more to vision in PD than OCT alone (62) and cognitive impairment is relevant (63).
Amyotrophic Lateral Sclerosis/Motor Neuron Disease
There is interesting, statistically correlative work on inner retinal layer atrophy in MND/ALS (64–66). More research is needed because it is difficult to understand what the underlying biological mechanism should be. Why should the macular RNFL thickness correlate with the forced vital capacity percent predicted and forced expiratory volume as suggested (66)? Although more research is needed, in our own experience, patients with ALS are not easy to image because of the rapid disease progression. Frequently, repositioning of the patient's head at the OCT chin rest is already difficult early in the disease course. Therefore, follow-up imaging can be extremely challenging.
INSIGHTS ON ONSET AND PROGRESSION OF RETROGRADE AXONAL DEGENERATION
There are 2 reasons for changes to the OCT in epilepsy: drug toxicity and surgery. Neurotoxicity of vigabatrin on retinal ganglion cells had been demonstrated by OCT (67,68).
Epilepsy surgery can damage Meyer's loop (69). It is impossible to completely prevent this complication. As part of their routine assessment, patients have a visual field examination and OCT before and after surgery (3). Longitudinal data show the presence of truly acquired RTD in humans. By matching the visual field with the macular OCT, highly accurate ROI-specific OCT atrophy analysis becomes possible (3). This permits to extract 3 patterns of axonal degeneration: (a) direct retrograde axonal degeneration that is very quick; (b) rapid RTD that is self-terminating within less than 1 year; (c) prolonged RTD that persists for more than one year (3). The difference between the 2 last patterns relates to the size of the lesion to Meyer's loop. Larger lesions trigger a mechanism of RTD, which cannot be captured by a short equation because the underlying biological process is most likely governed by spatial cellular stoichiometric relationships between glia, neurons, and axons. It is possible that there is a potentially salvageable “penumbra” area (3). The challenge for future research in the field is to now demonstrate that there are successful neuroprotective strategies to rescue this “penumbra.” If shown as a “proof of principle” in patients with epilepsy surgery, the approach may be expanded to other diseases such as MS.
A stroke causes trans-synaptic axonal degeneration (70). The changes observed for the pRNFL are clearly visible on OCT and progress over time (71). Since, it has become easier to demonstrate patterns and progression of RTD in stroke by analyzing the mGCIPL (72). Similar to the data from epilepsy, a time window of progression of RTD is emerging, which may be relevant for future treatment strategies.
The risk of a cerebrovascular disease and stroke is increased in patients with vascular pathology of the retina (73). The risk of stroke is substantially increased in patients with a retinal artery occlusion (RAO) (74). Clinically, the challenge is to separate embolic from nonembolic etiologies of monocular visual field loss (75). Pattern recognition in OCT is helpful to do so as was illustrated already in the 2 case vignettes with vascular pathology (Figs. 5 and 6).
There are very important insights from the association of perinatal damage to the visual pathways and the resulting OCT findings (76). Generally speaking, the degree of RTD quantified is more profound compared with RTD brain lesions acquired later in life. The final case vignette 4 in this review is one example where the “half moon” is shown to persist for life (Fig. 7 A–G). There is an opportunity to study the pattern of retinal atrophy in the context of perinatal pathology in much more detail as the literature remains largely anecdotal (76–78). Yet, OCT findings in this context almost always result in a patient referral.
Three Red Lines for Clinical Practice
This literature review at the interface between neurology and ophthalmology suggested that the INL acts as a tight barrier for RTD and a more permissive barrier for anterograde axonal degeneration. The understanding of the different dynamics of these pathologies is relevant. For the daily clinical practice, there are 3 red lines that had been illustrated in detail in the case vignettes. The patterns reviewed were all present because of individual retinal layer atrophy. The 3 red lines are aligned in a 3D space with respect to the macular. The first red line is vertically through the macula (Fig. 1A), the second red line is horizontally through the macula (Fig. 1B), and the third red line (front–back) aligned to the INL (Fig. 1C).
It is concluded that in clinical practice there are 3 red lines through the macular that indicate patterns of atrophy and with the differential diagnosis, reviewed here, as presented in summary table (Table 1).
TABLE 1. -
Overview on how 3 red lines help with the interpretation of the macular OCT
||Retrochiasmal lesions, brain surgery, stroke, Foster-Kennedy
||MRI brain, CT brain
||(N)AION, glaucoma, pathology at disc
||IOP, vascular workup
||“Rainbow” Above INL
||ON, MS, AD, (N)AION, glaucoma.
||Ophthalmology review stroke referral for new RAO
The relevant differential diagnosis discussed in this review is presented. The spectrum of the differential diagnosis can readily be expanded using the same approach. The OCT of the macular always needs to be interpreted together with the OCT of the optic disc. Recommended investigations in support of the differential diagnosis are listed for consideration. As a mnemonic and for bedside teaching “beware of the half moon” (Fig. 1
AD, Alzheimer disease; BRAO, branch retinal artery occlusion; IOP, intraocular pressure; INL, inner nuclear layer; MS, multiple sclerosis; ON, optic neuritis.
The author want to apologize to those colleagues who they were unable to cite due to space restrictions, but who have made important contributions to the field, either directly or indirectly.
1. Ramon Y, Cajal S. Degeneration and Regeneration of the Nervous System. Oxford, United Kingdom: Oxford Univ Press, 1928.
2. Evangelou Nikos, Omar SM Alrawashdeh. “Anatomy of the Retina and the Optic Nerve.” Optical coherence tomography in multiple sclerosis. Cham, Switzerland: Springer, 2016: 3–19.
3. de Vries-Knoppert WA, Baaijen JC, Petzold A. Patterns of retrograde axonal degeneration in the visual system. Brain. 2019;142:2775–2786.
4. Trapp B, Peterson J. Axonal transection in the lesions of multiple sclerosis. N Eng J Med. 1998;338:278–285.
5. Trip SA, Schlottmann PG, Jones SJ, Altmann DR, Garway-Heath DF, Thompson AJ, Plant GT, Miller DH. Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis. Ann Neurol. 2005;58:383–391.
6. Saidha S, Syc SB, Ibrahim MA, Eckstein C, Warner CV, Farrell SK, Oakley JD, Durbin MK, Meyer SA, Balcer LJ, Frohman EM, Rosenzweig JM, Newsome SD, Ratchford JN, Nguyen QD, Calabresi PA. Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography. Brain. 2011;134:518–533.
7. Gabilondo I, Martnez-Lapiscina EH, Martnez-Heras E, Fraga-Pumar E, Llufriu S, Ortiz S, Bullich S, Sepulveda M, Falcon C, Berenguer J, Saiz A, Sanchez-Dalmau B, Villoslada P. Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis. Ann Neurol. 2014;75:98–107.
8. Costello F, Hodge W, Pan YI, Eggenberger E, Coupland S, Kardon RH. Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography. Mult Scler. 2008;14:893–905.
9. Balk LJ, Twisk JWR, Steenwijk MD, Daams M, Tewarie P, Killestein J, Uitdehaag BMJ, Polman CH, Petzold A. A dam for retrograde axonal degeneration in multiple sclerosis? J Neurol Neurosurg Psychiatry. 2014;85:782–789.
10. Saidha S, Sotirchos ES, Ibrahim MA, Crainiceanu CM, Gelfand JM, Sepah YJ, Ratchford JN, Oh J, Seigo MA, Newsome SD, Balcer LJ, Frohman EM, Green AJ, Nguyen QD, Calabresi PA. Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study. Lancet Neurol. 2012;11:963–972.
11. Balk LJ, Coric D, Knier B, Zimmermann HG, Behbehani R, Alroughani R, Martinez-Lapiscina EH, Brandt AU, Sánchez-Dalmau B, Vidal-Jordana A, Albrecht P, Koska V, Havla J, Pisa M, Nolan RC, Leocani L, Paul F, Aktas O, Montalban X, Balcer LJ, Villoslada P, Outteryck O, Korn T, Petzold A; consortium, I. Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study. Mult Scler J. 2019;5:2055217319871582.
12. Gelfand JM, Cree BA, Nolan R, Arnow S, Green AJ. Microcystic inner nuclear layer abnormalities and neuromyelitis optica.. JAMA Neurol. 2013;70:629–633.
13. Knier B, Schmidt P, Aly L, Buck D, Berthele A, Mühlau M, Zimmer C, Hemmer B, Korn T. Retinal inner nuclear layer volume reflects response to immunotherapy in multiple sclerosis.. Brain. 2016;139:2855–2863.
14. Petzold A. Retinal glymphatic system: an explanation for transient retinal layer volume changes? Brain. 2016;139:2816–2819.
15. Wang X, Lou N, Eberhardt A, Yang Y, Kusk P, Xu Q, Förstera B, Peng S, Shi M, de-Guevara AL, Delle C, Sigurdsson B, Xavier ALR, Ertürk A, Libby RT, Chen L, Thrane AS, Nedergaard M. An ocular glymphatic clearance system removes β-amyloid from the rodent eye. Sci Translational Med. 2020;12:eaaw3210.
16. Coric D, Balk LJ, Uitdehaag BMJ, Petzold A. Diagnostic accuracy of optical coherence tomography Inter-Eye Percentage Difference (IEPD) for optic neuritis in multiple sclerosis. Eur J Neurol. 2017;24:1479–1484.
17. Petzold A, Chua SYL, Khawaja AP, Keane PA, Khaw PT, Reisman C, Dhillon B, Strouthidis NG; UK Biobank Eye and Vision Consortium, Foster PJ, Patel PJ. Retinal asymmetry in multiple sclerosis. Brain. 2020,:awaa361. doi: 10.1093/brain/awaa361. Epub ahead of print. PMID: 33253371.
18. Nolan-Kenney RC, Liu M, Akhand O, Calabresi PA, Paul F, Petzold A, Balk L, Brandt AU, Martı́nez-Lapiscina EH, Saidha S, Villoslada P, Al-Hassan AA, Behbehani R, Frohman EM, Frohman T, Havla J, Hemmer B, Jiang H, Knier B, Korn T, Leocani L, Papadopoulou A, Pisa M, Zimmermann H, Galetta SL, Balcer LJ. Optimal intereye difference thresholds by optical coherence tomography in multiple sclerosis: an international study. Ann Neurol. 2019;85:618–629.
19. Xu SC, Kardon RH, Leavitt JA, Flanagan EP, Pittock SJ, Chen JJ. Optical coherence tomography is highly sensitive in detecting prior optic neuritis. Neurology. 2019;92:e527–e535.
20. Rejdak K, Petzold A, Sharpe MA, Kay AD, Kerr M, Keir G, Thompson EJ, Giovannoni G. Cerebrospinal fluid nitrite/nitrate correlated with oxyhemoglobin and outcome in patients with subarachnoid hemorrhage. J Neurol Sci. 2004;219:71–76.
21. Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S, Petzold A. The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One. 2012;7:e34823.
22. Schippling S, Balk L, Costello F, Albrecht P, Balcer L, Calabresi P, Frederiksen J, Frohman E, Green A, Klistorner A, Outteryck O, Paul F, Plant G, Traber G, Vermersch P, Villoslada P, Wolf S, Petzold A. Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria. Mult Scler. 2015;21:163–170.
23. Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina EH, Lagreze WA, Schuman JS, Villoslada P, Calabresi P, Balcer L, Petzold A, Green AJ, Paul F, Brandt AU, Albrecht P; consortium, I. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology. 2016;86:2303–2309.
24. Petzold A, Keir G, Warren J, Fox N, Rossor MN. A systematic review and meta-analysis of CSF neurofilament protein levels as biomarkers in dementia. Neurodegener Dis. 2007;4:185–194.
25. Petzold A, de Boer, JF, Schippling S, Vermersch P, Kardon R, Green A, Calabresi PA, Polman C. Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2010;9:921–932.
26. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 2009;8:280–291.
27. Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, Freedman MS, Zackon DH, Kardon RH. Quantifying axonal loss after optic neuritis with optical coherence tomography. Ann Neurol. 2006;59:963–969.
28. Petzold A. Optical coherence tomography to assess neurodegeneration in multiple sclerosis. Methods Mol Biol. 2014;1304:131–141.
29. Gabilondo I, Martnez-Lapiscina EH, Fraga-Pumar E, Ortiz-Perez S, Torres-Torres R, Andorra M, Llufriu S, Zubizarreta I, Saiz A, Sanchez-Dalmau B, Villoslada P. Dynamics of retinal injury after acute optic neuritis. Ann Neurol. 2015;77:517–528.
30. Soelberg K, Specovius S, Zimmermann HG, Grauslund J, Mehlsen JJ, Olesen C, Neve ASB, Paul F, Brandt AU, Asgari N. Optical coherence tomography in acute optic neuritis: a population-based study. Acta Neurol Scand. 2018;138:566–573.
31. MacIntosh PW, Kumar SV, Saravanan VR, Shah VM. Acute changes in ganglion cell layer thickness in ischemic optic neuropathy compared to optic neuritis using optical coherence tomography. Int J Ophthalmol. 2020;13:120–123.
32. Kleerekooper I, Petzold A, Trip SA. Anterior visual system imaging to investigate energy failure in multiple sclerosis. Brain. 2020;143:1999–2008.
33. Frohman TC, Beh SC, Saidha S, Schnurman Z, Conger D, Conger A, Ratchford JN, Lopez C, Galetta SL, Calabresi PA, Balcer LJ, Green AJ, Frohman EM. Optic nerve head component responses of the multifocal electroretinogram in MS. Neurology. 2013;81:545–551.
34. Petzold A, Wattjes MP, Costello F, Flores-Rivera J, Fraser CL, Fujihara K, Leavitt J, Marignier R, Paul F, Schippling S, Sindic C, Villoslada P, Weinshenker B, Plant GT. The investigation of acute optic neuritis: a review and proposed protocol. Nat Rev Neurol. 2014;10:447–458.
35. Zatreanu L, Sibony PA, Kupersmith MJ. Optical coherence tomography in neuroretinitis: epipapillary infiltrates and retinal folds. J Neuro Ophthalmol. 2017;37:176–178.
36. Esaki Y, Hirano Y, Yasuda Y, Tomiyasu T, Suzuki N, Yasukawa T, Ogura Y. Multimodal imaging in a case of idiopathic neuroretinitis. Case Rep Ophthalmol. 2018;9:487–492.
37. Michel Z, Redd T, Bhavsar KV. Multimodal imaging of two unconventional cases of bartonella neuroretinitis. Retin Cases Brief Rep. 2019. doi: 10.1097/ICB.0000000000000893. Online ahead of print.
38. Rodríguez-Castelblanco Á, Cordero-Coma M. Leber's idiopathic stellate neuroretinitis: diagnostic and therapeutic conflicts. Archivos Sociedad Espanola Oftalmologia. 2019;94:413–416.
39. Gass JD. Are acute zonal occult outer retinopathy and the white spot syndromes (AZOOR complex) specific autoimmune diseases? Am J Ophthalmol. 2003;135:380–381.
40. Takai Y, Ishiko S, Kagokawa H, Fukui K, Takahashi A, Yoshida A. Morphological study of acute zonal occult outer retinopathy (AZOOR) by multiplanar optical coherence tomography. Acta Ophthalmol. 2009;87:408–418.
41. Makino S, Tampo H. Changes in optical coherence tomography findings in acute zonal occult outer retinopathy. Case Rep Ophthalmol. 2013;4:99–104.
42. Panneman E, Coric D, Tran L, de Vries-Knoppert W, Petzold A. Progression of anterograde trans-synaptic degeneration in the human retina is modulated by axonal convergence and divergence. Neuro Ophthalmol. 2019;43:382–390.
43. Burggraaff MC, de Vries-Knoppert WAEJ, Petzold A. Prefoveal floaters as a differential diagnosis to optic neuritis: “mouches dormantes” Acta Neurologica Belgica. 2017.
44. Foster P, Khawaja A, Balk L, Muthy Z, Petzold A. Oxford Textbook of Neurologic and Neuropsychiatric Epidemiology, Chapter 33 “Sensory Loss Vision” Oxford, United Kingdom: Oxford University Press, 2021.
45. Lawlor M, Danesh-Meyer H, Levin LA, Davagnanam I, De Vita E, Plant GT. Glaucoma and the brain: trans-synaptic degeneration, structural change, and implications for neuroprotection. Surv Ophthalmol. 2018;63:296–306.
46. Khawaja AP, Chua S, Hysi PG, Georgoulas S, Currant H, Fitzgerald TW, Birney E, Ko F, Yang Q, Reisman C, Garway-Heath DF, Hammond CJ, Khaw PT, Foster PJ, Patel PJ, Strouthidis N, Atan D, Aslam T, Barman SA, Barrett JH, Bishop P, Blows P, Bunce C, Carare RO, Chakravarthy U, Chan M, Chua SY, Crabb DP, Cumberland PM, Day A, Desai P, Dhillon B, Dick AD, Egan C, Ennis S, Foster P, Fruttiger M, Gallacher JE, Garway-Heath DF, Gibson J, Gore D, Guggenheim JA, Hammond CJ, Hardcastle A, Harding SP, Hogg RE, Hysi P, Keane PA, Khaw SPT, Khawaja AP, Lascaratos G, Lotery AJ, Macgillivray T, Mackie S, Martin K, McGaughey M, McGuinness B, McKay GJ, McKibbin M, Mitry D, Moore T, Morgan JE, Muthy ZA, O'Sullivan E, Owen CG, Patel P, Paterson E, Peto T, Petzold A, Rahi JS, Rudnikca AR, Self J, Sivaprasad S, Steel D, Stratton I, Strouthidis N, Sudlow C, Thomas D, Trucco E, Tufail A, Vitart V, Vernon SA, Viswanathan AC, Williams C, Williams K, Woodside JV, Yates MM, Yip J, Zheng Y. Comparison of associations with different macular inner retinal thickness parameters in a large cohort: the UK Biobank. Ophthalmology. 2020;127:62–71.
47. Baneke AJ, Aubry J, Viswanathan AC, Plant GT. The role of intracranial pressure in glaucoma and therapeutic implications. Eye. 2020;34:178–191.
48. Garway-Heath DF, Zhu H, Cheng Q, Morgan K, Frost C, Crabb DP, Ho T-A, Agiomyrgiannakis Y. Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: a diagnostic accuracy study. Health Technol Assess. 2018;22:1–106.
49. Xu L, Asaoka R, Kiwaki T, Murata H, Fujino Y, Matsuura M, Hashimoto Y, Asano S, Miki A, Mori K, Ikeda Y, Kanamoto T, Yamagami J, Inoue K, Tanito M, Yamanishi K. Predicting the glaucomatous central 10 degrees visual field from optical coherence tomography using deep learning and tensor regression. Am J Ophthalmol. 2020;218:304–313.
50. Wu Z, Weng DSD, Thenappan A, Ritch R, Hood DC. Evaluation of a region-of-interest approach for detecting progressive glaucomatous macular damage on optical coherence tomography. Translational Vis Sci Techn. 2018;7:14.
51. Biousse V, Newman NJ. Diagnosis and clinical features of common optic neuropathies. Lancet Neurol. 2016;15:1355–1367.
52. Parisi V, Restuccia R, Fattapposta F, Mina C, Bucci MG, Pierelli F. Morphological and functional retinal impairment in Alzheimerś disease patients. Clin Neurophysiol. 2001;112:1860–1867.
53. Hinton DR, Sadun AA, Blanks JC, Miller CA. Optic-nerve degeneration in Alzheimerś disease. N Engl J Med. 1986;315:485–487.
54. La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G, Sambati L, Pan BX, Tozer KR, Barboni P, Provini F, Avanzini P, Carbonelli M, Pelosi A, Chui H, Liguori R, Baruzzi A, Koronyo-Hamaoui M, Sadun AA, Carelli V. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol. 2016;79:90–109.
55. Chan VT, Sun Z, Tang S, Chen LJ, Wong A, Tham CC, Wong TY, Chen C, Ikram MK, Whitson HE, Lad EM, Mok VC, Cheung CY. Spectral-domain OCT measurements in Alzheimer's disease. Ophthalmology. 2019;126:497–510.
56. Ko F, Muthy ZA, Gallacher J, Sudlow C, Rees G, Yang Q, Keane PA, Petzold A, Khaw PT, Reisman C, Strouthidis NG, Foster PJ, Patel PJ, Consortium UBE. Association of retinal nerve fiber layer thinning with current and future cognitive decline: a study using optical coherence tomography. JAMA Neurol. 2018;75:1198–1205.
57. Petzold A, Balcer LJ, Calabresi PA, Costello F, Frohman TC, Frohman EM, Martinez-Lapiscina EH, Green AJ, Kardon R, Outteryck O, Paul F, Schippling S, Vermersch P, Villoslada P, Balk LJ, IMSVISUAL, E-E. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis., the Lancet. Neurology. 2017;16:797–812.
58. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. A novel human opsin in the inner retina. J Neurosci. 2000;20:600–605.
59. Güler AD, Ecker JL, Lall GS, Haq S, Altimus CM, Liao H-W, Barnard AR, Cahill H, Badea TC, Zhao H, Hankins MW, Berson DM, Lucas RJ, Yau K-W, Hattar S. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision. Nature. 2008;453:102–105.
60. Albrecht P, Müller AK, Südmeyer M, Ferrea S, Ringelstein M, Cohn E, Aktas O, Dietlein T, Lappas A, Foerster A, Hartung HP, Schnitzler A, Methner A. Optical coherence tomography in parkinsonian syndromes. PLoS One. 2012;7:e34891.
61. Chrysou A, Jansonius NM, van Laar T. Retinal layers in Parkinson's disease: a meta-analysis of spectral-domain optical coherence tomography studies. Parkinsonism Relat Disord. 2019;64: 40–49.
62. Weil RS, Schrag AE, Warren JD, Crutch SJ, Lees AJ, Morris HR. Visual dysfunction in Parkinson's disease. Brain. 2016;139:2827–2843.
63. Leyland L-A, Bremner FD, Mahmood R, Hewitt S, Durteste M, Cartlidge MRE, Lai MMM, Miller LE, Saygin AP, Keane PA, Schrag AE, Weil RS. Visual tests predict dementia risk in Parkinson disease. Neurol Clin Pract. 2020;10:29–39.
64. Roth NM, Saidha S, Zimmermann H, Brandt AU, Oberwahrenbrock T, Maragakis NJ, Tumani H, Ludolph AC, Meyer T, Calabresi PA, Paul F. Optical coherence tomography does not support optic nerve involvement in amyotrophic lateral sclerosis. Eur J Neurol. 2013;20:1170–1176.
65. Hübers A, Müller HP, Dreyhaupt J, Böhm K, Lauda F, Tumani H, Kassubek J, Ludolph AC, Pinkhardt EH. Retinal involvement in amyotrophic lateral sclerosis: a study with optical coherence tomography and diffusion tensor imaging. J Neural Transm. 2016;123:281–287.
66. Simonett JM, Huang R, Siddique N, Farsiu S, Siddique T, Volpe NJ, Fawzi AA. Macular sub-layer thinning and association with pulmonary function tests in Amyotrophic Lateral Sclerosis. Scientific Rep. 2016;6:29187.
67. Clayton LM, Dévilé M, Punte T, Kallis C, de Haan GJ, Sander JW, Acheson J, Sisodiya SM. Retinal nerve fiber layer thickness in vigabatrin-exposed patients. Ann Neurol. 2011;69:845–854.
68. Peng Y, Zhao Y, Hu W, Hu Y, He Y, Zhou Y. Reduction of retinal nerve fiber layer thickness in vigabatrin-exposed patients: a meta-analysis. Clin Neurol Neurosurg. 2017;157:70–75.
69. Jeelani NUO, Jindahra P, Tamber MS, Poon TL, Kabasele P, James-Galton M, Stevens J, Duncan J, McEvoy AW, Harkness W, Plant GT. Emispherical asymmetry in the Meyerś Loop a prospective study of visual-field deficits in 105 cases undergoing anterior temporal lobe resection for epilepsy. J Neurol Neurosurg Psychiatry. 2010;81:985–991.
70. Jindahra P, Petrie A, Plant GT. Retrograde trans-synaptic retinal ganglion cell loss identified by optical coherence tomography. Brain. 2009;132:628–634.
71. Jindahra P, Petrie A, Plant GT. The time course of retrograde trans-synaptic degeneration following occipital lobe damage in humans. Brain. 2012;135:534–541.
72. Lee J-I, Boerker L, Gemerzki L, Harmel J, Guthoff R, Aktas O, Gliem M, Jander S, Hartung H-P, Albrecht P. Retinal Changes After Posterior Cerebral Artery Infarctions Display Different Patterns of the Nasal und Temporal Sector in a Case Series. Front Neurol. 2020;11:508.
73. Rim TH, Teo AWJ, Yang HHS, Cheung CY, Wong TY. Retinal vascular signs and cerebrovascular diseases. J Neuro Ophthalmol. 2020;40:44–59.
74. Schorr EM, Rossi KC, Stein LK, Park BL, Tuhrim S, Dhamoon MS. Characteristics and outcomes of retinal artery occlusion: nationally representative data. Stroke. 2020;51:800–807.
75. Petzold A, Islam N, Hu HH, Plant GT. Embolic and nonembolic transient monocular visual field loss: a clinicopathologic review. Surv Ophthalmol. 2013;58:42–62.
76. Mehta JS, Plant GT. Optical coherence tomography (OCT) findings in congenital/long-standing homonymous hemianopia. Am J Ophthalmol. 2005;140:727–729.
77. Shinder R, Wolansky L, Turbin RE. Congenital homonymous hemianopia and cortical migration abnormalities in a young adult. J Pediatr Ophthalmol Strabismus. 2009;46:38–41.
78. Hatsukawa Y, Fujio T, Nishikawa M, Taylor D. Congenital optic tract hypoplasia. J AAPOS. 2015;19:383–385.