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Detection of inner, outer retinal disease possible with SD-OCT
One clinician says the technology is invaluable in detecting retinal degenerations, glaucoma and nonglaucomatous optic neuropathies.
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On rare occasions, a single clinical case reveals a novel finding resulting in an insight that enhances our ability to arrive at a diagnosis. Sometimes that novel finding and insight can then be applied to thousands of subsequent cases.
A defining case for me occurred in 2007, where a 27-year-old black male complained about an acute onset of vision disturbance along with unusual photopsias in the left eye only. Visual acuity was 20/15 OD and 20/30 OS.
The referring doctor noted all other findings to be normal, including an MRI of the patient’s anterior visual pathway. I observed a normal fundus as well, and then obtained multifocal electroretinograms (mfERGs), which are ideal to detect functional photoreceptor involvement. The profound loss of the mfERG in his left eye with a normal response from his right eye supported a diagnosis of an occult or hidden retinal disorder. With the symptoms of reduced vision and photopsias, such a case can be diagnosed as acute zonal occult outer retinopathy (AZOOR), a disorder first reported by Donald Gass, MD, in 1993.
Jerome Sherman
Unlike Prof. Gass more than a decade earlier, I had easy access to new spectral domain optical coherence tomography (SD-OCT). I did not resist the temptation to search for an anatomical or structural correlate to the functional mfERG abnormality.
Line in outer retina
This Topcon 3D OCT-1000 cross-section was taken through the fovea of the right (top image) and left (bottom image) eyes of a patient with AZOOR in the left eye only. Note the difference in the line (red arrows).
Images: Sherman J
This Zeiss Cirrus HD-OCT cross-section was taken through the fovea of the right (top) and left (bottom) eyes of the same patient. It appears here magnified and in gray scale. Again, note the difference in the line. The “disorganized” line or band in the left eye only is present in the eye with symptoms.
I was shocked to find that a line or band in the outer retina that I (and apparently everyone else) did not appreciate at the time as significant was dramatically different in the eye with symptoms when contrasted to the eye without symptoms. The line was disorganized and irregular in the affected eye, but completely normal in the unaffected eye. Could this line be a biomarker for photoreceptor integrity?
Schuman and colleagues mentioned this line briefly in the second edition of Optical Coherence Tomography of Ocular Diseases in 2004 as the “junction of the inner segment and outer segment of the photoreceptors.” However, the presence, absence, disorganization, fenestration(s) or other abnormalities of the IS/OS junction were not even alluded to in any of the case presentations in this book.
This same line was labeled as “connecting cilia” by Srinivasan and colleagues in 2008. In perhaps the first SD-OCT text also published in 2008, Decosta and colleagues did not use this line in case analysis or differential diagnosis.
My defining case was published in the August 2008 issue of Primary Care Optometry News (“Spectral domain OCT unmasks occult retinal disorders”) and documented that this line appeared to correlate with mfERG results in this singular case. Hence, structure and function both reflected the retinal disorder that was invisible to ophthalmoscopy.
In patients with an intact line under the fovea, visual acuity was normal (when optic neuropathies and media changes were ruled out), and in patients with an abnormal line under the fovea, visual acuity was decreased. These findings apply to virtually all patients.
Naming the line
I reasoned that this line needed a name that would be easy to remember and one that conveyed its significance, and PIL (for photoreceptor integrity line or layer) seemed appropriate. In achromatopsia, we demonstrated that the PIL was revealed to be missing in the central 1 mm (the location of the highest concentration of cones) (Greenberg et al.), and in retinitis pigmentosa patients with good visual acuity, the line was present centrally and missing outside the central 1 mm or so. Hence, the PIL reflected the integrity of rods as well as cones. At the time, the term IS/OS junction was catching on, and only a few referred to the line as the connecting cilia, but proof of a specific anatomic location was lacking.
Because an article could not include all the myriad cases with an abnormal PIL, the book, Photoreceptor Integrity Line as Revealed by Spectral Domain OCT, was published in December 2008. Larry Yannuzzi, MD, arguably the world’s most respected medical retinal specialist, was the second author.
In 2013, Rick Spaide, MD, who works with Prof. Yannuzzi at Vitreous-Retina-Macula Consultants of New York, published an important article with Catherine Curcio, PhD, about the anatomical site of this line. This convincing paper demonstrated that the anatomical site was not the IS/OS junction at all, but rather the ellipsoids in the inner segment.
An international panel with expertise in retinal imaging was assembled to arrive at a consensus for OCT imaging terminology, and the results were published in February 2014 (Staurenghi et al.).
Prof. Yannuzzi suggested that I begin using the term EZ for ellipsoid zone as recommended by an international group and discard the term PIL. I was reluctant because I favored a term easy to remember, PIL, and one that conveys the importance of the line or layer. As a clinician and educator, connecting cilia, IS/OS junction, IS ellipsoid, EZ or – EZnot – just does not work for me.
In October 2014, another major article revisited this anatomical nomenclature controversy and concluded that the ellipsoids in the inner segment cannot be responsible for the line (Jonnal et al.). The authors’ proof, using adaptive optics coupled with SD-OCT, also appears quite convincing. Some, in jest, now recommend that we use the term EZnot, for the layer that we all now use clinically but cannot determine its anatomical origin.
In reality, clinicians do not need to know the exact microstructural component of the photoreceptors that is the origin of this line. We all agree that the structure appears on OCT as a line or layer, that it reflects both cone and rod photoreceptors and that it conveys the integrity of these cells. Hence, the term PIL works just fine as the biomarker of photoreceptor integrity.
These multifocal ERGs in the same patient depict reduced outer retinal function in the left eye only (right image).
When I first began studying SD-OCT scans in detail a decade ago, the faint line or layer internal to the PIL, the external limiting membrane or ELM, appeared to have no clinical significance whatsoever. However, I was quite mistaken. As demonstrated in a PCON article in September 2013 which I was interviewed (“Irregular external limiting membrane may be biomarker for Stargardt’s”), a thickened, irregular ELM appears to be the biomarker for the early diagnosis of Stargardt’s disease in patients as young as 4 years old.
This has been recently confirmed by a group at Columbia University, where genetic defects on the ABCA4 gene were first discovered (Lee et al.). Because Stargardt’s may soon be a treatable disease, early detection is crucial.
In summary, the outer retinal lines, layers or bands on SD-OCT, which are invisible with ophthalmoscopy and fundus photography, contain at least two biomarkers: the PIL for photoreceptor integrity and the ELM for the diagnosis of early Stargardt’s disease. Will others be discovered? Perhaps yes.
Either way, SD-OCT is fast becoming the standard for ophthalmic care in the U.S. and around the world, and with good reason. Not only is it invaluable in retinal degenerations, but glaucoma and nonglaucomatous optic neuropathies can be easily detected and monitored with SD-OCT. Even screening for the simultaneous detection of inner retinal disease (ganglion cell bodies along with their axons and dendrites) and outer retinal disease (photoreceptors), as well as disorders in the vitreous and choroid, is now possible and changing the way many of us practice in the second decade of the 21st century.