38
QUESTION
WHY SHOULD I SEND MY RETINAL DEGENERATION PATIENTS TO SPECIALISTS IF THERE IS NO CURE FOR THEIR CONDITION?
Alessandro Iannaccone, MD, MS, FARVO
There are a number of reasons why a retinal degeneration patient should be referred to a retinal degeneration specialist even if there is no fully-effective treatment or cure yet for these conditions.
One of the most important reasons is that reaching an accurate clinical and molecular genetic diagnosis is key. Retinal degenerations are a large group of heterogeneous conditions sharing features of progressive retinal degenerative damage that can be grossly differentiated in 2 subgroups: inherited (IRDs) and non-inherited ones. Typical IRDs include retinitis pigmentosa (RP), Leber congenital amaurosis, cone and cone-rod dystrophies, and related conditions, including complex syndromic ones and disorders that, while genetically affecting the entire retina, tend to affect clinically much more so the macular region, such as Stargardt disease (STGD), Best disease, macular pattern dystrophies and related entities.
Non-inherited retinal degenerations mainly include autoimmune retinopathies of the secondary paraneoplastic type (cancer-associated retinopathy [CAR]) or primary non-paraneoplastic type (AIR). CAR is the best-known one, but primary AIR is actually far more common. It is not uncommon that patients referred as suspected cases of simplex (isolated) RP do not actually have RP, but in fact AIR. Other clinical pictures mimicking IRDs develop in the broader family of AIR as well; thus, distinguishing true IRDs from AIR and CAR is very important not only to make the correct diagnosis but also because AIR and CAR are at least partially treatable, and there are very important systemic prognostic implications if a patient has CAR instead of RP.1,2 This differential diagnostic task can be particularly challenging when a patient does not have a history of neoplastic disease.
Figure 38-1. Spectrum of presentation in the BBS. (A) Children with BBS can present with minimal changes, limited to mild vascular attenuation to (B) more overtly degenerative phenotypes with marked vascular attenuation, waxy disc pallor, and a generalized dystrophic appearance of the retina with initial bone spicule-like deposits. Note also the macular retinal pigment epithelium drop-out and the loss of foveal reflex in B, which is a typical presentation for BBS. These patients may appear to have a fair preservation of the ellipsoid zone on optical coherence tomography, but it is usually very faint, as common in ciliopathies, and associated with signal loss on autofluorescence. Systemic characteristics of BBS include (C) early-onset obesity, (D) clynodactyly of the fifth finger with scars from removed extra appendages of either fingers or (E) toes, up to (F) full-fledged polydactyly. Syndactyly or brachydactyly can also be observed in BBS.
Focusing on IRDs, reaching a precise clinical and molecular genetic diagnosis has very important counseling, prognostic and, in some cases, current or immediately forthcoming treatment implications. From a clinical standpoint, the differential diagnosis of IRDs can be challenging and very time consuming. Many times, you need to ask numerous targeted systemic questions, which normal review of systems questionnaires do not cover, to recognize that an RP patient does not have just RP but may have hearing loss because of Usher syndrome or Refsum disease, or that a patient seemingly affected with Leber congenital amaurosis is in fact at risk for kidney failure from having instead the Senior-Loken syndrome or the Bardet-Biedl syndrome (BBS), and so on. Examples of some of these more complex and challenging presentations are illustrated in Figures 38-1 and 38-2. A referral to a retinal degeneration specialist, who has also this broader expertise and is comfortable with all these nuances of IRD-related syndromes and the ophthalmic genetic underpinnings thereof will give you the peace of mind of knowing that these subtler, but very important, aspects will not be missed.
Establishing the inheritance pattern of an IRD is also a top priority from a counseling perspective. A retinal degeneration specialist will take care of this for you, and your patient will not need to go see a medical geneticist for further counseling. The latter is an extra expense for your patient, more time spent away from work engaging in clinical care, and it will not always be effective if the medical geneticist is not familiar with the specific IRD affecting your patient. The optimal setting is when the retinal degeneration specialist works in tandem with a genetic counselor who can assist with the collection of the family trees, coordinate the molecular genetic diagnostic testing and the counseling both at the time of the visit and subsequently, when molecular genetic test results become available. Take the example of a simplex male RP patient. Let’s assume he meets all the diagnostic criteria for RP. A common question you will be asked is, “What are the odds of my children becoming affected with RP?” When there is a family history of RP the counseling is easier, but when history is lacking, the most likely genetic inheritance pattern is autosomal recessive, but studies have shown that about 16% of these patients actually have X-linked RP,3 and a de novo dominant mutation, however rare an event, cannot be excluded either. A dedicated work-up by retinal degeneration specialists and their team will ensure that your patient receives adequate counseling from this perspective, proper molecular genetic diagnostic testing, and subsequently proper explanation of any and all findings.
Figure 38-2. Sensorineural hearing loss retinal degeneration syndromes. (A) Fundus findings in a 56-year-old patient with Usher syndrome Type IIA (USH2A), exhibiting typical RP with marked vascular attenuation and diffuse bone spicule-like deposits, symmetrically distributed between the 2 eyes. In USH2A, a Bull’s eye maculopathy is also often observed, as in the case presented here. The hearing loss of USH2A is congenital, affecting mainly the high frequencies and causing a typical wisp in the patient’s speech. Night blindness is the rule in Usher syndrome. Other conditions present with postverbal hearing loss, which does not compromise speech. One such example is Refsum disease. (B) Here we see the macular region of a 49-year-old woman with blurred vision, photophobia, a geographic atrophy-like clinical phenotype, and a 5-year history of insulin-dependent diabetes. (C) The angiogram reveals a streaky pattern of fine pigmentary changes typical for an advanced stage of a macular pattern dystrophy, as seen in the mitochondrial disease known as the maternally-inherited diabetes mellitus and deafness syndrome. About 2% of diabetics are estimated to have maternally-inherited diabetes mellitus and deafness. (D) Peripapillary and posterior pole retinal pigment epithelium and retinal atrophy and (E, F) bilateral ptosis in the context of progressive chronic external ophthalmoplegia characterize the cone-rod dystrophy of another mitochondrial disease, Kearns-Sayre syndrome (KSS). All manifestations in KSS are highly variable, and hearing loss can range from complete and congenital (like in Usher syndrome Type I) to mild and postverbal. This patient also required a penetrating keratoplasty to manage the rare finding of (F) marked corneal clouding, and (E, arrows in F) a blepharoplasty. Another key feature of KSS is predisposition to sudden heart block, requiring prophylactic pacemaker implantation. (G) An oval area of bull’s eye–like macular discoloration (arrows) and temporal pallor characterize the cone-rod dystrophy of Alström syndrome (ALMS), an obesity-hearing loss syndrome (H, and arrows pointing to a hearing aid device) with features overlapping also with BBS. Hearing loss is usually postverbal. Infantile-onset dilated cardiomyopathy is classic for ALMS. Unlike BBS, abnormal extremities are absent in ALMS.
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