Retinal Vitreous Resource Center: Professional
















Updated Retinal Bulletin

Gene Therapy for Choroideremia
Robert E. MacLaren from Oxford, England has published an article in The Lancet, January 2014, describing the results of six patients who received gene therapy for choroideremia.

The initial results of the retinal gene therapy showed improved rod and cone function. In all patients over six months, there was an increase in retinal sensitivity in the treated eyes that correlated with the vector dose of the gene therapy.

The study assessed the effects of an adeno-associated virus (AAV) vector encoding REP1 (AAV.REP1) in patients with choroideremia. Choroideremia is an x-linked recessive disease that causes blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1).

The findings warrant further assessment of gene therapy in choroideremia, age-related macular degeneration, retinitis pigmentosa, and Stargardt's disease.


Clinical Research Using iPS Cells
A Japanese government panel Wednesday June 25, 2013 approved the world's first clinical research using iPS cells. Massayo Takahoshi, M.D., Ph.d will serve as head of the clinical study in Kobe Japan.

Six patients with wet AMD will have skin cells taken and genetically reprogrammed to become iPS cells. These cells will be modulated to grow into RPE cells which will take 10 months. The sheets of the RPE cells will then be transplanted into the eyes under the retina of patients who have had abnormal blood vessels removed.

These patients will then be monitored over the next four years to determine how well the implants have performed and whether the body has accepted them.

We will all benefit from the information obtained about minimizing tumorigensis from the induced genetic mutations and possible viral contamination regardless of what level of efficacy is attained.


Retinal Subspecialist Re-referral
A patient who you are following that has had a retinal detachment repair or a vitrectomy for any reason is doing well. If the patient then develops any of the following signs or symptoms, it may justify a re-referral to a retinal subspecialist:

  • An intraocular pressure of below 6 mmHg.
  • An injected conjunctiva with associated pain.
  • A hazy cornea.
  • White, round-like deposits on the corneal endothelium.
  • Rubeosis on the iris.
  • Patient complains of seeing flashes of light or gnats in their eyes.
  • Vessel in-growth in the limbal area.
  • Patient complaining of seeing a shade or blurring in their field of vision.
  • Patient having difficulty seeing.
  • Intraocular pressure elevation above 30 mmHg.
  • Band keratopathy in eye with Silicone oil.
  • Patient complains of feeling like they have a lash in their eye.

A phone call to the retinal subspecialist may suffice or he/she may feel examining the patient is in order.


Acknowledged by the Foundation for Fighting Blindness
We were acknowledged by the Foundation for Fighting Blindness for our effort in one of six emerging retinal therapies receiving foundation funding as part of its Translational Research Acceleration Program (TRAP). The emerging treatments included those using stem cells, gene therapies, and pharmaceuticals.

Multilayered Cell Replacement Therapy
Many retinal diseases, including Stargardt disease, dry age-related macular degeneration, and choroideremia, lead to loss of photoreceptors and a supportive layer of cells called retina pigment epithelium (RPE). Dr. David Gamm of the University of Wisconsin is using induced pluripotent stem cells (iPSC) to develop a two-layered cell replacement therapy.

To minimize rejection of this and other treatments, he is also developing lines of iPSC from "super donors," individuals from across the United States whose immune profiles favorably math those of the country's general population. For these efforts, Dr. Gamm is collaborating with scientists from: University of California, Santa Barbara; University of Pennsylvania; Cellular Dynamics International; and Retina Vitreous Resource Center in Louisville, Kentucky.


Findings on OCT
You are following a patient with successful treatment of a subretinal neovascular membrane from any of the following disorders:

Or edema secondary to:

If this patient were to suddenly develop any of the following signs or symptoms or findings on OCT, this may justify a re-referral to the initial treating retinal subspecialist.

Signs and Symptoms

  • Decreased central visual acuity.
  • Complaints of blurred central vision.
  • Rubeosis on the iris.
  • Hazy vision of recent onset.
  • Patient states their vision is cloudy.
  • Hemorrhaging in the fovea on clinical retinal examination.

Oct Findings

  • An OCT finding of retinal thickening at or within 500 units of the center of the macula.
  • An OCT finding of hard exudate at or within 500 units of the center of the macula if associated with adjacent retinal thickening.
  • An OCT finding of a zone or zones of retinal thickening one disc-area in size, at least part of which is with one disc-diameter of the center of the macula.
  • Increased central retinal thickness on OCT.
  • Subretinal fluid over large contiguous drusen in the fovea on OCT.

A phone call to the retinal subspecialist may suffice or he/she may feel examining the patient is in order.


Retinal Subspecialist
A patient who you are following that has had a retinal detachment repair or a vitrectomy for any reason is doing well. If the patient then develops any of the following signs or symptoms, it may justify a re-referral to a retinal subspecialist:

  • An intraocular pressure of below 6 mmHg.
  • An injected conjunctiva with associated pain.
  • A hazy cornea.
  • White, round-like deposits on the corneal endothelium.
  • Rubeosis on the iris.
  • Patient complains of seeing flashes of light or gnats in their eyes.
  • Vessel in-growth in the limbal area.
  • Patient complaining of seeing a shade or blurring in their field of vision.
  • Patient having difficulty seeing.
  • Intraocular pressure elevation above 30 mmHg.
  • Band keratopathy in eye with Silicone oil.
  • Patient complains of feeling like they have a lash in their eye.

A phone call to the retinal subspecialist may suffice or he/she may feel examining the patient is in order.


Retinal Prostheses
Retinal prostheses have had a long history and now include more than 15 companies and research groups in six countries. Those currently in or near human testing include:

  • Boston Retinal Implant Project - Boston, Massachusetts
  • Second Sight - Sylmar, California
  • Retina Implant AG - Reutlingen, Germany
  • Intelligent Medical Implant - Bonn, Germany
  • Epi-Ret - Bonn, Germany
  • Optobionics

The two groups that appear to be further along in development are Second Sight and Retina Implant AG.

Argus II

Second Sight Argus II Prosthesis System
The Second Sight device uses a camera and transmitter mounted to eyeglasses, an implanted receiver, and an array of electrodes secured to interface epiretinally with retinal ganglion cells. A battery pack worn on the patient's belt powers the system.

The camera captures images as the subject's head moves to view objects and track movement. These images are processed by the transmitter and receiver and turned into electrical impulses on the epiretinal array. These electrical impulses are intended to stimulate the retina's remaining cells and generate corresponding perception of patters of light in the brain, which patients interpret as meaningful images.

Retina Implant AG Prothesis
The Retina Implant AG prosthesis doesn't have an external camera. Rather, it uses a light-sensitive microchip that is surgically implanted under the retina, in the macular region where photoreceptor cells are located. The implant moves with the eye, which provides for "more natural processing of the image." Aside from the subretinal micro-photodiodes, the only other equipment is a power module implanted behind the ear.

It is my expectation that the Retina Implant AG will probably prove to be the most helpful artificial vision device for restoring useful vision in patients with retinal dystrophies and possible dry age-related macular degeneration. There are multiple reasons for this point of view:

  1. The device's imaging functionality of the implant is in the eye, hence being coupled with eye movement.
  2. They were able to report letter reading, providing strong support for functional vision via electrical stimulants.
  3. Personal communication with Dr. Robert MacLaren in Cambridge, England, a surgeon who so far implanted six of these devices, stated that, "A great advantage of the subretinal device is that it moves with the eye and is therefore in a more natural position for acquiring a retinal image." He also added, "The use of the bipolar cells also adds an additional level of processing on top of the epiretinal approach developed by Second Sight."
  4. It is presently being studied at Wills Eye Institute in Philadelphia, Pennsylvania with Dr. Jay Federman. Its light sensitivity certainly is a great advantage for the Retina Implant AG. Stimulating the bipolar/horizontal cells from the subretinal space rather than ganglion cells from the retinal surface seems more physiological.

There are an estimated 1.2 million people worldwide with retinitis pigmentosa, including 100,000 in the United States. We can give our patients hope for improved vision in the future. The devices are well tolerated in the eye, and as the quality of the devices gets better, we may be able to show that there is real benefit from them for improved vision to change people's lives.


JETREA® (ocriplasmin) by ThromboGenics
Development of OCT (optic coherence tomography) has help clinicians gain a better understanding of the critical role played by the vitreous in macular and retinal vascular diseases.

With early-stage PVD (posterior vitreous detachment), fibrocellular organization of vitreous remnants left on the retinal surface during vitreoretinal separation is the most likely cause of idiopathic epiretinal membrane.

There has been a longstanding interest in developing pharmacologic methods for nonsurgical induction of PVD, a technique known as pharmacologic vitreolysis. Pharmacologic agents are candidates for vitreolysis if they have the ability to induce vitreous liquefaction, weakening the vitreoretinal adhesion or both. A variety of agents have been studies to date, including:

  • Collagenase
  • Chondroitinase
  • Dispase
  • Hyaluronidase
  • Nattohinase
  • Plasmin
  • Tissue plasminogen activator
  • Vitreosolve (Vitreoretinal Technologies, Inc., Irvin, CA)
  • Arginine-glycerine-aspartate peptide.
  • Ocriplasmin (formally microcplasmin)

Recently, two, Phase-3 clinical trials of ocriplasmin in patients with symptomatic vitreomacular adhesions were completed.

Vitreomacular adhesion (VMA) at the macula causes metamorphopsia or visual distortion. Ocriplasmin by ThromboGenics is the only agent that induces both liquefaction and separation of the vitreous from the retinal interface.

Vitreolysis Candidate

Ocriplasmin Efficacy
VMA = VMT

  • Pharmacologic resolution of VMA at 28 days was 26.5%.
  • Placebo group (p‹0.001) was 10.1%.
  • If patients with epiretinal membranes were excluded, 34.5% versus 14.3%.

Side Effects

There were 7.7% who had unexplained visual loss, which resolved within six months. Other side effects included:

  • Floaters - 13%
  • Eye pain - 10.5%
  • Photopsia - 10%
  • Blurred vision - 6.5%

Less than robust results of the ocriplasmin trials point to the complexity of pharmacologic vitreolysis and suggest that the ideal vitreolytic agent, or combination of agents, has yet to be identified. Other options would include:

  • Intravitreal gas injection (pneumatic vitreolysis)
  • Vitreous surgery

Vitreous surgery currently remains the gold standard for treating significant vitreomacular disorders and likely will continue to be the preferred treatment for some time.

The perfect vitreolytic drug capable of inducing PVDs consistently with a clear retinal surface and no toxicity concerns would be the preferred treatment.


Sustained Increased Intraocular Pressure Related to Intravitreal Antivascular Endothelial Growth Factor Therapy for Neovascular Age-related Macular Degeneration
The following article, Sustained Increased Intraocular Pressure Related to Intravitreal Antivascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration (J. Glaucoma; Volume 21, Number 4, April/May 2012), makes note of increased intraocular pressure following anti-VEGF drug therapy that we have noted in our practice as well. It appears that after seven (7) shots, there is an increased risk of patients developing sustained elevated intraocular presure, which they have never experienced in the past. The second observation is that it appears patients with an open capsule have an increased risk over patients with intact capsules for this sustained increased intraocular pressure. Most patients respond well to medical therapy with eye drops over time as the pressure goes down, but a few may proceed on to require filtering bleb surgery.

Proposed etiologies for the elevated pressure have been looked for. Researchers began looking for microscopic particulate contaminates. It has been thought that the molecular weight of the drugs may play a role in a blockage of the trabecular meshwork as well as some people thinking that the lubricant primarily used in tuberculin syringes was the culprit. This is the reason that many compounding pharmacies no longer send their drugs in tuperculin syringes.

At this point, the definite etiology for the pressure rise is unknow but is under continued investigation. It is important to note that this is a secondary complication with Avastin, Lucentis, and Eylea therapy that is just now coming to the forefront.

If we can answer any of your questions regarding this form of therapy, please feel free to let us know.


For Our Patients Receiving Avastin (Bevacizumab)
We are certain our Avastin (bezacizumab) is not counterfeit due to the following:

  1. We only order our Avastin (bezacizumab) from a local compounding pharmacy, accredited by the Professional Compounding Accreditation Board, who receives their supply directly from Genentech, the manufacturer of Avastin (bezacizumab). Each order is shipped in FDA-approved cartons directly from the manufacturer with the words "Genentech" or "Genentech - A Member ofthe Roche Group" printed on the packaging.

  2. FDA-approved Avastin (bezacizumab) contains a six-digit lot number on the product's packaging and all packaging is printed in English. All lot numbers are logged and confirmed with Genentech as the product is received by the compounding pharmacy.

  3. Counterfeit A vastin (bezacizumab) has letters in the lot numbers and is printed in multiple languages instead of English. Authentic Avastin (bezacizumab) does not have letters in the lot numbers.

  4. The counterfeit product packaging does not come close to looking similar to authentic A vastin (bezacizumab) packaging.

We are certain that our local compounding pharmacy is giving us only FDA-approved Avastin (bezacizumab) direct from the manufacturer.

If you have any further questions, concerns or comments, we will be happy to discuss this matter further with you.


Preliminary CATT Results
The Preliminary CATT (Comparison of AMD Treatment Trials) results are in and they support the use of either Avastin or Lucentis for the treatment of neovascular AMD. The May 2011 edition of the New England Journal of Medicine contained an editorial written by Philip J. Rosenfeld, M.D., Ph.D. which stated, "The CATT data support the continued global use of intravitreal bevacizumab as an effective, low-cost alternative to ranibizumab."


FDA Approves Telescope Implant for Age Related Macular Degeneration
Purpose:
To magnify images in eyes central blind spot that are blocked by disciform scars from wet age related macular degeneration or geographic atrophy caused by dry age related macular degeneration.

Eligibility:

  • Patient must be 75 years old or older.
  • Severe vision impairment in both eyes secondary to the end stage of age related macular degeneration.
  • Can not have had cataract surgery.

Cost:
$15,000.00
Medicare does not cover this.

Additional Aspects:
Patients must receive post-surgical rehabilitation with low-vision specialist. Meeting with the patients requires more time and patience than many physicians are accustomed to spending.

IMT

For more Information, please call Dr Singer at Medical Center Ophthalmology Services in San Antonio, Texas at (210) 697-2020.


Treatment Update For Retinitis Pigmentosa
Vitamin Palmitate A:
The recommendations from the clinical trial are that most adult patients with the common forms of RP take a daily 15,000 IU supplement of vitamin A palmitate under supervision of an ophthalmologist and avoid the use of high dose supplements of vitamin E, such as 400 IU. Consult with your physician regarding dosage for children.

A limited review of sources for vitamin A palmitate indicates that each supplier currently known to us (see below) is a company of good business standing that adheres to generally accepted good laboratory practices for manufacturing their products. The Retina Vitreous Resource Center can make no recommendation of one supplier over another regarding the quality of their product. Comparison and selections are your responsibility. You should call the listed companies for more information. The Retina Vitreous Resource Center has no further information to provide regarding these suppliers. (The prices are subject to change without notice.)

Disclaimer: the product described below have not been tested or evaluated by the Retina Vitreous Resource Center to determine their safety or effectiveness. Listing here of these suppliers and their products should not be misinterpreted as a recommendation or indication of proprietary interest in any of these companies.

Sources of Vitamin A Palmitate 15,000 IU
J.R. Carolson Laboratories Inc.
Attn: Customer Service - 1-800-323-4141
Pricing:
10 gel-caps is $8.90
240 gel-caps is $15.50 (shipping and handling $10.00)

Freeda Vitamins Inc.
1-800-777-3737 or 1-212-685-4980
Pricing:
100 tablets is $7.95

What Should You Do To Begin Vitamin A Treatment?
This is a serious undertaking. First consult with an ophthalmologist or another medical doctor. Do not start taking the vitamin A supplements on your own. Your doctor will want to do initial and subsequent annual evaluations, including tests to measure your blood level of vitamin A and to assess liver function. If these tests show that you have a pre-existing liver disease or abnormally high blood levels of vitamin A, your doctor may need to decrease your vitamin A intake accordingly. If you are not going to an ophthalmologist now, we suggest that you seek one who is willing to advise you regarding your eye care.

Since vitamin A in the palmitate form was used in the clinical trial of RP, the recommendations derived from that study apply specifically to the palmitate form. Although some other forms might be effective, that is not known because it was not studied. However, beta carotene, a natural precursor of the active form of vitamin A, is not a suitable substitute because it is not a predictable source of the vitamin.

Other Sources That May Help Retinitis Pigmentosa
1) Lutein 12mg Per Day
Puritans Low price at www.puritan.com
or 1-800-645-1030.
Pricing:
Lutein 6mg 100 caps (buy 1 get 1 free) total $13.59 Take (2) per day. Item #003481.

2) Omega 3 DHA 200mg Per Day
Puritans Low price at www.puritan.com
or 1-800-645-1030.
Pricing:
Omega 3 DHA 100mg soft-gels 120 soft-gels per bottle (buy 1 get 1 free) total $17.59. Take (2) per day item #001032. - and -
Walgreens.com
or 1-877-250-5823
Pricing:
Omega 3 DHA 100mg, soft-gels #30 Take (2) per day. $13.99

Omega 3 DHA can also be found in Salmon and Tuna (1) or (2) 3 ounce servings per week.

If you go to your local pharmacy to purchase Lutein or Omega 3 DHA, be sure the dosage is correct. As stated for the vitamin A, Retina Vitreous Resource Center can make no recommendation of one supplier over another regarding the quality of their product.


AAO Guidelines for Screening for Chloroquine and Hydroxychloroquine Retinopathy
Dear Colleague:
The most up-to-date guidelines from the AAO for screening for chloroquine and hydroxychloroquine retinopathy have just come out. The recommended new objective tests are:

The goal of screening is to recognize toxicity at an earlier stage than the development of a visible bull's eye maculopathy, which is a late change. Our Heidelberg Spectralis® HRA and OCT is one of the most sophisticated OCT instruments to do this.

We can provide these improved screening tools and newest knowledge about the prevalence of this toxicity question for your patients.

I would be happy to discuss this with you personally, if you have questions.

Sincerely,
Norman D. Radtke, M.D., F.A.C.S.
Vitreoretinal Surgery


FDA Approves Telescope Implant for Age Related Macular Degeneration

Purpose:
To magnify images in eyes central blind spot that are blocked by disciform scars from wet age related macular degeneration or geographic atrophy caused by dry age related macular degeneration.

Eligibility:

  • Patient must be 75 years old or older.
  • Severe vision impairment in both eyes secondary to the end stage of age related macular degeneration.
  • Can not have had cataract surgery.

Cost:
$15,000.00
Medicare does not cover this.

Additional aspects:
Patients must receive post-surgical rehabilitation with low-vision specialist. Meeting with the patients requires more time and patience than many physicians are accustomed to spending.


Acknowledgement of Our Research on Retinal Transplantation
Paul S. Baker, M.D., and Gary C. Brown from the Retina Service, Wills Eye Institute, Jefferson Medical College, in Philadelphia, Pennsylvania, wrote an article "Stem-cell therapy in retinal disease" for Current Opinion in Ophthalmology 2009; 20:175-181. They stated on page 178 of the article:

Although some studies were unable to demonstrate any positive effect on vision, other patients transplanted with fetal retinal sheets showed improved visual acuity over time (up to 6 years) [57**, 58].

The unprecedented double starring of our article in the reference meant "of outstanding interest."


References and Recommended Reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
*of special interest
**of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 226).

Radtke ND, Aramant RB, Petry HM, et al. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 2008; 146:172-182.

This study demonstrates the safety and clinical benefit of retina RPE grafts in human subjects with retinal degeneration. Visual improvement was observed in seven of ten patients (three retinitis pigmentosa and four AMD).

Radtke ND, Aramant RB, Seiler MJ, et al. Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa. Arch Ophthalmol 2004; 122:1159-1165.

We were honored that our work received such recognition from these esteemed professors.


Hyperbaric Oxygen Treatment
Treatment for patients with central retinal artery occlusions or branch retinal artery occlusions with Hyperbaric Oxygen is successful if patient is treated within 48 hours.

This treatment is available at Norton Audubon Hospital. Roberto Penne-Casanova, M.D. has been trained in the U.S. Air Force and appointments can be made by calling 502-636-8380. At this time the facility is only staffed Mondays, 8am-12pm, Tuesdays, 8am-12pm and Thursdays, 7:30am-4pm.


CATT Trial
After a one year delay the CATT Trial will begin recruiting patients in January 2008. It will have two primary purposes:

  • Compare the safety and efficiency of Lucentis and Avastin
  • Determine whether or not as-needed dosing can produce a visual result that is as robust as what has previously been demonstrated with fixed dosing

The study chairman is David F. Martin, M. D., at Emory University.


High Dose Avastin More Effective than Low Dose
Avastin dose of 2.5 mg is associated with greater visual acuity and fewer follow-up injections than the 1.25 mg dose of Avastin.

Reported at the Retina Society meeting by P. Yoganathan, M. D. from the University of Toronto.


Promising Results with Lutein and Zeaxanthin
Dietary intake of Lutein/Zeaxanthin is independently associated with decreased likelihood of neovascular AMD, geographic atrophy and large or extensive intermediate drusen in AREDS report No. 22.

If these cross-sectional results can be confirmed in prospective samples and experimental studies Lutein and Zeaxanthin may be considered an useful agent in food or supplement-based interventions designed to reduce the risk of AMD.


TruSopt
TruSopt (dorzolamide) reduces cystoid macular edema in patients with Retinitis Pigmentosa. Gerald Fishman, M.D., University of Illinois at Chicago, demonstrated that all patients in his study showed a significant reduction in swelling in at least one eye after using TruSopt three times a day for one to two months. Results of the study were published in the January 10, 2007, issue of the British Journal of Ophthalmology.


POT-4
POT-4 is a derivative of Compstatin, a peptide that inhibits complement activation. Complement activation plays a significant role in the cause of AMD. POT-4 is initially being developed for treatment of AMD. Potentia Pharmaceuticals, Inc. is beginning Phase I clinical trials in Tucson and Miami.


Nutrition for the Well-Being of the Eye
Omega 3 fatty acids have been shown to increase the general sense of well-being and promote high health. They are present in fish and are highest in mackerel, white fish, tuna, and salmon.

Zinc has a specific role in the normal functioning of photoreceptors in the eye. Zinc is found in high protein foods such as beef, pork, and whole grain cereals.

Recently, it has been suggested that the carotenoids, Lutein (pronounced loo-teen) and Zeaxanthin (pronounced zee-uh-zan-thin) play an important role in eye health.

In the Eye Disease Case Control Study, medical researchers found that individuals experienced a significantly lower risk for developing age related macular degeneration when they had high amounts of Lutein and Zeaxanthin in their blood.

Sources of Lutein include yellow peppers, mango, blueberries, and green leafy vegetables such as kale, spinach, chard, and broccoli. Sources of Zeaxanthin include orange sweet peppers, broccoli, corn, lettuce, spinach, tangerines, oranges, and eggs.


Testing a New Long Acting Drug for Wet Age Related Macular Degeneration
Regeneron Pharmaceuticals, Inc., will be testing the investigational drug, VEGF Trap, in a Phase III clinical trial. VEGF Trap is a human Fc-fusion protein that binds and blocks VEGF in the retina when injected intravitreally. VEGF Trap may prove to be a long acting therapy since it is able to more potently bind VEGF than currently available anti-VEGF therapies. This trial will compare VEGF Trap to Lucentis.



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