All posts in Updated Retinal Bulletin

Ocriplasmin Injection

Two recent articles published in the Archives of Ophthalmology expose the risks of Ocriplasmin injection into the vitreous:

1. Acute Panretinal Structural and Functional Abnormalities After Intravitreous Ocriplasmin Injection — JAMA Ophthalmol. 2014;132(4):484-486.

Conclusion: Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.

2. Vision Loss After Intravitreal Ocriplasmin: Correlation of Spectral-Domain Optical Coherence Tomography and Electroretinography — JAMA Ophthalmol. 2014;132(4):487-490.

Conclusion: On the basis of these findings, it is possible that ocriplasmin may have a diffuse enzymatic effect on photoreceptors or the retinal pigment epithelium that is not limited to areas of vitreomacular adhesion. The rod photoreceptors may be more susceptible than cone photoreceptors to the effects of ocriplasmin. Further work is needed to understand mechanisms of visual impairment after ocriplasmin.

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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.

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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.

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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.

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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.

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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.

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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.

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Retinal Prostheses

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.

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.

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JETREA® (ocriplasmin) by ThromboGenics

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.

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.

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Sustained Increased Intraocular Pressure

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.

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