Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis. [1]
Intravitreal injections were proposed over a century ago however the number performed remained relatively low until the mid 2000s. Until 2001, intravitreal injections were mainly used to treat end-ophthalmitis. The number of intravitreal injections stayed fairly constant, around 4,500 injections per year in the US. [2] The number of injections tripled to 15,000 in 2002 when triamcinolone injections were first used to treat diabetic macular oedema. [2] [3] This use continued to drive an increase to 83,000 injections in 2004. [2] In 2005 bevacizumab and ranibizumab intravitreal injections for the treatment of wet-AMD caused a rise in injections to 252,000. [2] In 2008, over 1 million intravitreal injections were performed. This doubled to 2 million just 3 years later in 2011 when another anti-VEGF intravitreal injection aflibercept became available for the treatment of wet AMD. [2] Intravitreal injections hit an all-time high in 2016 reaching over 5.9 million injections in the US. [1]
The most common reason intravitreal injections are used is to administer anti-vascular endothelial growth factor (anti-VEGF) therapies to treat wet age related macular degeneration (AMD) and diabetic retinopathy. Both of these conditions cause damage to the retina leading to vision loss. There are three widely used Anti-VEGF drugs to treat these conditions: ranibizumab (Lucentis®; Genentech), bevacizumab (Avastin®; Genentech), and aflibercept (Eylea®; Regeneron Pharmaceuticals). Bevacizumab has not been FDA approved to treat wet AMD however in the US it is the first line anti-VEGF therapy for over half of ophthalmologists due to its efficacy and drastically lower cost. [4] These three drugs bind to VEGF molecules preventing them from binding to VEGF receptors on the surface of endothelial cells thereby stopping the abnormal angiogenesis that causes wet AMD. All three of these therapies have vastly improved outcomes for sufferers who had limited treatment options prior to their invention but must be administered via intravitreal injection.
Steroids may be administered via intravitreal injection to treat diabetic and vasculo-occlusive macular edema, exudative macular degeneration, pseudophakic cystoid macular edema, and posterior uveitis. Common steroids used to treat these conditions include dexamethasone and triamcinolone acetonide (Triescence, Alcon Laboratories, Inc.). Steroid implants, such as the dexamethasone implant (Ozurdex, Allergan, Inc.), are used for long-term treatment of macular edema. Both of these steroid work by modulating inflammatory cytokines. [5]
Endophthalmitis, or a bacterial infection within the eye causing inflammation of the sclera, is one of the most severe complications due to intravitreal injections. Incidence of endophthalmitis after intravitreal injection per patient has been reported to range from 0.019 to 1.6%. [6] Endophthalmitis can also result in white or yellow discharge inside the eyelid, and a white, cloudy cornea. A layer of white blood cells called hypopyon may develop between the iris and the cornea. Endophthalmitis is considered an ophthalmological emergency and requires immediate treatment in many cases. It is treated with injections of antibiotics and antifungal compounds as appropriate. In severe cases a vitrectomy, or removal of vitreous humor, may be required to surgically remove infectious debris. [7]
Another complication of intravitreal medication administration is inflammation. Intraocular inflammation is one of the main causes of temporary pain and vision loss after an intravitreal injection. Severe inflammation can cause permanent damage to the eye. The risk of inflammation varies based on the specific drug being administered. One clinical trial of ranibizumab for age-related macular degeneration administered intravitreally reported intraocular inflammation rates between 1.4% and 2.9%. Bevacizumab, another medication for the same purpose, resulted in an incidence between 0.09% and 0.4%. [6]
Rhegmatogenous retinal detachment, when the retina breaks allowing vitreous fluid to leak into the subretinal space, resulting from intravitreal injection is rare, occurring at most in 0.67% of people. [6] This fluid can cause sensory tissues to detach from the retina, thus losing their source of nutrition, and slowly killing the cells. [8]
Subconjunctival hemorrhage is the most common type of hemorrhage following intravitreal injection with a reported incidence of nearly 10% of injections. People taking aspirin may be at higher risk for hemorrhage after intravitreal injection. Choroidal hemorrhage and subretinal hemorrhage are less common than subconjunctival hemorrhage, but both have been reported to occur following intravitreal injection. [6]
At least one study has noted that up to 8.6% of intravitreal injections may be administered in the incorrect eye. Factors identified by Mimouni et al. in 2020 which may lead to a person identifying the wrong eye for self-administration include length of time since last injection and previous injections in both eyes. [9]
Treatments administered via intravitreal injection are not cures and therefore repeated injections are necessary for managing conditions. For example, anti-VEGF therapies must be injected monthly or bi-monthly for the rest of their lives in order to treat wet age related macular degeneration. A growing body of evidence has shown repeat intravitreal injections have their own increased risks and complications.
A 3x rise in intraocular pressure after an intravitreal injection is expected and usually only lasts a few minutes. [10] Studies have shown an increased risk of sustained elevated intraocular pressure due to repeated intravitreal injections. [6] Elevated intraocular pressure leads to tissue damage, this is how glaucoma damages the eye. Many theories as to why this is have been postulated however many focus on the effect of the repeated eye trauma. The risk of elevated intraocular pressure is so great that it is recommended clinicians monitor intraocular pressure before and after intravitreal injection. [11] Mount Sinai researchers have developed a method to measure retina damage from long term intravitreal injection using optimal coherence tomography angiography (OCTA). OCTA captures the motion of red blood cells in blood vessels noninvasively allowing researchers to measure blood flow in the macula and optic nerve. From this data they were able to show areas of cumulative damage.
In 2004 with the rise of intravitreal injections, a group of experts established the first general guidelines for administering intravitreal injections. Until an update in 2014 these were consensus guidelines in the US. In 2014 a panel of 16 health professionals with expertise in different aspects of the injection reviewed and revised the original guidelines. Together they released areas of general agreement, areas with no clear consensus, and recommended sequence of steps for intravitreal injection. [11]
Use of a lid speculum is no longer essential. Now a lid speculum, manual lid retraction or a similar maneuver can be used to keep the eyelids out of the way during the procedure.
The strong 2004 consensus that the pupil should be routinely dilated to examine the posterior segment of the eye post injection was dropped. Some of the 2014 panelists did not dilate the pupil for routine injections while others found this examination to be highly important. As no consensus was reached this recommendation was dropped from the 2014 guidance.
In 2004 the committee did not come to a consensus on routine use of pre-, peri- or postinjection antibiotics. Since then evidence has emerged suggesting that peri-injection antibiotics do not meaningfully lower the risk of post-injection infection and periodic multi-day administration of topical ophthalmic antibiotics facilitates the colonization of drug-resistant bacteria. [12] [13] [14] [15] [16] [17] For these reasons in 2014 the committee decided against recommending routine antibiotics.
The new guidelines include hand washing and glove use consistent with the modern-day medical practice of universal precautions. Although the use of gloves was agreed upon by the committee some panelists cited studies showing no impact of glove use on endophthalmitis rate. [12] [15]
In 2004, the topic of droplet contamination was not addressed. Since then new evidence has come to light showing that streptococcal species cause a disproportionate number of post intravitreal injection endophthalmitis cases compared to other forms of ocular surgery. [18] [19] This is likely due to aerosolized droplet contamination from either the practitioners' or patients' mouth. [20] The 2014 guidelines were updated to address these findings recommending both clinicians and patients wear face masks during the procedure.
The new guidelines recommend monitoring intraocular pressure both pre- and post-injection. This recommendation stemmed from new evidence showing that routine intravitreal administration of anti-VEGF therapies may increase intraocular pressure for a sustained time period. [21]
The 2014 guidelines addressed bilateral injections done in the same visit. The committee recommended treating each eye as a separate procedure and use different lots or batches of medication whenever possible. The panel was not able to support the use of sterile drapes in the procedure as retrospective studies showed no increased rate of endophthalmitis in injections done without drapes. [22]
Intravitreal injections have vastly improved outcomes for patients with retinal diseases however the risk and patient burden associated with repeated injections has prompted researchers to pursue less invasive methods of application. There has been significant emphasis on finding methods to administer treatments topically over the last 50 years. [23] This research has garnered more attention thanks to the increase in intravitreal injections and the growing evidence linking repeat injections to adverse events.
Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries.
The National Eye Institute (NEI) is part of the U.S. National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. The mission of NEI is "to eliminate vision loss and improve quality of life through vision research." NEI consists of two major branches for research: an extramural branch that funds studies outside NIH and an intramural branch that funds research on the NIH campus in Bethesda, Maryland. Most of the NEI budget funds extramural research.
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view.
Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.
Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).
Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration, diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.
Endophthalmitis, or endophthalmia, is inflammation of the interior cavity of the eye, usually caused by an infection. It is a possible complication of all intraocular surgeries, particularly cataract surgery, and can result in loss of vision or loss of the eye itself. Infection can be caused by bacteria or fungi, and is classified as exogenous, or endogenous. Other non-infectious causes include toxins, allergic reactions, and retained intraocular foreign bodies. Intravitreal injections are a rare cause, with an incidence rate usually less than 0.05%.
Presumed ocular histoplasmosis syndrome (POHS) is a syndrome affecting the eye, which is characterized by peripheral atrophic chorioretinal scars, atrophy or scarring adjacent to the optic disc and maculopathy.
Pegaptanib sodium injection is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.
Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.
Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.
Branch retinal vein occlusion is a common retinal vascular disease of the elderly. It is caused by the occlusion of one of the branches of central retinal vein.
Punctate inner choroiditis (PIC) is an inflammatory choroiditis which occurs mainly in young women. Symptoms include blurred vision and scotomata. Yellow lesions are mainly present in the posterior pole and are between 100 and 300 micrometres in size. PIC is one of the so-called White Dot Syndromes. PIC has only been recognised as a distinct condition as recently as 1984 when Watzke identified 10 patients who appeared to make up a distinct group within the White Dot Syndromes.
Joan Whitten Miller is a Canadian-American ophthalmologist and scientist who has made notable contributions to the treatment and understanding of eye disorders. She is credited for developing photodynamic therapy (PDT) with verteporfin (Visudyne), the first pharmacologic therapy for retinal disease. She also co-discovered the role of vascular endothelial growth factor (VEGF) in eye disease and demonstrated the therapeutic potential of VEGF inhibitors, forming the scientific basis of anti-VEGF therapy for age-related macular degeneration (AMD), diabetic retinopathy, and related conditions.
Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.
Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.
Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.
Pachychoroid disorders of the macula represent a group of diseases affecting the central part of the retina of the eye, the macula. Due to thickening and congestion of the highly vascularized layer underneath the macula, the choroid, damage to the retinal pigment epithelium and the retinal photoreceptor cells ensues. This leads to impaired vision. The best known representative of the pachychoroid disease spectrum, central serous chorioretinopathy, is the fourth most common cause of irreversible damage to the macula:.
Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.
Polypoidal choroidal vasculopathy (PCV) is an eye disease primarily affecting the choroid. It may cause sudden blurring of vision or a scotoma in the central field of vision. Since Indocyanine green angiography gives better imaging of choroidal structures, it is more preferred in diagnosing PCV. Treatment options of PCV include careful observation, photodynamic therapy, thermal laser, intravitreal injection of anti-VEGF therapy, or combination therapy.