StemCell Therapy

OverviewWhat is retinal detachment?

Retinal detachment, or a detached retina, is a serious eye condition that affects your vision and can lead to blindness if not treated. It happens to a layer of tissue called the retina that lines the back of the eye. It involves the retina pulling away from tissues supporting it. Symptoms include flashes of light, floaters or seeing a shadow in your vision. Floaters are dark spots and squiggles in your vision.

You may experience warning signs like these before the retina detaches, as in the case of retinal tears. Retinal detachment often happens spontaneously, or suddenly. The risk factors include age, nearsightedness, history of eye surgeries or trauma, and family history of retinal detachments.

Call your eye care provider or go to the emergency room right away if you think you have a detached retina.

The retina senses light and sends signals to the brain so we can see. When the retina detaches, it cant do its job. Your vision might become blurry. And you might lose vision permanently if the detachment isnt repaired. Getting prompt treatment can save your eyesight.

Your risk for retinal detachment increases as you age. Youre also at higher risk if you have or had:

Having certain eye conditions also raises your risk for retinal detachment:

If youre at high risk for retinal detachment, talk to your healthcare provider. Your provider can help you set an eye exam and suggest other steps to protect your eye health.

Retinal detachment is rare for people who have none of the risk factors listed here.

The three causes of retinal detachment are:

Some people dont notice any symptoms of retinal detachment, while others do. It depends on severity if a larger part of the retina detaches, youre more likely to experience symptoms.

Symptoms of retinal detachment can happen suddenly and include:

Retinal detachment is usually painless. But its a serious problem that can threaten your vision. Contact a healthcare provider if you notice any symptoms.

You need an eye exam to diagnose retinal detachment. Your eye care provider will use a dilated eye exam to check your retina. Theyll put eye drops in your eyes. The drops dilate, or widen, the pupil. After a few minutes, your provider can get a close look at the retina.

Your provider may recommend other tests after the dilated eye exam. These tests are noninvasive and wont hurt. They help your provider see your retina clearly and in more detail:

Your eye care provider will discuss treatment options with you. You may need a combination of treatments for the best results.

Treatments include:

Laser (thermal) therapy or cryopexy (freezing). Sometimes, your provider will diagnose a retinal tear before the retina starts pulling away. Your provider uses a medical laser or a freezing tool to seal the tear. These devices create a scar that holds the retina in place.

Pneumatic retinopexy. Your provider may recommend this approach if the detachment isnt as extensive. During pneumatic retinopexy:

After surgery, your provider will recommend that you keep your head still for a few days to promote healing. You also may be told not to lie on your back.

Scleral buckle. During this procedure:

Vitrectomy. During a vitrectomy, your provider:

If your provider uses an oil bubble, youll have it removed a few months later. Gas and air bubbles get reabsorbed.

If you have a gas bubble, you may have to avoid activities at certain altitudes. The altitude change can increase the size of the gas bubble and the pressure in your eye. You'll have to avoid flying and traveling to high altitudes. Your provider will tell you when you can start these activities again.

You cant prevent retinal detachment, but you can take steps to lower your risk:

People who have an average risk of eye disease should get eye exams once a year. If youre at higher risk for eye disease, you may need checkups more frequently. Talk to your provider to figure out your best exam schedule.

Your outlook depends on factors like how your vision was before the retinal detachment, how extensive your detachment was and if there are any other complicating factors. Your provider will talk to you about what type of vision improvement you can expect.

In general, surgery for retinal detachment is very successful the repair works about nine out of 10 times. Sometimes, people need more than one procedure to return the retina to its place.

Its possible to get a detached retina more than once. You may need a second surgery if this happens. Talk to your provider about preventive steps you can take to protect your vision. If you notice symptoms returning, call your provider right away.

After retinal detachment surgery, you may have some discomfort. It can last for a few weeks. Your provider will discuss pain medicine and other forms of relief. Youll also need to take it easy for a few weeks. Talk with your provider about when you can exercise, drive and get back to your regular activities.

Other things you can expect after surgery:

If you have retinal detachment (or face a higher risk), ask your provider:

A note from Cleveland Clinic

Retinal detachment is a painless but serious condition. If you notice detached retina symptoms, such as sudden eye floaters, flashes of light or darkening of your vision, get care right away. Call your eye care provider or go to the emergency room. Preventive care is always the best, so protect your eyes and vision health by having regular eye exams.

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Retinal Detachment: Symptoms, Causes & Prevention - Cleveland Clinic

Toxic effects of breathing oxygen at high concentrations

Medical condition

Oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen (O2) at increased partial pressures. Severe cases can result in cell damage and death, with effects most often seen in the central nervous system, lungs, and eyes. Historically, the central nervous system condition was called the Paul Bert effect, and the pulmonary condition the Lorrain Smith effect, after the researchers who pioneered the discoveries and descriptions in the late 19th century. Oxygen toxicity is a concern for underwater divers, those on high concentrations of supplemental oxygen (particularly premature babies), and those undergoing hyperbaric oxygen therapy.

The result of breathing increased partial pressures of oxygen is hyperoxia, an excess of oxygen in body tissues. The body is affected in different ways depending on the type of exposure. Central nervous system toxicity is caused by short exposure to high partial pressures of oxygen at greater than atmospheric pressure. Pulmonary and ocular toxicity result from longer exposure to increased oxygen levels at normal pressure. Symptoms may include disorientation, breathing problems, and vision changes such as myopia. Prolonged exposure to above-normal oxygen partial pressures, or shorter exposures to very high partial pressures, can cause oxidative damage to cell membranes, collapse of the alveoli in the lungs, retinal detachment, and seizures. Oxygen toxicity is managed by reducing the exposure to increased oxygen levels. Studies show that, in the long term, a robust recovery from most types of oxygen toxicity is possible.

Protocols for avoidance of the effects of hyperoxia exist in fields where oxygen is breathed at higher-than-normal partial pressures, including underwater diving using compressed breathing gases, hyperbaric medicine, neonatal care and human spaceflight. These protocols have resulted in the increasing rarity of seizures due to oxygen toxicity, with pulmonary and ocular damage being mainly confined to the problems of managing premature infants.

In recent years, oxygen has become available for recreational use in oxygen bars. The US Food and Drug Administration has warned those who have conditions such as heart or lung disease not to use oxygen bars. Scuba divers use breathing gases containing up to 100% oxygen, and should have specific training in using such gases.

The effects of oxygen toxicity may be classified by the organs affected, producing three principal forms:[3][4]

Central nervous system oxygen toxicity can cause seizures, brief periods of rigidity followed by convulsions and unconsciousness, and is of concern to divers who encounter greater than atmospheric pressures. Pulmonary oxygen toxicity results in damage to the lungs, causing pain and difficulty in breathing. Oxidative damage to the eye may lead to myopia or partial detachment of the retina. Pulmonary and ocular damage are most likely to occur when supplemental oxygen is administered as part of a treatment, particularly to newborn infants, but are also a concern during hyperbaric oxygen therapy.

Oxidative damage may occur in any cell in the body but the effects on the three most susceptible organs will be the primary concern. It may also be implicated in damage to red blood cells (haemolysis),[5][6] the liver,[7] heart,[8] endocrine glands (adrenal glands, gonads, and thyroid),[9][10][11] or kidneys,[12] and general damage to cells.[13]

In unusual circumstances, effects on other tissues may be observed: it is suspected that during spaceflight, high oxygen concentrations may contribute to bone damage.[14] Hyperoxia can also indirectly cause carbon dioxide narcosis in patients with lung ailments such as chronic obstructive pulmonary disease or with central respiratory depression.[14] Hyperventilation of atmospheric air at atmospheric pressures does not cause oxygen toxicity, because sea-level air has a partial pressure of oxygen of 0.21bar (21kPa) whereas toxicity does not occur below 0.3bar (30kPa).

Central nervous system oxygen toxicity manifests as symptoms such as visual changes (especially tunnel vision), ringing in the ears (tinnitus), nausea, twitching (especially of the face), behavioural changes (irritability, anxiety, confusion), and dizziness. This may be followed by a tonicclonic seizure consisting of two phases: intense muscle contraction occurs for several seconds (tonic phase); followed by rapid spasms of alternate muscle relaxation and contraction producing convulsive jerking (clonic phase). The seizure ends with a period of unconsciousness (the postictal state). The onset of seizure depends upon the partial pressure of oxygen in the breathing gas and exposure duration. However, exposure time before onset is unpredictable, as tests have shown a wide variation, both amongst individuals, and in the same individual from day to day.[19] In addition, many external factors, such as underwater immersion, exposure to cold, and exercise will decrease the time to onset of central nervous system symptoms. Decrease of tolerance is closely linked to retention of carbon dioxide.[21][22] Other factors, such as darkness and caffeine, increase tolerance in test animals, but these effects have not been proven in humans.[23][24]

Pulmonary toxicity symptoms result from an inflammation that starts in the airways leading to the lungs and then spreads into the lungs (tracheobronchial tree). The symptoms appear in the upper chest region (substernal and carinal regions).[26][27] This begins as a mild tickle on inhalation and progresses to frequent coughing. If breathing increased partial pressures of oxygen continues, patients experience a mild burning on inhalation along with uncontrollable coughing and occasional shortness of breath (dyspnea). Physical findings related to pulmonary toxicity have included bubbling sounds heard through a stethoscope (bubbling rales), fever, and increased blood flow to the lining of the nose (hyperaemia of the nasal mucosa).[27] X-rays of the lungs show little change in the short term, but extended exposure leads to increasing diffuse shadowing throughout both lungs. Pulmonary function measurements are reduced, as noted by a reduction in the amount of air that the lungs can hold (vital capacity) and changes in expiratory function and lung elasticity.[27] Tests in animals have indicated a variation in tolerance similar to that found in central nervous system toxicity, as well as significant variations between species. When the exposure to oxygen above 0.5bar (50kPa) is intermittent, it permits the lungs to recover and delays the onset of toxicity.[29]

In premature babies, signs of damage to the eye (retinopathy of prematurity, or ROP) are observed via an ophthalmoscope as a demarcation between the vascularised and non-vascularised regions of an infant's retina. The degree of this demarcation is used to designate four stages: (I) the demarcation is a line; (II) the demarcation becomes a ridge; (III) growth of new blood vessels occurs around the ridge; (IV) the retina begins to detach from the inner wall of the eye (choroid).[30]

Oxygen toxicity is caused by exposure to oxygen at partial pressures greater than those to which the body is normally exposed. This occurs in three principal settings: underwater diving, hyperbaric oxygen therapy, and the provision of supplemental oxygen, particularly to premature infants. In each case, the risk factors are markedly different.

Exposures, from minutes to a few hours, to partial pressures of oxygen above 1.6 bars (160kPa)about eight times normal atmospheric partial pressureare usually associated with central nervous system oxygen toxicity and are most likely to occur among patients undergoing hyperbaric oxygen therapy and divers. Since sea level atmospheric pressure is about 1bar (100kPa), central nervous system toxicity can only occur under hyperbaric conditions, where ambient pressure is above normal.[31][32] Divers breathing air at depths beyond 60m (200ft) face an increasing risk of an oxygen toxicity "hit" (seizure). Divers breathing a gas mixture enriched with oxygen, such as nitrox, can similarly have a seizure at shallower depths, should they descend below the maximum operating depth allowed for the mixture.

The lungs and the remainder of the respiratory tract are exposed to the highest concentration of oxygen in the human body and are therefore the first organs to show toxicity. Pulmonary toxicity occurs only with exposure to partial pressures of oxygen greater than 0.5bar (50kPa), corresponding to an oxygen fraction of 50% at normal atmospheric pressure. The earliest signs of pulmonary toxicity begin with evidence of tracheobronchitis, or inflammation of the upper airways, after an asymptomatic period between 4 and 22 hours at greater than 95% oxygen,[34] with some studies suggesting symptoms usually begin after approximately 14 hours at this level of oxygen.[35]

At partial pressures of oxygen of 2 to 3bar (200 to 300kPa)100% oxygen at 2 to 3 times atmospheric pressurethese symptoms may begin as early as 3 hours after exposure to oxygen.[34] Experiments on rats breathing oxygen at pressures between 1 and 3 bars (100 and 300kPa) suggest that pulmonary manifestations of oxygen toxicity may not be the same for normobaric conditions as they are for hyperbaric conditions.[36] Evidence of decline in lung function as measured by pulmonary function testing can occur as quickly as 24 hours of continuous exposure to 100% oxygen,[35] with evidence of diffuse alveolar damage and the onset of acute respiratory distress syndrome usually occurring after 48 hours on 100% oxygen.[34] Breathing 100% oxygen also eventually leads to collapse of the alveoli (atelectasis), whileat the same partial pressure of oxygenthe presence of significant partial pressures of inert gases, typically nitrogen, will prevent this effect.[37]

Preterm newborns are known to be at higher risk for bronchopulmonary dysplasia with extended exposure to high concentrations of oxygen.[38] Other groups at higher risk for oxygen toxicity are patients on mechanical ventilation with exposure to levels of oxygen greater than 50%, and patients exposed to chemicals that increase risk for oxygen toxicity such the chemotherapeutic agent bleomycin.[35] Therefore, current guidelines for patients on mechanical ventilation in intensive care recommends keeping oxygen concentration less than 60%.[34] Likewise, divers who undergo treatment of decompression sickness are at increased risk of oxygen toxicity as treatment entails exposure to long periods of oxygen breathing under hyperbaric conditions, in addition to any oxygen exposure during the dive.[31]

Prolonged exposure to high inspired fractions of oxygen causes damage to the retina.[39][40][41] Damage to the developing eye of infants exposed to high oxygen fraction at normal pressure has a different mechanism and effect from the eye damage experienced by adult divers under hyperbaric conditions.[42][43] Hyperoxia may be a contributing factor for the disorder called retrolental fibroplasia or retinopathy of prematurity (ROP) in infants.[42][44] In preterm infants, the retina is often not fully vascularised. Retinopathy of prematurity occurs when the development of the retinal vasculature is arrested and then proceeds abnormally. Associated with the growth of these new vessels is fibrous tissue (scar tissue) that may contract to cause retinal detachment. Supplemental oxygen exposure, while a risk factor, is not the main risk factor for development of this disease. Restricting supplemental oxygen use does not necessarily reduce the rate of retinopathy of prematurity, and may raise the risk of hypoxia-related systemic complications.[42]

Hyperoxic myopia has occurred in closed circuit oxygen rebreather divers with prolonged exposures.[43][45][46] It also occurs frequently in those undergoing repeated hyperbaric oxygen therapy.[40][47] This is due to an increase in the refractive power of the lens, since axial length and keratometry readings do not reveal a corneal or length basis for a myopic shift.[47][48] It is usually reversible with time.[40][47]

A possible side effect of hyperbaric oxygen therapy is the initial or further development of cataracts, which are a increase in opacity of the lens of the eye which reduces visual acuity, and can eventually result in blindness. This is a rare event, associated with lifetime exposure to raised oxygen concentration, and may be under-reported as it develops very slowly. The cause is not fully understood, but evidence suggests that raised oxygen levels may cause accelerated deterioration of the vitreous humour due to degradation of lens crystallins by cross-linking, forming aggregates capable of scattering light. This may be an end-state development of the more commonly observed myopic shift associated with hyperbaric treatment.[49]

The biochemical basis for the toxicity of oxygen is the partial reduction of oxygen by one or two electrons to form reactive oxygen species, which are natural by-products of the normal metabolism of oxygen and have important roles in cell signalling.[51] One species produced by the body, the superoxide anion (O2),[52] is possibly involved in iron acquisition.[53] Higher than normal concentrations of oxygen lead to increased levels of reactive oxygen species.[54] Oxygen is necessary for cell metabolism, and the blood supplies it to all parts of the body. When oxygen is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most vascularised tissues being most vulnerable. During times of environmental stress, levels of reactive oxygen species can increase dramatically, which can damage cell structures and produce oxidative stress.[19][55]

While all the reaction mechanisms of these species within the body are not yet fully understood,[56] one of the most reactive products of oxidative stress is the hydroxyl radical (OH), which can initiate a damaging chain reaction of lipid peroxidation in the unsaturated lipids within cell membranes.[57] High concentrations of oxygen also increase the formation of other free radicals, such as nitric oxide, peroxynitrite, and trioxidane, which harm DNA and other biomolecules.[19][58] Although the body has many antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the capacity of the systems that prevent or repair it.[59][60][61] Cell damage and cell death then result.[62]

Diagnosis of central nervous system oxygen toxicity in divers prior to seizure is difficult as the symptoms of visual disturbance, ear problems, dizziness, confusion and nausea can be due to many factors common to the underwater environment such as narcosis, congestion and coldness. However, these symptoms may be helpful in diagnosing the first stages of oxygen toxicity in patients undergoing hyperbaric oxygen therapy. In either case, unless there is a prior history of epilepsy or tests indicate hypoglycaemia, a seizure occurring in the setting of breathing oxygen at partial pressures greater than 1.4bar (140kPa) suggests a diagnosis of oxygen toxicity.[63]

Diagnosis of bronchopulmonary dysplasia in newborn infants with breathing difficulties is difficult in the first few weeks. However, if the infant's breathing does not improve during this time, blood tests and x-rays may be used to confirm bronchopulmonary dysplasia. In addition, an echocardiogram can help to eliminate other possible causes such as congenital heart defects or pulmonary arterial hypertension.[64]

The diagnosis of retinopathy of prematurity in infants is typically suggested by the clinical setting. Prematurity, low birth weight, and a history of oxygen exposure are the principal indicators, while no hereditary factors have been shown to yield a pattern.

The prevention of oxygen toxicity depends entirely on the setting. Both underwater and in space, proper precautions can eliminate the most pernicious effects. Premature infants commonly require supplemental oxygen to treat complications of preterm birth. In this case prevention of bronchopulmonary dysplasia and retinopathy of prematurity must be carried out without compromising a supply of oxygen adequate to preserve the infant's life.

Oxygen toxicity is a catastrophic hazard in scuba diving, because a seizure results in high risk of death by drowning.[66] The seizure may occur suddenly and with no warning symptoms. The effects are sudden convulsions and unconsciousness, during which victims can lose their regulator and drown.[67] One of the advantages of a full-face diving mask is prevention of regulator loss in the event of a seizure. Mouthpiece retaining straps are a relatively inexpensive alternative with a similar but less effective function.[66] As there is an increased risk of central nervous system oxygen toxicity on deep dives, long dives and dives where oxygen-rich breathing gases are used, divers are taught to calculate a maximum operating depth for oxygen-rich breathing gases, and cylinders containing such mixtures should be clearly marked with that depth.[22]

The risk of seizure appears to be a function of dose a cumulative combination of partial pressure and duration. The threshold for oxygen partial pressure below which seizures never occur has not been established, and may depend on many variables, some of them personal. the risk to a specific person can vary considerably depending on individual sensitivity, level of exercise, and carbon dioxide retention, which is influenced by work of breathing.[66]

In some diver training courses for these types of diving, divers are taught to plan and monitor what is called the 'oxygen clock' of their dives. This is a notional alarm clock, which ticks more quickly at increased oxygen pressure and is set to activate at the maximum single exposure limit recommended in the National Oceanic and Atmospheric Administration Diving Manual.[22] For the following partial pressures of oxygen the limits are: 45 minutes at 1.6bar (160kPa), 120 minutes at 1.5bar (150kPa), 150 minutes at 1.4bar (140kPa), 180 minutes at 1.3bar (130kPa) and 210 minutes at 1.2bar (120kPa), but it is impossible to predict with any reliability whether or when toxicity symptoms will occur.[70][71] Many nitrox-capable dive computers calculate an oxygen loading and can track it across multiple dives. The aim is to avoid activating the alarm by reducing the partial pressure of oxygen in the breathing gas or by reducing the time spent breathing gas of greater oxygen partial pressure. As the partial pressure of oxygen increases with the fraction of oxygen in the breathing gas and the depth of the dive, the diver obtains more time on the oxygen clock by diving at a shallower depth, by breathing a less oxygen-rich gas, or by shortening the duration of exposure to oxygen-rich gases.[73] This function is provided by some technical diving decompression computers and rebreather control and monitoring hardware.[74][75]

Diving below 56m (184ft) on air would expose a diver to increasing danger of oxygen toxicity as the partial pressure of oxygen exceeds 1.4bar (140kPa), so a gas mixture must be used which contains less than 21% oxygen (a hypoxic mixture). Increasing the proportion of nitrogen is not viable, since it would produce a strongly narcotic mixture. However, helium is not narcotic, and a usable mixture may be blended either by completely replacing nitrogen with helium (the resulting mix is called heliox), or by replacing part of the nitrogen with helium, producing a trimix.

Pulmonary oxygen toxicity is an entirely avoidable event while diving. The limited duration and naturally intermittent nature of most diving makes this a relatively rare (and even then, reversible) complication for divers. Established guidelines enable divers to calculate when they are at risk of pulmonary toxicity.[78][79][80] In saturation diving it can be avoided by limiting the oxygen content of gas in living areas to below 0.4 bar.

The presence of a fever or a history of seizure is a relative contraindication to hyperbaric oxygen treatment.[81] The schedules used for treatment of decompression illness allow for periods of breathing air rather than 100% oxygen (oxygen breaks) to reduce the chance of seizure or lung damage. The U.S. Navy uses treatment tables based on periods alternating between 100% oxygen and air. For example, USN table 6 requires 75minutes (three periods of 20minutes oxygen/5minutes air) at an ambient pressure of 2.8 standard atmospheres (280kPa), equivalent to a depth of 18 metres (60ft). This is followed by a slow reduction in pressure to 1.9atm (190kPa) over 30minutes on oxygen. The patient then remains at that pressure for a further 150minutes, consisting of two periods of 15minutes air/60minutes oxygen, before the pressure is reduced to atmospheric over 30minutes on oxygen.

Vitamin E and selenium were proposed and later rejected as a potential method of protection against pulmonary oxygen toxicity.[83][84][85] There is however some experimental evidence in rats that vitamin E and selenium aid in preventing in vivo lipid peroxidation and free radical damage, and therefore prevent retinal changes following repetitive hyperbaric oxygen exposures.[86]

Bronchopulmonary dysplasia is reversible in the early stages by use of break periods on lower pressures of oxygen, but it may eventually result in irreversible lung injury if allowed to progress to severe damage. One or two days of exposure without oxygen breaks are needed to cause such damage.[14]

Retinopathy of prematurity is largely preventable by screening. Current guidelines require that all babies of less than 32weeks gestational age or having a birth weight less than 1.5kg (3.3lb) should be screened for retinopathy of prematurity at least every two weeks.[87] The National Cooperative Study in 1954 showed a causal link between supplemental oxygen and retinopathy of prematurity, but subsequent curtailment of supplemental oxygen caused an increase in infant mortality. To balance the risks of hypoxia and retinopathy of prematurity, modern protocols now require monitoring of blood oxygen levels in premature infants receiving oxygen.[88]

In low-pressure environments oxygen toxicity may be avoided since the toxicity is caused by high partial pressure of oxygen, not merely by high oxygen fraction. This is illustrated by modern pure oxygen use in spacesuits, which must operate at low pressure (also historically, very high percentage oxygen and lower than normal atmospheric pressure was used in early spacecraft, for example, the Gemini and Apollo spacecraft).[89] In such applications as extra-vehicular activity, high-fraction oxygen is non-toxic, even at breathing mixture fractions approaching 100%, because the oxygen partial pressure is not allowed to chronically exceed 0.3bar (4.4psi).[89]

During hyperbaric oxygen therapy, the patient will usually breathe 100% oxygen from a mask while inside a hyperbaric chamber pressurised with air to about 2.8bar (280kPa). Seizures during the therapy are managed by removing the mask from the patient, thereby dropping the partial pressure of oxygen inspired below 0.6bar (60kPa).

A seizure underwater requires that the diver be brought to the surface as soon as practicable. Although for many years the recommendation has been not to raise the diver during the seizure itself, owing to the danger of arterial gas embolism (AGE), there is some evidence that the glottis does not fully obstruct the airway.[91] This has led to the current recommendation by the Diving Committee of the Undersea and Hyperbaric Medical Society that a diver should be raised during the seizure's clonic (convulsive) phase if the regulator is not in the diver's mouthas the danger of drowning is then greater than that of AGEbut the ascent should be delayed until the end of the clonic phase otherwise.[67] Rescuers ensure that their own safety is not compromised during the convulsive phase. They then ensure that where the victim's air supply is established it is maintained, and carry out a controlled buoyant lift. Lifting an unconscious body is taught by most recreational diver training agencies as an advanced skill, and for professional divers it is a basic skill, as it is one of the primary functions of the standby diver. Upon reaching the surface, emergency services are always contacted as there is a possibility of further complications requiring medical attention.[92] The U.S. Navy has procedures for completing the decompression stops where a recompression chamber is not immediately available.

The occurrence of symptoms of bronchopulmonary dysplasia or acute respiratory distress syndrome is treated by lowering the fraction of oxygen administered, along with a reduction in the periods of exposure and an increase in the break periods where normal air is supplied. Where supplemental oxygen is required for treatment of another disease (particularly in infants), a ventilator may be needed to ensure that the lung tissue remains inflated. Reductions in pressure and exposure will be made progressively, and medications such as bronchodilators and pulmonary surfactants may be used.[94]

Divers manage the risk of pulmonary damage by limiting exposure to levels shown to be generally acceptable by experimental evidence, using a system of accumulated oxygen toxicity units which are based on exposure time at specified partial pressures. In the event of emergency treatment for decompression illness, it may be necessary to exceed normal exposure limits to manage more critical symptoms.[95]

Retinopathy of prematurity may regress spontaneously, but should the disease progress beyond a threshold (defined as five contiguous or eight cumulative hours of stage 3 retinopathy of prematurity), both cryosurgery and laser surgery have been shown to reduce the risk of blindness as an outcome. Where the disease has progressed further, techniques such as scleral buckling and vitrectomy surgery may assist in re-attaching the retina.

Repeated exposure to potentially toxic oxygen concentrations in breathing gas is fairly common in hyperbaric activity, particularly in hyperbaric medicine, saturation diving, underwater habitats, and repetitive decompression diving. Research at the National Oceanic and Atmospheric Administration (NOAA) by R.W. Hamilton and others determined acceptable levels of exposure for single and repeated exposures. A distinction is made between acceptable exposure for acute and chronic toxicity, but these are really the extremes of a possible continuous range of exposures. A further distinction can be made between routine exposure and exposure required for emergency treatment, where a higher risk of oxygen toxicity may be justified to achieve a reduction of a more critical injury, particularly when in a relatively safe controlled and monitored environment.

The Repex (repetitive exposure) method, developed in 1988, allows oxygen toxicity dosage to be calculated using a single dose value equivalent to 1 minute at atmospheric pressure called an Oxygen Tolerance Unit (OTU), is used to avoid toxic effects over several days of operational exposure. Some dive computers will automatically track the dosage bases on depth and selected gas mixture. The limits allow a greater exposure when the person has not been exposed recently, and daily allowable dose decreases with an increase in consecutive days with exposure.[95] These values may not be fully supported by current data.[97]

A more recent proposal uses a simple power equation, Toxicity Index (TI) = t2 PO2c, where t is time and c is the power term. This was derived from the chemical reactions producing reactive oxygen or nitrogen species, and has been shown to give good predictions for CNS toxicity with c = 6.8 and for pulmonary toxicity for c = 4.57.[97]

For pulmonary toxicity, time is in hours, and PO2 in atmospheres absolute, TI should be limited to 250.

For CNS toxicity, time is in minutes, PO2 in atmospheres absolute, and a TI of 26,108 indicates a 1% risk.

Although the convulsions caused by central nervous system oxygen toxicity may lead to incidental injury to the victim, it remained uncertain for many years whether damage to the nervous system following the seizure could occur and several studies searched for evidence of such damage. An overview of these studies by Bitterman in 2004 concluded that following removal of breathing gas containing high fractions of oxygen, no long-term neurological damage from the seizure remains.[19][98]

The majority of infants who have survived following an incidence of bronchopulmonary dysplasia will eventually recover near-normal lung function, since lungs continue to grow during the first 57 years and the damage caused by bronchopulmonary dysplasia is to some extent reversible (even in adults). However, they are likely to be more susceptible to respiratory infections for the rest of their lives and the severity of later infections is often greater than that in their peers.[99][100]

Retinopathy of prematurity (ROP) in infants frequently regresses without intervention and eyesight may be normal in later years. Where the disease has progressed to the stages requiring surgery, the outcomes are generally good for the treatment of stage 3 ROP, but are much worse for the later stages. Although surgery is usually successful in restoring the anatomy of the eye, damage to the nervous system by the progression of the disease leads to comparatively poorer results in restoring vision. The presence of other complicating diseases also reduces the likelihood of a favourable outcome.

The incidence of central nervous system toxicity among divers has decreased since the Second World War, as protocols have developed to limit exposure and partial pressure of oxygen inspired. In 1947, Donald recommended limiting the depth allowed for breathing pure oxygen to 7.6m (25ft), which equates to an oxygen partial pressure of 1.8bar (180kPa). Over time this limit has been reduced, until today a limit of 1.4bar (140kPa) during a recreational dive and 1.6bar (160kPa) during shallow decompression stops is generally recommended. Oxygen toxicity has now become a rare occurrence other than when caused by equipment malfunction and human error. Historically, the U.S. Navy has refined its Navy Diving Manual Tables to reduce oxygen toxicity incidents. Between 1995 and 1999, reports showed 405 surface-supported dives using the heliumoxygen tables; of these, oxygen toxicity symptoms were observed on 6 dives (1.5%). As a result, the U.S. Navy in 2000 modified the schedules and conducted field tests of 150 dives, none of which produced symptoms of oxygen toxicity. Revised tables were published in 2001.[105]

The variability in tolerance and other variable factors such as workload have resulted in the U.S. Navy abandoning screening for oxygen tolerance. Of the 6,250 oxygen-tolerance tests performed between 1976 and 1997, only 6 episodes of oxygen toxicity were observed (0.1%).[106][107]

Central nervous system oxygen toxicity among patients undergoing hyperbaric oxygen therapy is rare, and is influenced by a number of a factors: individual sensitivity and treatment protocol; and probably therapy indication and equipment used. A study by Welslau in 1996 reported 16 incidents out of a population of 107,264 patients (0.015%), while Hampson and Atik in 2003 found a rate of 0.03%.[108][109] Yildiz, Ay and Qyrdedi, in a summary of 36,500 patient treatments between 1996 and 2003, reported only 3 oxygen toxicity incidents, giving a rate of 0.008%.[108] A later review of over 80,000 patient treatments revealed an even lower rate: 0.0024%. The reduction in incidence may be partly due to use of a mask (rather than a hood) to deliver oxygen.[110]

Bronchopulmonary dysplasia is among the most common complications of prematurely born infants and its incidence has grown as the survival of extremely premature infants has increased. Nevertheless, the severity has decreased as better management of supplemental oxygen has resulted in the disease now being related mainly to factors other than hyperoxia.[38]

In 1997 a summary of studies of neonatal intensive care units in industrialised countries showed that up to 60% of low birth weight babies developed retinopathy of prematurity, which rose to 72% in extremely low birth weight babies, defined as less than 1kg (2.2lb) at birth. However, severe outcomes are much less frequent: for very low birth weight babiesthose less than 1.5kg (3.3lb) at birththe incidence of blindness was found to be no more than 8%.[102]

Central nervous system toxicity was first described by Paul Bert in 1878.[111][112] He showed that oxygen was toxic to insects, arachnids, myriapods, molluscs, earthworms, fungi, germinating seeds, birds, and other animals. Central nervous system toxicity may be referred to as the "Paul Bert effect".[14]

Pulmonary oxygen toxicity was first described by J. Lorrain Smith in 1899 when he noted central nervous system toxicity and discovered in experiments in mice and birds that 0.43bar (43kPa) had no effect but 0.75bar (75kPa) of oxygen was a pulmonary irritant.[29] Pulmonary toxicity may be referred to as the "Lorrain Smith effect".[14] The first recorded human exposure was undertaken in 1910 by Bornstein when two men breathed oxygen at 2.8bar (280kPa) for 30minutes, while he went on to 48minutes with no symptoms. In 1912, Bornstein developed cramps in his hands and legs while breathing oxygen at 2.8bar (280kPa) for 51minutes.[3] Smith then went on to show that intermittent exposure to a breathing gas with less oxygen permitted the lungs to recover and delayed the onset of pulmonary toxicity.[29]

Albert R. Behnke et al. in 1935 were the first to observe visual field contraction (tunnel vision) on dives between 1.0bar (100kPa) and 4.1bar (410kPa).[113][114] During World War II, Donald and Yarbrough et al. performed over 2,000 experiments on oxygen toxicity to support the initial use of closed circuit oxygen rebreathers.[39] Naval divers in the early years of oxygen rebreather diving developed a mythology about a monster called "Oxygen Pete", who lurked in the bottom of the Admiralty Experimental Diving Unit "wet pot" (a water-filled hyperbaric chamber) to catch unwary divers. They called having an oxygen toxicity attack "getting a Pete".[116][117]

In the decade following World War II, Lambertsen et al. made further discoveries on the effects of breathing oxygen under pressure and methods of prevention.[118][119] Their work on intermittent exposures for extension of oxygen tolerance and on a model for prediction of pulmonary oxygen toxicity based on pulmonary function are key documents in the development of standard operating procedures when breathing increased pressures of oxygen. Lambertsen's work showing the effect of carbon dioxide in decreasing time to onset of central nervous system symptoms has influenced work from current exposure guidelines to future breathing apparatus design.[21][22]

Retinopathy of prematurity was not observed before World War II, but with the availability of supplemental oxygen in the decade following, it rapidly became one of the principal causes of infant blindness in developed countries. By 1960 the use of oxygen had become identified as a risk factor and its administration restricted. The resulting fall in retinopathy of prematurity was accompanied by a rise in infant mortality and hypoxia-related complications. Since then, more sophisticated monitoring and diagnosis have established protocols for oxygen use which aim to balance between hypoxic conditions and problems of retinopathy of prematurity.[102]

Bronchopulmonary dysplasia was first described by Northway in 1967, who outlined the conditions that would lead to the diagnosis.[122] This was later expanded by Bancalari and in 1988 by Shennan, who suggested the need for supplemental oxygen at 36weeks could predict long-term outcomes.[123] Nevertheless, Palta et al. in 1998 concluded that radiographic evidence was the most accurate predictor of long-term effects.[124]

Bitterman et al. in 1986 and 1995 showed that darkness and caffeine would delay the onset of changes to brain electrical activity in rats.[23][24] In the years since, research on central nervous system toxicity has centred on methods of prevention and safe extension of tolerance.[125] Sensitivity to central nervous system oxygen toxicity has been shown to be affected by factors such as circadian rhythm, drugs, age, and gender.[126][127][128][129] In 1988, Hamilton et al. wrote procedures for the National Oceanic and Atmospheric Administration to establish oxygen exposure limits for habitat operations.[78][79][80] Even today, models for the prediction of pulmonary oxygen toxicity do not explain all the results of exposure to high partial pressures of oxygen.[130]

Recreational scuba divers commonly breathe nitrox containing up to 40% oxygen, while technical divers use pure oxygen or nitrox containing up to 80% oxygen to accelerate decompression. Divers who breathe oxygen fractions greater than of air (21%) need to be educated on the dangers of oxygen toxicity and how to manage the risk. To buy nitrox, a diver may be required to show evidence of relevant qualification.[131]

Since the late 1990s the recreational use of oxygen has been promoted by oxygen bars, where customers breathe oxygen through a nasal cannula. Claims have been made that this reduces stress, increases energy, and lessens the effects of hangovers and headaches, despite the lack of any scientific evidence to support them.[132] There are also devices on sale that offer "oxygen massage" and "oxygen detoxification" with claims of removing body toxins and reducing body fat.[133] The American Lung Association has stated "there is no evidence that oxygen at the low flow levels used in bars can be dangerous to a normal person's health", but the U.S. Center for Drug Evaluation and Research cautions that people with heart or lung disease need their supplementary oxygen carefully regulated and should not use oxygen bars.[132]

Victorian society had a fascination for the rapidly expanding field of science. In "Dr. Ox's Experiment", a short story written by Jules Verne in 1872, the eponymous doctor uses electrolysis of water to separate oxygen and hydrogen. He then pumps the pure oxygen throughout the town of Quiquendone, causing the normally tranquil inhabitants and their animals to become aggressive and plants to grow rapidly. An explosion of the hydrogen and oxygen in Dr Ox's factory brings his experiment to an end. Verne summarised his story by explaining that the effects of oxygen described in the tale were his own invention (they are not in any way supported by empirical evidence).[134] There is also a brief episode of oxygen intoxication in his "From the Earth to the Moon".[135]

General

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Oxygen toxicity - Wikipedia

Eye condition

Medical condition

A posterior vitreous detachment (PVD) is a condition of the eye in which the vitreous membrane separates from the retina.[1]It refers to the separation of the posterior hyaloid membrane from the retina anywhere posterior to the vitreous base (a 34mm wide attachment to the ora serrata).

The condition is common for older adults; over 75% of those over the age of 65 develop it. Although less common among people in their 40s or 50s, the condition is not rare for those individuals. Some research has found that the condition is more common among women.[2][3]

When this occurs there is a characteristic pattern of symptoms:

As a posterior vitreous detachment proceeds, adherent vitreous membrane may pull on the retina. While there are no pain fibers in the retina, vitreous traction may stimulate the retina, with resultant flashes that can look like a perfect circle.[citation needed]

If a retinal vessel is torn, the leakage of blood into the vitreous cavity is often perceived as a "shower" of floaters. Retinal vessels may tear in association with a retinal tear, or occasionally without the retina being torn.[citation needed]

A Weiss ring can sometimes be seen with ophthalmoscopy as very strong indicator that vitreous detachment has occurred. This ring can remain free-floating for years after detachment.[citation needed]

The risk of retinal detachment is the greatest in the first 6 weeks following a vitreous detachment, but can occur over 3 months after the event.

The risk of retinal tears and detachment associated with vitreous detachment is higher in patients with myopic retinal degeneration, lattice degeneration, and a familial or personal history of previous retinal tears/detachment.

The vitreous (Latin for "glassy") humor is a gel which fills the eye behind the lens. Between it and the retina is the vitreous membrane. With age the vitreous humor changes, shrinking and developing pockets of liquefaction, similar to the way a gelatin dessert shrinks and detaches from the edge of a pan. At some stage the vitreous membrane may peel away from the retina. This is usually a sudden event, but it may also occur slowly over months.

Age and refractive error play a role in determining the onset of PVD in a healthy person. PVD is rare in emmetropic people under the age of 40 years, and increases with age to 86% in the 90s. Several studies have found a broad range of incidence of PVD, from 20% of autopsy cases to 57% in a more elderly population of patients (average age was 83.4 years).[4][citation needed]

People with myopia (nearsightedness) greater than 6 diopters are at higher risk of PVD at all ages.Posterior vitreous detachment does not directly threaten vision. Even so, it is of increasing interest because the interaction between the vitreous body and the retina might play a decisive role in the development of major pathologic vitreoretinal conditions, such as epiretinal membrane.[citation needed]

PVD may also occur in cases of cataract surgery, within weeks or months of the surgery.[5]

The vitreous membrane is more firmly attached to the retina anteriorly, at a structure called the vitreous base. The membrane does not normally detach from the vitreous base, although it can be detached with extreme trauma. However, the vitreous base may have an irregular posterior edge. When the edge is irregular, the forces of the vitreous membrane peeling off the retina can become concentrated at small posterior extensions of the vitreous base. Similarly, in some people with retinal lesions such as lattice retinal degeneration or chorio-retinal scars, the vitreous membrane may be abnormally adherent to the retina. If enough traction occurs the retina may tear at these points. If there are only small point tears, these can allow glial cells to enter the vitreous humor and proliferate to create a thin epiretinal membrane that distorts vision. In more severe cases, vitreous fluid may seep under the tear, separating the retina from the back of the eye, creating a retinal detachment. Trauma can be any form from a blunt force trauma to the face such as a boxer's punch or even in some cases has been known to be from extremely vigorous coughing or blowing of the nose.

Posterior Vitreous Detachment is diagnosed via dilated eye examination. For some patients the vitreous gel is extremely clear and so it can be hard to see the PVD. In these cases, additional imaging such as Optical Coherence Tomography (OCT) or ocular ultrasound are used.[6]

Therapy is not required or indicated in posterior vitreous detachment, unless there are associated retinal tears, which need to be repaired.[7] In absence of retinal tears, the usual progress is that the vitreous humor will continue to age and liquefy and floaters will usually become less and less noticeable, and eventually most symptoms will completely disappear.[7] Prompt examination of patients experiencing vitreous humor floaters combined with expeditious treatment of any retinal tears has been suggested as the most effective means of preventing certain types of retinal detachments.[8]

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Posterior vitreous detachment - Wikipedia

Photodynamic therapy (PDT) is a treatment option for pachychoroid diseases such as central serous chorioretinopathy (CSC), pachychoroid neovasculopathy (PNV),polypoidal choroidal vasculopathy (PCV), and peripapillary pachychoroid syndrome (PPS). On the other hand, morphological changes of choroidal vessels in the irradiated field after PDT have also been discussed, with occlusion of choriocapillaris and stenosis of choroidal middle and large vessels being reported. Here, we report a case of vortex vein occlusion after half-fluence PDT (HF-PDT) combined with an anti-vascular endothelial growth factor (VEGF) agent for PNV. In this case, HF-PDT achieved complete occlusion of PNV; in addition, a vortex vein that flowed in PNV but was located outside the PDT irradiation field was fully occluded three months post-treatment. At the occluded site of the vortex vein, indocyanine green video angiography revealed pulsation downstream of the vortex vein. Such occlusion of a largevessel by HF-PDT has not been reported previously. Occlusion could be induced by two factors: the potentiality of PDT and risk factors for thromboembolism, such as older age, smoking, and arrhythmia. Further studies are required to determine the mechanisms of these large vessel occlusions.

Pachychoroid disease is a disease concept that describes a phenotype characterized by an attenuation of the choriocapillaris overlying dilated choroidal veinsand is associated with retinal pigment epithelial dysfunction and neovascularization [1]. Central serous chorioretinopathy (CSC), pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy (PCV), focal choroidal excavation (FCE), and peripapillary pachychoroid syndrome (PPS) reside within the pachychoroid disease spectrum [1].

PNV is characterized by type 1 macular neovascularization (MNV) in eyes with pachychoroid features. To distinguish PNV from neovascular age-related macular degeneration (nAMD), the current diagnostic criteria for PNV can be summarized as (1) the presence of pachychoroid features and (2) the absence of drusen [2].

Currently, anti-vascular endothelial growth factor (VEGF) therapy is the gold standard for nAMD, and its efficacy for PNV has been reported [3-5]. However, more extensive injections of anti-VEGF compared to PCV may be required to treat PNV. Photodynamic therapy (PDT) is one of the treatment options for not only CSCbut also nAMD; PDT therapy can regress MNV and reduce vascular permeability of the choriocapillaris and choroidal thickness, which can contribute to the absorption of retinal fluid [6]. PDT combined with anti-VEGF agents appears to be a more potent tool for PCV treatment. The endovascular valve edge-to-edge repair study (EVEREST) II trial [7] revealed that the combination therapy of PDT and ranibizumab for PCV was superior to ranibizumab alone with respect to improvement of visual acuity and frequencies of polyp-regression. Recently, half-fluence PDT (HF-PDT) combined with anti-VEGF agents was also applied to patients with PNV to stabilize MNV and the choroid [8].

After PDT treatment, a circumscribed occlusion of the choriocapillaris was identified in the area where PDT was exposed using indocyanine green angiography (IA) [9]. In this study, eyes were surgically removed seven days after PDT, and a histological study of the PDT exposedarea also revealed an occluded choriocapillaris filled with emboli, which was accompanied by deformed erythrocytes, degranulated platelets, and fibrin. These results suggest that the essential effect of PDT is the clogging of capillary vessels in the choroid.

In this case presentation, we present an unusual case in which a large vortex vein was occluded after HF-PDT with aflibercept intravitreal injection in a patient with PNV.

An 89-year-old man was referred to our hospital because of impaired vision in the right eye. He had a medical history of arrhythmia (not medicated)and benign prostatic hyperplasia. His smoking history was 12 cigarettes per day for 30 years (from the age of 20 to 50 years). Best-corrected visual acuity was 20/32 in the right eye and 20/20 in the left eye. Optical coherence tomography (OCT) revealed serous retinal detachment accompanied by flat retinal pigment epithelial detachment in the right macula, in addition to a thickened choroid-associated dilatation of outer choroidal vessels in the same eye (Figure1B). OCT angiography (OCTA) revealed choroidal neovascularization beneath the pigment epithelial detachment (Figure 1C). IA also identified choroidal neovascularization in the same area as OCTA, and dilated vortex veins adjacent to the CNV were detected (Figure 1D). Choroidal vascular hyperpermeability was observed in the late stage of IA. We diagnosed PNV and performed reduced fluence PDT (RF-PDT) with intravitreal aflibercept injection. Three months after treatment, the serous retinal detachment disappeared, and choroidal thickening decreased (Figure2A). The CNV was successfully regressed and reduced in both IA and OCTA. IA was used to detect a circumscribed hypofluorescent area where HF-PDT was applied (Figure 2B, 2C).

Three months post-treatment, IA also revealed occlusion of a vortex vein that branched in the inferior posterior region, outside the irradiated area (Figure 3A, 3B). A complete interruption in the vortex vein was observed without a downstream flow of the vessel in a movie of the IA (Heidelberg Engineering, Heidelberg, Germany) (Video1). Interestingly, pulsation of the vortex vein at this portion was also detected, and the blood seemed to stream inversely when compared to the bloodstream at the initial visit. Fourteen months post-treatment, the IA movie revealed complete occlusion of the vortex vein, with no recanalization and no pulsation (Figure3C).

Fortunately, no recurrence of MNV developed, the patient did not complain of any changes in vision during the follow-up period, and his final visual acuity remained unchanged at 20/32.

This case suggests that PDT can cause not only clotting of capillary vesselsbut also occlusion of large choroidal vessels.

Vascular occlusion at the level of the choroidal capillary plate after PDT has been reported previously [9,10]; however, occlusion of large vessels, as observed in this study, has not been reported before.

Previous studies have identified that verteporfin is essentially taken up by abnormal neovascularization, leading to selective cytotoxicity of vascular endothelial cells through the production of oxidative radicals. This reactivity can cause regression of neovascularization and resolution of the leakage from the neovascular membrane [11-13].

On the other hand, PDT also affected normal choroidal vessels, specifically both normal choriocapillaris and middle and large choroidal vessels [10,14,15]. As mentioned in the introduction, the circumscribed hypofluorescent area where the PDT had been exposed was detected in IA after PDT treatment, and the area contained both normal and abnormal choroidal vessels [9]. OCT image analysis revealed thinning of the choroid after PDT treatment [16], and the vascular density in both the choriocapillaris and the middle layer of the choroid significantly decreased after the treatment. Moreover, the maximum vessel diameter in the outer choroidal layer in the area exposed to PDT was significantly reduced but not occluded [9]. In this case, occlusion of the large vortex vein outside the irradiated area could have been induced by three factors: the potentiality of PDT, the existenceofa vessel branch traversing the irradiated area, which could have caused thromboembolism to the distal part,and risk factors for thromboembolism, such as older age, smoking, and arrhythmia [17].

On the other hand, indocyanine green angiography in the early phase showed hyperfluorescent plaque overlying a large caliber choroidal vessel in Figure1D, which possibly corresponded toan anastomotic vessel connecting the upper and lower vortex veins [18].In this case, the superior and inferior vortex veins were asymmetric. They seemed to be connected by anastomosis at the horizontal watershed zone. The superior vortex vein had a larger diameter, and the inferior vortex vein had a thinnerdiameter. Thus, thesuperior vortex vein should be responsiblefor compensatoryvenous flow before treatment. After treatment, blood flow seemed to return upward in a V-shape due to the trunk occlusion. The trunk of the inferior vortex vein couldbe no longer needed and considered to have been occluded by disuse.

With the detection of the occlusive vortex vein, a pulsation was detected downstream of the occlusive portion in the IA. Pulsation of the retinal artery was previously reported in cases with central retinal vein occlusion, and the authors concluded that pulsation meant a delay in the retinal bloodstream. In pachychoroid spectrum diseases, pulsation in the choroidal large vasculature has also been detected in treatment-nave cases [19]. These results suggest that choroidal overload might be associated with the disturbance of choroidal circulation. In this case, the backflow of the vortex vein downstream of the occlusive portion may have led to turbulent flow in this area.

To the best of our knowledge, we report a first case in which a vortex vein located outside the irradiated area was occluded after HF-PDT combined with intravitreal aflibercept. At the occluded site of the vortex vein, indocyanine green video angiography revealed pulsation downstream of the vortex vein. Pulsation on IA can be used as a biomarker to suggest an overload of choroidal circulation.

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Occlusion of a Vortex Vein After Treatment With Half-Fluence Photodynamic Therapy Combined With Intravitreal Aflibercept Injection for Pachychoroid...

A 16-year-old boy hailing from Kalaburagi, who was declared blind and was provided a blind certificate, has now got the gift of vision through a free advanced surgery and treatment at a private hospital in Bengaluru.

The boy, Ganesh (name changed), had been complaining ofprogressive worsening of vision in both eyes since he was aged three. However, owing to financial constraints, his family could not get him timely treatment.

He came to Sankara Eye Hospital in the city through the hospitals Gift of Vision initiative. On examination, the boy was diagnosed with severe retinal detachment complications with numerous retinal angiomas and associated scarring, specific for a condition known as Von-Hippel Lindau disease (VHL).

VHL is a hereditary condition associated with tumours arising in multiple organs mainly in the brain, spinal cord and retina. This genetic disorder has a high risk of getting transmitted to the children. Following a detailed discussion with the family members, doctors learnt that theboys grandmother was the only surviving member of the family. The boys parents and two siblings had succumbed to the disease a few years back. VHL as a disease can be catastrophic not only to the patient but also to the entire family.

After having made the diagnosis, a team of doctors under the supervision ofMahesh Shanmugam, Head Ocular Oncology and Vitreoretinal diseases, atthe hospital successfully performed the surgery free of cost. Through the surgery, the doctors fixed the complicated retinal detachment and also treated the multiple tumours with laser therapy to prevent them from causing any further damage to the eye. The boy was able to see within two weeks after the surgery and is now leading a near normal life.

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Teen declared blind regains sights with free advanced treatment in Bengaluru - The Hindu

In this new eraof the renaissance ofnon-penetrating glaucoma surgeries, newer implants, and shunt procedures, the role of trabeculectomy (TRAB) as the gold standard of glaucoma procedures is ambivalent. Even though many practitioners claim that TRAB will not survive in the near future, it still remains the first choice for most glaucoma surgeons. in cases with advanced damage, rapid progression despite maximal medical therapy, and in patients where the target intraocular pressure (IOP) required is very low. 'Trabeculectomy' procedure reported by Cairns in 1968 has undergone various modifications to increase outflow and achieve long-term success [1]. But the main issues with TRAB include short and long-term complications like hypotony, hypotonic maculopathy, wipe-out phenomenon, bleb leaks, cataracts, choroidal effusion, and hemorrhage [2]. These complications are accelerated with the concomitant use of anti-fibrotic, but without them, the chances of short-term failure are also relatively high [3,4].The advent of novel minimally invasive glaucoma surgeries (MIGS) and non-penetrating surgeries (NPGS) have paved the path for lesser complicated yet effective ways of controlling IOP [5-8]. This review article summarizes the evolution and modifications of TRAB and its comparison of efficacy with neoteric shunt procedures while trying to answer whether TRAB has a future in the modern surgical world.

Glaucoma surgery now encompasses a variety of surgeries apart from conventional trabeculectomy (Figure 1).

Trabeculectomy underwent significant changes from an initial sclerotomy toan anterior sclerotomy, latera sclerectoiridectomy in 1906 orlimbal trephination andiridencleisis to provide a permanent fistula by using iris as a wick between the anterior chamber and the subconjunctival space [2]. This was modifiedwith a peripheral iridectomy and thermal sclerostomy (1958), or posterior lip sclerectomybefore guarded filtration surgeries were introduced to offset the catastrophic complications with full-thickness procedures[2,8,9].

Cairns JE initially described trabeculectomy in 1968 [1] that was later modified by Watson in 1970 [10,11]. Over the years, it has undergone modifications and supplementations to improve long-term success and reduce complications. Cairns described TRAB as a bypass procedure of making a deep scleral flap with excision of a small segment of the canal of Schlemm with trabecular tissue, Removal of the trabecular barrier at that point thus allowed an alternative resistance-free pathway. Few clinicians consider the namea misnomer, as cutting mainly the Schlemm's canal and adjoining corneal tissue will also serve the purpose, and clearing the trabecular tissue alone is not mandatory [11].But the initial procedure was associated with complications of a full-thickness procedure and had high rates of failure [3,4,10-12].

Early trabeculectomy filtering procedures were associated with a high rate of complications like hypotony, hypotonic maculopathy, choroidal detachment, suprachoroidal hemorrhage, bleb-related infections, and endophthalmitis [12-18]. Early cases of bleb leaks, shallow anterior chamber, and hypotony can be resolved with the use of large bandage contact lenses, pressure patching, symblepharon rings, and the Simmons shell. However, a flat anterior chamber with lens-corneal touch requires immediate surgical intervention to prevent rapid cataract development and irreversible corneal endothelial damage [12-14]. Initial studies have reported hypotony and choroidal detachment as late as 2-26 months following primary uncomplicated surgery that warrants a repeat surgery [14,15]. These complications forced surgeons to search for newer surgeries or ways to increase the safety profile while not compromising on the surgical success of trabeculectomy.

Watson and Barnett later modified this procedure by making a 5 x 5 mm partial-thickness flap and making a corneoscleral window for the passage of aqueous humor [10]. The original TRAB technique described by Cairns never intended to make a drainage bleb, but later it was observed that cases with good bleb had a higher success rate. It was then that the focus shifted to considering TRAB as a filtration surgery, and more attention was focused on the surgical techniques, which facilitated the creation of diffuse drainage blebs [16-18]. In the late 1960s, in order to create a track between the subconjunctival space and the anterior chamber, various methods of ab-interno and ab-externo approaches were tried using pulsed Nd: YAG laser, carbon dioxide laser, and excimer laser [16-19]. However, higher failure rates with laser surgeries make TRAB the standard procedure of choice for ensuring long-term success [19]. Newer procedures with comparable IOP outcomes are still evolving and are yet to replace TRAB as the gold standard for preservation of visual function in early-moderate glaucoma and more so for advanced stages of glaucoma, where TRAB still remains the surgery of choice.

Antifibrotics to the Rescue

Increased use of anti-fibrotic agents like mitomycin C (MMC) and 5-fluorouracil (5-FU) along with TRAB started in the early 1990s to enhance the success rate, long-term survival rate, and decrease the progression of glaucoma [15,19-26]. In recent years, the use of MMC has significantly increased, while that of 5-FU has declined as a preferred practice pattern for primary TRAB [19-22]. A United Kingdom surveyrecently reported the use of anti-fibrotic agents in primary TRAB in 93% of their cases, of which63% used 5-FU and 97% used MMC[20]. Various doses and duration of MMC use have been tried to offset delayed complications like bleb thinning, bleb leaks, or endophthalmitis. The American Glaucoma Society survey in 2016, claimed the dosage of MMC as 0.4 mg/mL (ranging from 0.2 to 0.5 mg/mL) applied for 2 minutes (range 45s-3 minutes) for primary TRAB, as the most popular and safer method[20]. Considering the role of angiogenesis in TRAB failure by wound modulation, the use of anti-VEGF agents is being tried in place of antifibrotics in TRAB. Liu et al. [21] reviewed eight randomized control trials (RCT) on TRAB with bevacizumab and concluded that bevacizumab and MMC had similar efficacy in IOP reduction. However, bevacizumab has been associated with a higher risk of leaking bleb and encystation, withother major issues being cost-effectiveness and off-label use [22]. The most recent RCT on intracameral bevacizumab in TRAB showed comparable surgical efficacy and IOP reduction to MMC, but with an increased rate of bleb leaks [23]. Recently the use of Ologen collagen matrix has been found to effectively modulate fibrous tissue formation thus decreasing the chances of failure[24,25]. Few surgeons have also tried using a combination of Ologen and MMC, with encouraging results [25]. A five-year follow-up study comparing Ologen to MMC also showed comparable results in both efficacy and safety between the two groups [26]. However, the cost of the Ologen implant is a major limiting factor for developing countries.

How Trabeculectomy Lost the Battle

Though TRAB success rates improved with the use of antifibrotics, the rates of delayed complication rates also increased parallelly, which again questioned the efficacy of TRAB as a standard glaucoma filtering surgery [15-18,27-30]. Belyea et al. studied 385 eyes that underwent TRAB with antifibrotics (MMC and 5-FU) and found an incidence of late repetitive multifocal bleb leaks in 1.8% of the eyes [15]. The incidence was equal among the two antifibrotics according to their study. The median period of the presentation was 20 months post-surgery.Singh et al. [27] studied the complications associated with the use of 0.2 mg/ml of MMC in TRAB and reported late bleb leaks, scleral necrosis, and hypotonic maculopathy as the major complications. It is now understood that their use results in the formation of thin and avascular blebs even in the delayed postoperative period, paving way for the easier migration of pathogens across the bleb and increased chance of delayed-onset endophthalmitis and blebitis. Incidence of bleb relation infection with MMC TRAB procedures reduced from 5.7% to 1.2% after the 1990s, after the introduction of MMC into clinical practice [28]. A recent study by Vaziri et al. [29] reported the incidence of endophthalmitis post trabeculectomy to be 0.45 0.2% for confirmed cases and 1.3 0.34% for confirmed plus presumed cases. The most common microbiological flora isolated from eyes with bleb-related infections includes Staphylococcus aureus, coagulase-negative staphylococci, Corynebacterium, and Haemophilus influenza [30].

Safe TRABRe-emergence and Renewal

Since there was an increasing understanding of the causes of MMC-related bleb complications, safer techniques were now sought to prevent these delayed complications [15,18,30-31]. Khaw et al. [31]. designed a range of strategies commonly known as Moorfield's safe surgery techniques to improve the control of IOP as well as to preserve visual acuity by minimizing bleb-related complications and hypotony. Three major objectives in the adoption of the technique include:1) prevention of hypotony; 2) prevention of thin uncomfortable cystic blebs and 3) prevention of limbal leaks of aqueous. Various steps adopted to prevent hypotony include a fornix-based conjunctival flap, making a small sclerotomy punch, continuous intraoperative anterior chamber infusion to achieve optimal pressure titration and to prevent hypotony, posterior placement of the MMC loaded sponges ensuring posterior flow, avoidance of >3minutes of MMC application at any single time, and a thorough wash of the area after each application. To prevent cystic uncomfortable blebs, selection of a superior location under the eyelid, larger area of treatment, fornix-based flap to minimize posterior scarring, and posterior diversion of aqueous by altering scleral flap construction, are some useful measures for safer TRAB with lower complication rates. Adopting a corneal groove-closure technique also helps in preventing limbal leaks of aqueous. Adoption of these techniques reduced the delayed complication rates associated with MMC use and this ushered in a resurgence of TRAB in glaucoma until the advent of technologically assisted filtering procedures [31].

Minimally Invasive Glaucoma Surgery (MIGS)

Those procedures wherein the trabecular meshwork (TM) is incised /excised under direct supervision using specialized instruments are called ab-Interno or microinvasive glaucoma surgery [32-38]. These include the usage of trabectome, kahook dual blade, microhook ab-interno trabeculectomy, gonioscopy assisted transluminal trabeculotomy (GATT, Figure 2A), ab-interno goniotomy (Figure 2B), and ab-interno trabeculotomy 360 degrees. These are usually not associated with a bleb, require smaller incisions of entry, and are therefore not associated with bleb-related complications (Figures 1-2).A meta-analysis found the success rate of trabectome alone to be 46%, and when combined with phacoemulsification to increase to 85%, both achieving >30% IOP reduction [32]. With gonioscopy-assisted transluminal trabeculotomy (GATT), results have shown an IOP decrease of approximately 7.7 mmHg and 11.1 mmHg at 6 and 12 months, respectively. The number of anti-glaucoma medications (AGMs) reduced by 0.9 and 1.1 on average at 6 and 12 months [33].Similarly, trabeculotomy 360 procedures performed on patients with refractory primary open-angle glaucoma (POAG) reported a 20% IOP reduction in 59% of patients, with the average number of anti-glaucoma medications dropping from 1.7 1.3 to 1.1 1.0 medications [34]. However, this had a 25% failure rate, with the majority requiring a second procedure within 12 months. Another study comparing ab-interno trabeculectomy with trabectome with ab-externo trabeculectomy found a lower success rate (22.4% Vs 76.1%), with 43.5 % requiring a second procedure for effective IOP control [35]. Even now, these procedures are used for moderate to early glaucoma, while TRAB remains the time-tested surgery for advanced glaucoma. Further, none of these procedures have been reported to offer long-term preservation of visual function better than TRAB or to be cost-effective for the patient in developing countries.

Non-penetrating glaucoma surgeries (NPGS)

Metanalysis comparing TRAB and non-penetrating glaucoma surgeries (NPGS) has concluded that TRAB results in much better control of IOP than NPGS [28-32].Though the complications rates with TRAB are higher, it is preferablein cases with advanced chronic glaucoma and pseudoexfoliation glaucoma, where NPGS offers a lower success rate[32]. In 1964, Krasnov published his first report on a novel technique called "sinusotomy," which consisted of removing a lamellar band of the scleraand opening the Schlemm's canal over 120 [36]. He believed that the aqueous outflow resistance was mainly at the level of scleral aqueous drainage veins and not in the trabecular meshwork. Hence, no superficial scleral flap covered the sclerectomy in this technique. However, the sinusotomy procedure was eventually abandoned due to the difficult learning curve and less reduction in IOP compared with TRAB.

In 1989, Fyodorov and Kozlov described another technique called deep sclerectomy. In this procedure, careful scraping of the Schlemm's canal bed is done to remove a homogenous "external trabecular membrane" that allows aqueous humor to exit through the remaining inner trabecular layers [37]. Later in 1999, Stegmann et al. [38] reported 'viscocanalostomy' where a high molecular weight viscoelastic substance is injected into the opening of Schlemm's canal to enlarge the canal. This procedure allows the aqueous to bypass the juxtacanalicular trabecular meshwork and also drains the aqueous from the exposed Descemet's window. These surgeries were designed as a safer alternative to reduce complications of a full penetrating procedure while allowing filtration through the Schlemm's canal.

Micro-invasive glaucomaimplants, targeting the conventional outflow pathway, have emerged in the field of glaucoma over the last two decades to address an unmet need for better therapeutic options [32-45]. Various approaches have been adopted by these procedures to bring down the IOP by directly bypassing the trabecular meshwork, dilating the Schlemm's canal, and enhancing the uveoscleral outflow by assessing the suprachoroidal space and decreasing the aqueous production by ablating the ciliary body. One study reported a mean reduction of 7.0 4.0 mmHg withI-stent combined with phacoemulsification versusa mean IOP reduction of 5.4 3.7 mmHg with phacoemulsification alone, with 84% of the former eyes being medication free [39]. Another trialevaluated the safety and efficacy of CyPass stunt (ab-interno-supraciliary space shunt) and reported a higher reduction of IOP (77% vs 66%) in eyes that underwent stent implantation along with cataract surgery. Furthermore, 85% of eyes in the CyPass group were medication-free at two years [40]. However, the device was later withdrawn due to certain safety concerns over follow-up [41]. Gabbay and Ruben did a retrospective analysis on the safety of CyPass stents and reported few other adverse effects over a short follow-up like postoperative pressure sikes (28%), hyphema, vitreous hemorrhage, choroidal effusion, and retinal detachment [42].A hydrogel implant (XEN) is a newer FDA-approved implant that helps in shunting aqueous outflowinto the subconjunctival space. Studies have reported a >20% reductionin IOP in 75.4% of patients, with a decrease in an average number of AGMs from 3.5to 1.7 at 12 months postoperatively [43]. Studies comparing the latest XEN implant to conventional TRAB have claimed a higher and more efficacious IOP reduction with TRAB[44,45]. Though MIGS is now recognized as an alternative to TRAB, the major concerns include the steep learning curveand the varying safety profiles of different surgical procedures. Further, the cost-effectiveness, need for sophisticated machinery and instruments, and the need for frequent follow-up/additional surgeries, questions the actual effectiveness for visual function and the long-term applicability of these procedures worldwide.

TRAB Versus Lensectomy

Since cataract extraction alone was reported to cause IOP reduction, TRAB has been compared with cataract extraction alone in POAGand primary angle-closure glaucoma (PACG) [46-57]. Tham et al. [46] compared phacoemulsification (PHACO) alone to TRAB with MMC in medically uncontrolled angle-closure glaucoma without cataracts. Both groups resulted in significant and comparable IOP reduction at 24 months after surgery (IOP reduction of 34% for PHACO alone vs. 36% for TRAB+MMC, {P=0.76}). Nevertheless, TRAB+MMC-treated eyes required fewer AGMs than PHACO alone eyes.The same group studied the effect of combined phaco trabeculectomy (PT) to phacoemulsification alone (PHACO) and claimed that the former procedure is more effective than PHACO alone group in controlling IOP in medically uncontrolled chronic angle closure glaucoma eyes with coexisting cataract [47]. However, the PT group was associated with more surgical complications. An analogous study on POAG patients was done by Takihara et al. [49] and they concluded that TRAB with MMC in pseudophakic eyes post phacoemulsification is less successful compared with that in phakic eyes. However, no significant intergroup difference was noted in the number of postoperative antiglaucoma medications, surgical complications or in the number of laser suture lysis procedures.

TRAB Combined Cataract and Glaucoma Surgery

There had been numerous studies comparing TRAB with phaco trabeculectomy with anecdotal results(Table 1) [50-57].However, a recent metanalysis on phaco trabeculectomy (PT) versus TRAB (TRAB) with or without later phacoemulsification did not find a significant difference in IOP reduction between the two procedures. A total of 25 studies were included comprising2315 eyes that underwent PT and 2216 eyes that underwent TRAB, wherein, PT was associated with a lower risk of postoperative complications and better best-corrected visual acuity (BCVA) compared to TRAB [50]. Li et al. also evaluated the effect of PT versus TRAB alone and concluded that the PT group had better outcomes when compared to TRAB. However, the sample size and the follow-up period were less in their study [51]. Contrary to this Lochhead et al. stated that TRAB was better with a significant difference in the IOP reduction and surgical success when compared to PT [52]. Chang et al. [53] compared the effect of PT with 5-FU to TRAB with 5-FU and found conflicting results wherein the surgical success rate was similar for both, with a greater mean IOP reduction in the latter. Choy BN asserted an equal IOP control with the TRAB group having more diffuse blebsand less incidence of failure [54]. Another study by Tan et al. gave contrasting results with a higher rate of complications in the TRAB group than in the PT group [55]. Lam and Wechsler found comparable IOP reduction in both eyes at 5 years with both procedures, though, the number of AGMs required postoperatively was higher in the PT group [56].

TRAB Versus Tube Surgery

Implants have revolutionized glaucoma surgery, especially in refractory cases [58-65]. A recent metanalysis comparing five systematic reviews on TRAB versus shunt surgeries concludedthat shunt surgeries might achieve greater qualified success than TRAB [58]. It is, however, not clear whether the aqueous shunts are superior to TRAB owing to the lack of sufficient evidence with regards to aspects like cost-effectiveness and long-term visual function preservation. Studies comparing TRAB versus tube surgeries and their outcomes are listed in Table 2. Another meta-analysis by HaiBo et al. comparing Ahmed glaucoma valve implant (AGV) to TRAB also reported no significant difference in IOP reduction between the two surgeries [59]. Similarly, Tseng et al. [60] conducted a Cochrane database systematic review on the safety and efficacy of aqueous shunts (both Ahmed and Baerveldt implants) in comparison with conventional TRAB and concluded there were not many differences between aqueous shunts and TRAB for glaucoma treatment. A systematic review by Hong et al. [61] on glaucoma drainage devices (GDDs, including Ahmed, Molteno, Baerveldt, Krupin) with a total of 52 studies and 2682 patients, concluded that GDD is more effective in refractory glaucoma. To summarize, TRAB with MMC seems to be equally effective as tube-shunt surgeries with preservation of long-term visual function being achievedby both surgeries, albeit with TRAB achieving it for a longer time [63].

TRAB Versus Laser Trabeculoplasty

Laser trabeculoplasty has been a well-established technique for lowering IOP in POAG and ocular hypertension patients over the last two decades [66-70]. Wise and Witter reported IOP reduction by 10 mm Hg in 40 patients with phakic eyes, using argon laser, with 65% of these eyes requiring AGMs to control IOP [66]. The Glaucoma Laser Trial Research Group compared argon laser trabeculoplasty (ALT) to antiglaucoma medicationand found better control in IOP with laser trabeculoplasty alone compared to a single AGM at 6 months, 1 year, and 2 years [67]. Studies evaluating selective laser trabeculoplasty (SLT) and glaucoma surgery are lacking in the literature. The EMGT (Early Manifest Glaucoma Trial) study observed that a 1 mmHg reduction in IOP from baseline decreased the risk of progression by 10% [68]. The advanced glaucoma intervention study (AGIS) looked at the effect of ALT before or after TRAB and found no change in white individuals. Neither prior ALT nor prior TRAB had a statistically significant effect on the failure of other procedures [69]. For 168 patients with uncontrolled chronic glaucoma, Migdal and Hitchings conducted a prospective clinical study comparing laser trabeculoplasty, medical therapy, and surgery as the primary therapy and concluded that the surgical group had the lowest average intraocular pressures and was the most successful at managing IOP diurnal swings [70]. Whilst laser trabeculoplasty resulted in a smaller reduction in pressure, these individuals were more likely to have high-pressure spikes.

TRAB In POAG

The role of TRAB in primary open-angle glaucoma patients (POAG) is well-established, however, there had been few anecdotal reports from few studies on its IOP reduction rates and visual field progression rates [71-75]. A recent study by Mataki et al. [71] in POAG documented a visual field (VF) progression of 0.7 decibels (dB)/year with a mean IOP of 15.7 mmHg. Similarly in a US-based study, Iverson et al. [72] reported a VF progression rate of 1.1 dB/year pre-operatively that had a mean IOP of 13.5 mmHg. Caprioli et al. [73] also confirmed in their study that TRAB can improve or maintain long-term visual function, a resultthat has not been proved unequivocally with other newer or older glaucoma surgeries.

TRAB In PACG

TRAB is the most common procedure used to reduce the IOP in both acute primary-angle closure glaucoma and chronic primary-angle closure glaucoma that are unresponsive to medical and laser treatment [76-77]. The overall success rate of TRAB varies from 68% to 100% depending upon the race and population [77]. However, because of the complications associated with TRAB, including cataract development, this is now less preferred.Adding to this is the high incidence of malignant glaucoma in this group of patients.

TRAB in Pseudoexfolaition Glaucoma

Pseduoexfoliative glaucoma (XFG) is known to be more aggressive than other types of glaucoma with a high rate of intraoperative complications like vitreous loss, zonular damage, clinically significant choroidal detachment, and choroidal hemorrhage [78-81]. Popovic and Sjostrand [80] compared the efficacy of TRAB in XFG eyes and POAG eyes and reported comparable results in both with a marginally better outcome in XFG eyes. Contrary to this, a recent study by Li et al. proclaimed significantly lower long-term success rates at 3 years and 5 years of follow-up in XFG eyes than in POAG eyes, though the short-term success rates were similar [81]. Ehrnrooth et al. [78] compared 55 POAG eyes with 83 XFG eyes and found a significantly higher overall success rate for patients with POAG than XFG and reported that a higher preoperativeIOP>30 mm Hg in the early postoperative period having an adverse effect on the surgical success of TRAB in XFG. Another study by Gurlu et al. [79] found no significant difference in the long-term success of TRAB between the two groups whose clinical characteristics are otherwise similar.

TRAB in Normal Tension Glaucoma (NTG)

Several landmark trials and studies have reported the efficacy of TRAB in NTG [82-87]. Naito et al. studied the effectiveness of TRAB in NTG patients with IOP<15 mmHg and found a significant reduction in mean IOP (8.1 2.9 mmHg) and the number of AGMs (0.8 1.5) [86]. In the Collaborative Normal-Tension Glaucoma Treatment Study (CNTGS) [83,84], nearly half of the eyes had undergone surgery, with an average post-operative IOP of 10.6 mmHg. The EMGT study [82], suggested that ALT may have a limited function in the treatment of NTG. A recent study that evaluated the effectiveness and long-term outcomes of TRAB using Moorfields technique claimed to have more successful long-term outcomes along with better safety and visual acuity preservation [87].

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Trabeculectomy: Does It Have a Future? - Cureus

FARMINGTON HILLS, Mich. - Ocuphire Pharma, Inc. (Nasdaq: OCUP), a clinical-stage ophthalmic biopharmaceutical company focused on developing and commercializing therapies for the treatment of refractive and retinal eye disorders, announced the issuance of U.S. Patent No. 11,400,077. The patent provides added intellectual property protection for the company's late-stage product candidate, Nyxol (phentolamine mesylate), with claims directed to methods for treating mydriasis using phentolamine mesylate. The patent is eligible for listing in the U.S. FDA Orange Book and has a term extending into year 2039.

'We are very pleased with the issuance of this new patent for Nyxol, which extends our intellectual property protection in the U.S. by an additional five years into 2039,' said Mina Sooch, MBA, Founder and CEO of Ocuphire Pharma. 'Last year we were granted a new U.S. Patent for presbyopia extending our existing patent estate into year 2039 and now we are very pleased with the issuance of this new patent for Nyxol in reversal of mydriasis,' said Mina Sooch, MBA, President and CEO of Ocuphire Pharma. 'As we own the worldwide rights to Nyxol for all indications, this added protection will position us to maximize the commercial value of Nyxol for at least 15 years in reversal of mydriasis as we plan to submit an NDA to the FDA later this year. If approved, Nyxol could be launched in the second half of 2023.'

Nyxol Eye Drops Patent Estate

Ocuphire owns all of the worldwide rights to Nyxol for all indications. Ocuphire's patent estate for Nyxol includes patents and patent applications for phentolamine mesylate formulations and methods of using phentolamine mesylate. Ocuphire's patent estate for Nyxol contains nine issued U.S. patents, eight pending U.S. non-provisional patent applications, as well as issued patents in Australia, Canada, Europe, Japan, and Mexico and pending patent applications in Australia, Canada, Europe, Japan, and other foreign countries. Ocuphire's first set of U.S. and foreign patents expire in year 2034, while Ocuphire's second set of U.S. patents expire in year 2039. Patents, if granted based on Ocuphire's pending foreign patent applications, would expire in year 2039.

Reversal of Mydriasis Market Opportunity

An estimated 100 million eye dilations are conducted every year in the U.S. to examine the back of the eye either for routine check-ups, disease monitoring or surgical procedures across all eye care practice groups. Depending on the individual and the color of their eyes, the pharmacologically-induced dilation can last anywhere from 6 to 24 hours in adults. Dilated eyes have heightened sensitivity to light and an inability to focus on near objects, causing difficulty reading, working and driving. Currently, there are no approved or available treatment options to safely reverse mydriasis. If approved, Nyxol has the potential to be the only FDA-approved drug for the reversal of mydriasis, uniquely modulating the pupil by blocking or 'relaxing' the ?1 receptors found only on the iris dilator muscle. This mechanism is differentiated from other miotics in that Nyxol moderately reduces the pupil size without engaging the ciliary muscle, resulting in favorable safety and tolerability seen across 12 completed trials in 3 indications by avoiding accommodative ciliary spasm, associated headaches and browaches, narrow angle closure, or risk of retinal detachment.

About Ocuphire Pharma

Ocuphire is a publicly-traded (NASDAQ: OCUP), clinical-stage ophthalmic biopharmaceutical company focused on developing and commercializing small-molecule therapies for the treatment of refractive and retinal eye disorders. The Company's lead product candidate, Nyxol eye drops?(0.75% phentolamine ophthalmic solution), is a once-daily, preservative-free eye drop formulation of phentolamine mesylate, a non-selective alpha-1 and alpha-2 adrenergic antagonist designed to reduce pupil size, and is being developed for several indications, including reversal of pharmacologically-induced mydriasis (RM), presbyopia and dim light or night vision disturbances (NVD), and has been studied in 12 completed clinical trials. Ocuphire has reported positive data from MIRA-2 and MIRA-3 registration trials and MIRA-4 pediatric safety trial for the treatment of RM. Ocuphire also reported positive topline data from the VEGA-1 Phase 2 trial of Nyxol for treatment of presbyopia, both Nyxol as a single agent and Nyxol with low dose pilocarpine ('LDP') 0.4% as adjunctive therapy. The Company recently reported positive topline results from LYNX-1 Phase 3 trial of Nyxol for NVD. Ocuphire's second product candidate, APX3330, is an oral tablet designed to inhibit angiogenesis and inflammation pathways relevant to retinal and choroidal vascular diseases, such as diabetic retinopathy (DR) and diabetic macular edema (DME) and has been studied in 11 Phase 1 and 2 trials. The Company announced in March the completion of enrollment in?the ZETA-1 Phase 2b clinical trial of APX3330 to treat DR/DME. Please visit?www.clinicaltrials.gov?to learn more about Ocuphire's ongoing APX3330 Phase 2b trial in DR/DME ZETA-1 (NCT04692688) and completed Nyxol trials: Phase 3 registration trial in NVD LYNX-1 (NCT04638660), Phase 3 registration trials in RM MIRA-2?(NCT04620213) and MIRA-3 (NCT05134974), MIRA-4 Phase 3 pediatric safety study (NCT05223478), and Phase 2 trial in presbyopia VEGA-1 (NCT04675151). As part of its strategy, Ocuphire will continue to explore opportunities to acquire additional ophthalmic assets and seek strategic partners for late-stage development, regulatory preparation, and commercialization of drugs in key global markets. For more information, visit?www.ocuphire.com.

Forward Looking Statements

Statements contained in this press release regarding matters that are not historical facts are 'forward-looking statements' within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, the success and timing of planned regulatory filings, the timing of planned commercialization of Nyxol in RM, the market for RM, business strategy, pre-commercialization activities, our ability to protect our intellectual property rights, and the potential for and success of commercialization of Ocuphire's product candidates, including Nyxol. These forward-looking statements are based upon Ocuphire's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: (i) the success and timing of regulatory submissions and pre-clinical and clinical trials, including enrollment and data readouts; (ii) regulatory requirements or developments; (iii) changes to clinical trial designs and regulatory pathways; (iv) changes in capital resource requirements; (v) risks related to the inability of Ocuphire to obtain sufficient additional capital to continue to advance its product candidates and its preclinical programs; (vi) legislative, regulatory, political and economic developments, (vii) changes in market opportunities, (viii) the effects of COVID-19 on clinical programs and business operations, (ix) the success and timing of commercialization of any of Ocuphire's product candidates and (x) the maintenance of Ocuphire's intellectual property rights. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive and should be read in conjunction with statements that are included herein and elsewhere, including the risk factors detailed in documents that have been and may be filed by Ocuphire from time to time with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Ocuphire undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Contact:

Corporate

Mina Sooch

President & CEO

Ocuphire Pharma, Inc.

E: ir@ocuphire.com

WEB: http://www.ocuphire.com

Investors

Corey Davis, Ph.D.

LifeSci Advisors

E: cdavis@lifesciadvisors.com

Continued here:

Ocuphire Extends U.S. Patent Protection for Late-Stage Drug Candidate Nyxol for Reversal of Mydriasis by Five More Years into 2039 with New Patent...

1Manchester Royal Eye Hospital, Manchester, UK; 2Centre for Ophthalmology and Vision Sciences, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

Correspondence: Andrew Walkden, Manchester Royal Eye Hospital, Oxford Road, Manchester, Greater Manchester, M13 9WL, UK, Tel +44 161-276-1234, Email [emailprotected]

Purpose: The COVID-19 pandemic has led to drastic changes to the daily lives of those living in the United Kingdom. We hypothesized that the effect of the imposed lockdown on both behaviour and social interaction has the potential to influence the characteristics of microbial keratitis presenting locally to Manchester Royal Eye Hospital a major tertiary eye centre in the UK.Methods: We conducted a retrospective case-note review of all positive corneal scrape cultures identified by our local microbiology laboratory during the year since the announcement of lockdown measures in the UK (23 March 2020 to 23 March 2021). Culture results were compared with previously collated, published baseline data from prior to the onset of the COVID-19 pandemic (2004 2019). Statistical analysis was undertaken, predominantly looking at the incidence of microbial keratitis and the variety of cultured pathogens.Results: A total of 6243 corneal scrape results were reviewed. Comparison of data between the COVID-19 pandemic and subsequent lockdown did not show a significant change in the incidence of culture-positive microbial keratitis: mean annual positive samples during 2004 2019 were 128 (35%) vs 91 (29%) during lockdown (P=0.096). No statistically significant shifts in the incidence of organism subtypes fungi, acanthamoeba, Gram-positive bacteria, or Gram negative bacteria were identified (P=0.196, 1, 0.366, and 0.087, respectively).Conclusion: Contrary to our hypothesis, our results suggest that the COVID-19 pandemic did not alter the incidence or characteristics of microbial keratitis presenting to Manchester Royal Eye Hospital in the year following the implementation of lockdown measures in the UK.

Microbial keratitis is a condition encountered across the world that can lead to irreversible sight loss.1 The incidence of the condition and causative microbes have been shown to have geographic and seasonal variation as a result of differing risk factors across regions.2,3 Previously identified risk factors include socioeconomic status, contact lens wear and hygiene practices, trauma, recent surgery, and a compromised ocular surface.4,5 Environmental factors, such as humidity, climate, and pathogenic environments, have also been shown to play a role.69

As the COVID-19 pandemic evolves and with the near-global enforcement of measures to curb the spread of the SARS-COV-2 virus, the behaviours and activities of the general population have drastically changed. Lockdown measures and social distancing were introduced in the UK on 23 March 2020 with the aim of reducing contact between humans and to limit transmission of the virus. This strategy is widely accepted by multiple international bodies to be the most effective strategy in limiting virus transmission.10

One of the most significant measures in place to deter the spread of this airborne virus is the use of face masks to limit and capture the spread of infective respiratory droplets. In the earlier stages of the pandemic, it was hypothesized that face masks may redirect expiratory airflow upwards towards the eyes, resulting in dispersion of oral flora onto the ocular surface and increasing the risk of post-intravitreal injection endophthalmitis. Patel et al recently published a large multicentre retrospective study of 505,968 intravitreal injections performed in the US that did not suggest that patient face-mask use influenced the rate of presumed acute-onset bacterial endophthalmitis (OR 0.74, 95% CI 0.511.19; P=0.097), but in fact reduced the rate of culture-positive endophthalmitis (OR 0.46, 95% CI 0.220.99; P=0.041).11 As the incidence of oral florarelated endophthalmitis is overall an extremely rare event, despite this studys large sample, the authors concluded that the study was underpowered and unable to demonstrate an effect of patient mask use on the incidence of oral floraassociated endophthalmitis.11 Consequently, an association between mask use and oral florarelated endophthalmitis and other ocular infections, such as microbial keratitis, remains unestablished.

Beyond mask use, we also hypothesized that other behavioural factors related to the pandemic may have played a role in affecting patients ocular surfaces and their exposure to pathogens. These included: infection-prevention measures, social distancing, social isolation, handwashing, disinfection protocols, widespread use of alcohol hand gels, change in lifestyle, indoor living, less traffic-related pollution, less contact lens wear at home, and increased screen time whilst working from home. The aim of this study was to assess what impact the COVID-19 pandemic has had on the incidence and characteristics of microbial keratitis presenting to Manchester Royal Eye hospital a major tertiary eye hospital in the UK.

Using the NHS Health Research Authority decision tool for ethics approval, this study was deemed not to require any ethics approval, as it employed anonymous unidentifiable retrospective patient data that was not generalisable and the study protocol did not involve any deviation from the expected standard of patient care.

Data were collected in the form of all corneal scrape specimens sampled in the year from the UK commencing its first national lockdown (23 March 2020). This period will be referred to as lockdown in the remainder of the text. Data were retrieved using our microbiology laboratorys established electronic database, and included date of the scrape with culture results and antimicrobial sensitivities. Equivalent data for 20042019 were also retrieved to use as our comparison control. Scrape data were categorised according to organism subtypes: fungi, acanthamoeba, and Gram-positive and Gram-negative bacteria.

Statistical analysis was performed using SPSS 25.0 and 2, two-sample t, and MannWhitney U tests between pre-COVID and post-COVID groups where applicable. P0.05 was considered statistically significant.

The methodology for corneal scrape specimen sampling was standardised as per departmental policy. This policy, as well as the microbiological methods utilised for organism identification and antibiotic-sensitivity testing at Manchester Royal Eye hospital, was described by Tan et al in 2017.12

A total of 6243 scrape results were included in this study. During the lockdown period, 312 scrapes were sent for analysis, with 91 (29%) producing a positive culture result. This is comparable with pre-lockdown figures of an average of 364 scrapes per annum with a culture-positive result of 128 (35%, P=0.096 using 2 testing (Table 1). We did note that there was a suggestion that the rate of positive scrape results was reduced, perhaps alluding to a decreased infection rate overall; however, these results did not achieve statistical significance. As such, the null hypothesis remains true, i.e., the incidence of microbial keratitis was not significantly influenced by the COVID-19 pandemic or measures implemented during the lockdown period. Table 2 shows the raw-data trends of scrape organisms grown from 2004 to the lockdown period. Table 3 compares the mean number of organism subtypes prior to lockdown and also during the lockdown period.

Table 1 Cross-tabulation of scrape positivity for pre-lockdown vs lockdown

Table 2 Data trends of scrape organisms 20042019 and for lockdown (2020)

Table 3 Mean number of keratitis subtypes prior to lockdown with number of cases during lockdown

The aim of this study was to assess the effect of the COVID-19 pandemic and the resultant national lockdown on the incidence and microbiological characteristics of microbial keratitis presenting to a major tertiary eye hospital in Manchester in the UK. Research in the early stages of the pandemic focused on identifying the systemic implications of a new virus. Whilst the literature suggests that dry eyes, conjunctivitis, keratitis and vein/cavernous sinus thrombosis, and other ocular pathology may be associated with COVID-19 infection, overall ocular morbidity from this viral infection is accepted to be minimal.1319

With the awareness of changing antimicrobial trends and contact lens usage, the authors have previously discussed the importance of understanding local pathogenic variations, with other units also examining their own data.3,12,2025 Large-scale societal and behavioural changes, such as social distancing and mask wearing, have the potential to have profound effects on certain diseases and can aid our understanding of disease pathogenesis. Our knowledge of the SARS-COV-2 virus is increasing as we see and treat more cases of the disease. However, the longer-term effects of the virus are likely to be more subtle, both in terms of any future morbidity from the disease itself but also the implications of trying to manage future waves of the pandemic, with long-term mask usage likely to continue for the foreseeable future.

With the widespread introduction of infection-prevention protocols and the enforced usage of personal protective equipment, reports regarding the increased incidence of dry-eye symptoms started to emerge from the literature.13,2629 It has been postulated that personal protective equipment and mask use may lead to a compromised tear film as a result of increased evaporation or even mechanical processes that lead to malposition of the eyelids, e.g., mask tape leading to ectropion, in addition to altered airflow surrounding the periocular area.26,29 A compromised tear film is known to result in reduced precorneal tear-film corneal coverage and epithelial microbreaks, which can increase the risk of ocular infections due to a reduction in the innate host ability of pathogen clearance when in contact with the ocular surface.26,30 Exacerbations in dermatological conditions in health-care workers and the general population have also been reported.31 Rosacea and other facial manifestations of dermatological disease are known to influence the ocular surface.32 The above theories led us to our hypothesis that COVID-19 or associated change in behaviours in our local population may have influenced the local incidence and characteristics of microbial keratitis.

Tan et al conducted a 12-year analysis of microbial keratitis presenting to Manchester Royal Eye Hospital.12 To the authors knowledge, this is the largest study of microbial keratitis trends in the UK to date.2225 Using an expanded dataset, we did not find any particular deviation from the baseline incidence of organisms when compared with those encountered during the lockdown period. We do however note that there are potential flaws with our statistical methodology, although conclusions may still be drawn from the results. This is in part due to the necessity to compare an average of 16 years worth of data with that of only 1 year of lockdown data. As this was a real-world study, examining a real world pandemic scenario, this is impossible to avoid. It is thus important to continue to examine the microbial trends, as continued mask wearing and social distancing may well play an evolving role into the future. As such, when comparing the statistical means from the pre-lockdown data to the results of the lockdown period, one does note that the values for the lockdown dataset are lower in numbers for all cases, particularly notable for the fungal keratitis subset. This may thus be unmasking an inherent and unavoidable type 2 error, which could only be corrected were the pandemic to continue in its current form for several years longer which, hopefully for everyone involved, will not happen.

Another limitation of this study was the inability to directly identify any causative factors that may influence the incidence and characteristics of microbial keratitis. One accepted limitation of our large sample is the lack of patient demographic data. The primary aim of this paper was to look at the causative pathogens of the microbial infections, rather than specific patient demographics. This has been done in detail for specific pathogens in other publications.21 Further to this, we note that the COVID-19 status of patients producing positive culture results was not assessed. Given the COVID-19 protocols at our hospital, only patients admitted for severe keratitis received a COVID-19 PCR test. We encouraged as many patients as possible to be treated on an outpatient basis, resulting in these patients not having their COVID-19 status assessed. These data are thus unobtainable. Whilst all our inpatients were screened as negative for COVID-19 (n=13), the selection bias of screening out milder presentations of keratitis does not allow for any further reliable and generalizable conclusions. Multiple factors may influence the annual incidence of microbial keratitis, and thus we opted to use a 16-year (as far as our electronic microbiological records extend) control period to allow for any expected annual confounding factors that may have influenced trends in keratitis rates.12

Lockdown measures in the UK were linked with a marked decrease in emergency department presentations.33 This effect was also identified in our own eye emergency department.34 This raised the concern that patients requiring urgent treatment for ocular conditions, such as microbial keratitis, may not seek appropriate urgent care.35 Sight-threatening conditions, such as retinal detachment, were found to be reduced compared to pre-lockdown figures.34 We are somewhat reassured that there was no significant fluctuation in the number of corneal scrape samples, suggesting that the number of presentations of microbial keratitis has not reduced dramatically, although the painful nature of the condition is likely to play a part in ensuring patients present to ophthalmic services, which may well be the determining factor for why patients present to the emergency department ahead of other painless forms of sight loss. A non-significant decrease in the incidence of samples for microbial keratitis may suggest that patients with milder infections have been able to access and receive treatment by other health-care providers specifically set up as part of the NHS response to the pandemic.36 Another potentially confounding factor may be that measures introduced in order to reduce patientdoctor contact time may have resulted in some less severe cases not receiving microbiological sampling. However, despite this, the standard protocol within our unit is to sample any ulcer with an associated infiltrate >1 mm in size. This may have inherently screened out more mild cases that were not sampled.

With all of the aforementioned being considered, our dataset would suggest that the use of widespread infection-prevention measures have not had a negative impact on our local populations corneal health. Whilst the results are not generalizable, these findings could be used to inform infection-control measures and protocols for patients with microbial keratitis presenting to similar tertiary ophthalmic services in the UK. Our local arrangements for the delivery of emergency eye care for microbial keratitis, infection-prevention practices, and encouraging changes in behaviour of our local population do not appear to have significantly affected the incidence or characteristics of microbial keratitis. We would encourage other units to assess their local incidence and characteristics of microbial keratitis so that the full impact of infection-prevention protocols on ocular health can be ascertained.

In conclusion, this retrospective study reviewed and compared all corneal scrapes undertaken at Manchester Royal Eye Hospital between 2004 and until 1 year following the enforcement of lockdown measures in the UK. We analysed the rates of culture-positive cases of infectious keratitis and characterised infections into subgroups. Overall, no statistically significant differences were identified in the incidence of microbial keratitis or the rates of causative pathogens. We did note that there was perhaps a small trend towards a reduced incidence of cases, in particular in the fungal subgroup. However, given data limitations and multiple confounding variables, the significance of this is uncertain. It is our hope that these findings may be useful in informing ophthalmic health-care providers assessing and treating patients with microbial keratitis in their own local populations and that it adds to an emerging body of evidence as we continue to recover from the COVID-19 pandemic.

No funding was received for this work from any sources.

None of the authors has any competing interests or affiliations.

1. Green MD, Apel AJ, Naduvilath T, Stapleton FJ. Clinical outcomes of keratitis. Clin Exp Ophthalmol. 2007;35(5):421426. doi:10.1111/j.1442-9071.2007.01511.x

2. Shah A, Sachdev A, Coggon D, Hossain P. Geographic variations in microbial keratitis: an analysis of the peer-reviewed literature. Br J Ophthalmol. 2011;95(6):762767. doi:10.1136/bjo.2009.169607

3. Walkden A, Fullwood C, Tan SZ, et al. Association between season, temperature and causative organism in microbial keratitis in the UK. Cornea. 2018;37(12):15551560. doi:10.1097/ICO.0000000000001748

4. Green M, Apel A, Stapleton F. Risk factors and causative organisms in microbial keratitis. Cornea. 2008;27(1):2227. doi:10.1097/ICO.0b013e318156caf2

5. Keay L, Edwards K, Naduvilath T, et al. Microbial keratitis predisposing factors and morbidity. Ophthalmology. 2006;113(1):109116. doi:10.1016/j.ophtha.2005.08.013

6. Houang E, Lam D, Fan D, Seal D. Microbial keratitis in Hong Kong: relationship to climate, environment and contact-lens disinfection. Trans R Soc Trop Med Hyg. 2001;95(4):361367. doi:10.1016/S0035-9203(01)90180-4

7. Green M, Apel A, Stapleton F. A longitudinal study of trends in keratitis in Australia. Cornea. 2008;27(1):3339. doi:10.1097/ICO.0b013e318156cb1f

8. Ni N, Nam EM, Hammersmith KM, et al. Seasonal, geographic, and antimicrobial resistance patterns in microbial keratitis: 4-year experience in eastern Pennsylvania. Cornea. 2015;34(3):296302. doi:10.1097/ICO.0000000000000352

9. Lin CC, Lalitha P, Srinivasan M, et al. Seasonal trends of microbial keratitis in south India. Cornea. 2012;31(10):11231127. doi:10.1097/ICO.0b013e31825694d3

10. HM Government. Social distancing review: report. HM Government; 2021.

11. Patel SN, Tang PH, Storey PP, et al. The influence of universal face mask use on endophthalmitis risk after intravitreal anti-VEGF injections during the COVID-19 pandemic. Ophthalmology. 2021;18:45.

12. Tan SZ, Walkden A, Au L, et al. Twelve-year analysis of microbial keratitis trends at a UK tertiary hospital. Eye. 2017;31(8):12291236. doi:10.1038/eye.2017.55

13. Chen L, Deng C, Chen X, et al. Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China: a cross-sectional study. Acta Ophthalmol. 2020;98(8):e951e959. doi:10.1111/aos.14472

14. Nasiri N, Sharifi H, Bazrafshan A, Noori A, Karamouzian M, Sharifi A. Ocular manifestations of COVID-19: a systematic review and meta-analysis. J Ophthalmic Vis Res. 2021;16(1):103112. doi:10.18502/jovr.v16i1.8256

15. Siedlecki J, Brantl V, Schworm B, et al. COVID-19: ophthalmological aspects of the SARS-CoV 2 global pandemic. Klin Monbl Augenheilkd. 2020;237(5):675680. doi:10.1055/a-1164-9381

16. Bertoli F, Veritti D, Danese C, et al. Ocular findings in COVID-19 patients: a review of direct manifestations and indirect effects on the eye. J Ophthalmol. 2020;2020:e4827304. doi:10.1155/2020/4827304

17. Douglas KAA, Douglas VP, Moschos MM. Ocular manifestations of COVID-19 (SARS-CoV-2): a critical review of current literature. In Vivo (Brooklyn). 2020;34(3 Suppl):16191628. doi:10.21873/invivo.11952

18. Sen M, Honavar SG, Sharma N, Sachdev MS. COVID-19 and eye: a review of ophthalmic manifestations of COVID-19. Indian J Ophthalmol. 2021;69(3):488509. doi:10.4103/ijo.IJO_297_21

19. Hu K, Patel J, Swiston C, Patel BC. Ophthalmic Manifestations of Coronavirus (COVID-19). StatPearls Treasure Island (FL): StatPearls Publishing; 2021.

20. Griffin B, Walkden A, Okonkwo A, Au L, Brahma A, Carley F. Microbial keratitis in corneal transplants: a 12-year analysis. Clin Ophthalmol. 2020;14:35913597. doi:10.2147/OPTH.S275067

21. Zafar H, Tan SZ, Walkden A, et al. Clinical characteristics and outcomes of moraxella keratitis. Cornea. 2018;37(12):15511554. doi:10.1097/ICO.0000000000001749

22. Ting DSJ, Settle C, Morgan SJ, Baylis O, Ghosh S. A 10-year analysis of microbiological profiles of microbial keratitis: the North East England Study. Eye. 2018;32(8):14161417. doi:10.1038/s41433-018-0085-4

23. Tavassoli S, Nayar G, Darcy K, et al. An 11-year analysis of microbial keratitis in the South West of England using brain-heart infusion broth. Eye. 2019;33(10):16191625. doi:10.1038/s41433-019-0463-6

24. Orlans HO, Hornby SJ, Bowler IC. In vitro antibiotic susceptibility patterns of bacterial keratitis isolates in Oxford, UK: a 10-year review. Eye. 2011;25(4):489493. doi:10.1038/eye.2010.231

25. Henry CR, Flynn HW, Miller D, Forster RK, Alfonso EC. Infectious Keratitis progressing to endophthalmitis: a 15-year study of microbiology, associated factors, and clinical outcomes. Ophthalmology. 2012;119(12):24432449. doi:10.1016/j.ophtha.2012.06.030

26. Moshirfar M, West WB, Marx DP. Face mask-associated ocular irritation and dryness. Ophthalmol Ther. 2020;9(3):397400. doi:10.1007/s40123-020-00282-6

27. Hong N, Yu W, Xia J, Shen Y, Yap M, Han W. Evaluation of ocular symptoms and tropism of SARSCoV2 in patients confirmed with COVID19. Acta ophthalmologica. 2020;98(5):e649e655.

28. Wu P, Duan F, Luo C, et al. Characteristics of ocular findings of patients with coronavirus disease 2019 (COVID-19) in Hubei Province, China. JAMA Ophthalmol. 2020;138(5):575578. doi:10.1001/jamaophthalmol.2020.1291

29. Chadwick O, Lockington D. Addressing post-operative Mask-Associated Dry Eye (MADE). Eye. 2020;35(6):15431544. doi:10.1038/s41433-020-01280-5

30. Bhargava R. Contact lens use at the time of SARS-CoV-2 pandemic for healthcare workers. Indian J Med Res. 2020;151(5):392394. doi:10.4103/ijmr.IJMR_1492_20

31. Damiani G, Gironi LC, Grada A, et al. COVID-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): multi-center, real-life, telemedical, and observational prospective study. Dermatol Ther. 2021;34(2):e14848. doi:10.1111/dth.14848

32. Stone DU, Chodosh J. Ocular rosacea: an update on pathogenesis and therapy. Curr Opin Ophthalmol. 2004;15(6):499502. doi:10.1097/01.icu.0000143683.14738.76

33. Thornton J. Covid-19: a&E visits in England fall by 25% in week after lockdown. BMJ. 2020;369:m1401. doi:10.1136/bmj.m1401

34. Young JF, Harron KL, Bilal L, Richardson JAL, Dhawahir-Scala FE. The effect of lockdown due to COVID-19 on a large emergency eye department: the manchester experience. J Clin Exp Ophthalmol. 2020;11(6):43.

35. Power B, Donnelly A, Murphy C, Fulcher T, Power W. Presentation of infectious keratitis to ED during COVID-19 lockdown. J Ophthalmol. 2021;2021:14. doi:10.1155/2021/5514055

36. Kanabar R, Craven W, Wilson H, et al. Evaluation of the manchester COVID-19 Urgent Eyecare Service (CUES). Eye. 2021;4:19.

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Impact of the COVID-19 Pandemic on the Incidence and Characteristics o | OPTH - Dove Medical Press

Introduction

Gene therapy has become an emerging treatment modality for both inherited and acquired diseases. Therapeutic genes can be delivered into the nuclei of target cells via viral and non-viral vectors. The viral vector approach utilizes the natural ability of viruses to infect human cell genomes. Viral pathologic genetic sequences are replaced by the desired therapeutic genes, and target cells are then infected with the modified viruses leading to incorporation of the therapeutic material into the nuclei. The non-viral vector approach uses different chemical and physical methods to deliver the therapeutic genetic material.1

While gene therapy is used to treat inherited diseases with loss of function mutations, it can also be used to treat acquired diseases. Target cells are infected with therapeutic genes which encode for specific drugs, so that the infected cells can produce the desired drugs in vivo.2 This concept has considerable potential; patients can be treated once, and their tissues are transformed into bio-factories that produce the medications indefinitely.

The eye is considered a good candidate for gene therapy; it is small and compartmentalized, requires relatively small numbers of vectors/gene copies, and has special immune response features that can favor viral-mediated gene therapy.3 Gene therapy for ocular diseases has already been approved by the United States Food and Drug Administration (FDA) to treat pediatric patients with Leber congenital amaurosis harboring a particular gene deficiency, named RPE65.4 Multiple promising clinical trials are currently being conducted for many other ocular diseases, described below.

Similar to every novel approach, gene therapy has its own set of challenges. Insertional oncogenesis, an inadvertent activation of oncogenes by insertion of transduced genetic material near proto-oncogenes, is a potential limiting factor.5 The irreversibility and unpredictable longevity of gene therapy effects highlights the lack of control once the treatment is administered.6

Different vector types and subtypes induce variable immune and inflammatory responses. These responses can nullify the effect of gene therapy or prevent repeated therapy in the same patient. In addition, different modes of delivery, whether intravitreal, subretinal or suprachoroidal, induce variable immune and inflammatory reactions. Given the etiological complexity of these responses and their detrimental effect on gene therapy efficacy, many studies have tried to analyze the factors that influence these responses.

Recently available data from clinical trials have shown that ocular gene therapy has been associated with severe ocular inflammation with resultant vision loss. Therefore, in this review, we would like to discuss ocular gene therapy with special focus on the resultant immune and inflammatory reactions in the light of the recent updates.

Viral vectors that are used for ocular gene therapy include adenovirus (AV), adeno-associated virus (AAV), and lentivirus. Non-viral vectors utilize different chemical and physical methods to deliver naked genetic material into the cells.1

Adenovirus is a double-stranded deoxyribonucleic acid (DNA) virus that can efficiently transduce dividing and non-dividing cells. It can induce a high amount of protein production by inserting numerous copies of the same gene into a cell.7 Adenovirus offers multiple advantages, including broad range of tissue tropism (transduction of both retina and anterior segment), a well-characterized genome, ease of genetic manipulation, capacity of carrying large genes, non-replicative nature in a host, and producibility at a large scale.3,7

Although adenovirus was the first vector to be evaluated in clinical trials, it is not currently used in ocular gene therapy clinical trials except for one trial studying retinoblastoma. Adenovirus has fallen out of favor due to the resulting robust immune response that causes inflammation and elimination of the transduced cells.8 Severe side effects have been reported using adenovirus, as severe as death of a patient with systemic fever and liver damage in a clinical trial for metabolic disease.9 Although it does not usually replicate inside hosts, a replication-competent virus can be inadvertently created by combination of adenoviral derived vectors with pre-existing adenoviral genome in the targeted cells, causing active systemic adenoviral infection in the patient.10

Adeno-associated virus (AAV) is the most commonly used vector for ocular gene therapy trials. AAV is a small (25 nm), replication defective, single-stranded DNA, non-enveloped virus belonging to the Parvoviridae family. It has been evaluated as a gene therapy vector for metabolic, hematological, ophthalmological, muscular, infectious disorders, and cancers.11 Currently, 13 different AAV serotypes have been identified in primates. They differ in their capsid components and display variable cellular tropism, transduction efficiency, and immunogenicity.7

Bennett et al have reported that AAV2 and AAV8 can infect retinal cells from the vitreous, but it was limited to the inner retina.12 AAV2 has also been used effectively through a subretinal injection to transduce retinal pigment epithelium (RPE) in a number of gene therapy trials and animal models.3,4 For AAV8, subretinal delivery leads to efficient photoreceptor transduction.13,14 AAV2 is commonly used in ocular gene therapy trials and is the vector used in the first FDA-approved ocular gene therapy voretigene neparvovec-rzyl (Luxturna) for Leber congenital amaurosis.4

AAVs deliver the genetic material as an extragenomic circular episome and do not integrate it into the human genome. This mechanism significantly decreases the risk of insertional oncogenesis. Similar to adenovirus, AAVs can also infect dividing and non-dividing cells.15,16 AAVs limited capacity to carry large-sized genetic material restricts their use in gene delivery for some diseases that are coded by large genes such as Usher syndrome.17

Unlike adenoviruses, AAVs generate relatively mild innate and adaptive immune responses, which allow for stable long-term transgene expression.13,15,18,19 These characteristics make AAV vectors particularly suited for applications in a variety of chronic ocular diseases.

Around 70% of the normal population have preexisting antibodies (Abs) against AAV2. On the other hand, AAV8 was isolated from non-human primates (NHPs). Therefore, there is a lower percentage of humans with Abs against it (around 38%).20 The presence of antiviral Abs has been correlated with minimal or absent gene expression following gene therapy.21 Thus, the use of AAV8-based vector therapy has the potential to be more effective than AAV2. However, there is still cross-reactivity of anti-AAV Abs against different serotypes.21

AAVs can be rapidly eliminated by the humoral immune response in patients who have previously been exposed to the virus.22 The immune reactions include induction of neutralizing antibodies that reduce the number of capsids reaching the target cells, innate immune pathways silencing the gene cassette within the host cell, and cell-mediated T-cell immune responses against foreign protein expression.18

Lentivirus is a complex, single-stranded ribonucleic acid (RNA) retrovirus that has been studied as a vector. Similar to the two previous vectors, it possesses the ability to induce a stable transduction in both dividing and non-dividing cells in a broad range of target organs.23 Lentiviral vectors are derived from primate lentiviruses human immunodeficiency virus (HIV), equine infectious anemia virus (EIAV) and simian immunodeficiency virus.3 Lentiviruses integrate their complementary DNA (reverse-transcribed RNA) into the chromosome of target cells enabling sustained gene expression but, like all integrative systems, can increase the risk of insertional mutagenesis and oncogenesis.7,24 They can be manufactured in high numbers and their genome can be deleted to reduce the inflammatory response. They also have high transgene carrying capacity allowing delivery of large-sized therapeutic genes that cannot be packed into AAV vectors. Such viral composition is particularly useful for diseases with large causative genes such as Stargardt disease and Usher syndrome.22,25,26

Lentiviruses are possibly more immunogenic than AAVs.27 Binley et al found that 5 out of 6 non-human primates that were injected with EIAV in their subretinal space developed a peripheral perivascular retinal whitening. However, this whitening (which probably represented a form of intraocular inflammation) was transient and resolved with treatment.28 In general, multiple studies have shown that lentiviruses are relatively safe and can result in effective and sustained gene transduction for a significant time.2830

Non-viral vectors were developed as an alternative to viral vectors to avoid their associated immune responses. Non-viral vectors are used to transfer large DNA-like plasmids, small DNA (eg, oligodeoxynucleotides), and RNA molecules through different chemical and physical methods.31

Chemical methods include lipid-based delivery systems, polymers, and cell-penetrating peptides. They form nano-complexes with the genetic material that can either penetrate the cell membrane or be endocytosed. These complexes also protect genetic material from premature degradation. Nanoparticles carrying genetic material have been shown to effectively transduce the outer retina if injected subretinally.6,32

Physical methods are more variable and technically utilize different approaches to facilitate the genetic materials delivery into the cells. Examples are electrical pulses, ultrasound, magnetic fields, gene guns, and lasers. High voltage short electrical pulses (electrotransfection) are highly efficient in transducing the ciliary body to produce the desired drug autonomously.6,32,33

The main advantages of non-viral methods include the lower risk of immune stimulation and insertional mutagenesis (as most do not integrate with chromosomes), the ability to deliver a large amount of genetic materials, and the ease of production. Short-term expression of the transduced genetic material can be considered as a major disadvantage of this method.6,32

The eye constitutes an excellent site for gene therapy due to its anatomy, ease of access, immune-privileged state, which limits the immune responses and inflammatory reactions against the delivered genetic product, and tight blood-ocular barriers that limit the systemic exposure of the drug. Its relatively small size also grants a minor volume of drug to have effective results. In addition, the assessment of treatment implications can be performed non-invasively via diagnostic imaging, and the second eye can be used as a control group.34 Several studies are focusing on possible gene therapies for an array of ocular diseases from the cornea to the retina. A summary of completed and/or current ocular gene therapy clinical trials can be found in Table 1.

Gene therapy has been studied as a potential treatment option for both inherited and non-inherited corneal diseases. Examples of studied non inherited diseases for gene therapy were Herpes simplex keratitis (HSK), dry eye Sjogrens syndrome (SS), corneal graft rejection, and corneal neovascularization.35 Mucopolysaccharidosis (MPS), Meesmann epithelial corneal dystrophy, ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome, aniridia, and Fuchs endothelial corneal dystrophy are among the inherited diseases where corneal gene therapy is applied in several animal studies.35

As 72% of the cases with primary open-angle glaucoma are hereditary and there is a monogenic inheritance component in juvenile-onset open-angle glaucoma, gene therapy may be beneficial.36 Preclinical and Phase I studies have shown that gene therapy using small interference RNA (siRNA) that suppresses 2-adrenergic-receptor synthesis, via topical drops, might be effective in lowering intraocular pressure (IOP) in glaucoma patients. Phase II studies have also been conducted.3739

Because the retina is fragile in patients with X-linked Retinoschisis XLRS, the risk for subsequent retinal detachments increases following gene therapy if performed via the subretinal route. Therefore, the intravitreal route is preferred for the transfer of vectors in this condition.40 There are currently two clinical trials in which the AAV vector expressing RS1 gene is delivered intravitreally to XLRS patients. The preliminary results were reported that the gene product was well tolerated, and ocular adverse events, including dose-related inflammation, resolved using topical and oral corticosteroids.41

Stargardt disease is caused by ABCA4 mutations leading to accumulation of lipofuscin pigment inside the RPE causing degeneration of both RPE and photoreceptor cells.42 A phase I/II clinical trial investigated the utility of EIAV-vector carrying the ABCA4 gene that is delivered through the subretinal route, but it was terminated in 2015.43 Other clinical trials for Stargardt Disease are being planned.

Choroideremia occurs secondary to a mutation in the CHM gene leading to progressive RPE and photoreceptor cell death.44 There are some challenges for gene therapy in choroideremia, including insufficient resemblance of animal models to functional and morphological manifestations of the disease, and uncertainty of which retinal layer is affected most.45,46 Gene therapy outcomes for choroideremia have been less successful than RPE65-related Leber congenital amaurosis (LCA).47 There are currently nine clinical trials registered on ClinicalTrials.gov evaluating interventional gene therapies for these patients all of which use AAV vectors. Only one of them uses the intravitreal route, and the remaining eight deliver the drug subretinally.

Retinitis Pigmentosa (RP) is a heterogeneous disease, and it occurs in an autosomal recessive (AR) pattern in 5060% of the cases.48 The most common genes include RPGR (retinitis pigmentosa GTPase regulator) which accounts for ~70% of X-linked RP; rhodopsin (RHO) which causes ~25% of AD RP, and the Usherin2A (USH2A) gene that is linked to approximately 20% of AR RP.49 Currently, there are multiple clinical trials assessing different viral and non-viral vectors, through intravitreal and subretinal injections, for different types of RP.

A novel approach, which is described as optogenetic therapy, is also under investigation for retinitis pigmentosa. It is based on delivering genetic information that codes for light sensitive proteins to non-photoreceptor retinal neurons such as ganglion cells, rendering them sensitive to light stimulation and hence, bypassing the photoreceptors. This approach has the potential to improve visual perception in cases of RP and other inherited retinal diseases where the photoreceptors are severely damaged.50

Usher syndrome displays AR inheritance with different large-sized causative genes, including MYO7A, USH2A and GPR98. Similar to Stargardt disease, lentiviruses are required to deliver the large-sized genetic material.51,52 A single clinical trial was conducted for Usher syndrome with a mutation in MYO7A gene using a lentivirus vector through a subretinal injection, but it was terminated.53 Recently, a promising phase I/II clinical trial was initiated to evaluate the safety and tolerability of an intravitreal RNA antisense oligonucleotide for Usher syndrome.54

For achromatopsia, there are six different gene mutations (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) of which CNGA3 and CNGB3 are the most common.55 Clinical trials are being conducted targeting these two genes with an AAV vector through subretinal injection.

Leber congenital amaurosis (LCA) is an AR disease with mutations in numerous genes. LCA2 occurs specifically due to RPE65 gene mutations, a gene expressed highly in RPE cells. Despite the significant visual impairment in LCA, retinal cells and photoreceptors are relatively spared.56 Therefore, RPE65-mediated LCA has shown to be a favorable candidate for ocular gene therapy as it requires a certain amount of viable cells to be effective. The FDA approved the first gene therapy for ocular disease following the Phase III clinical trial of AAV2-hRPE65v2 (voretigene neparvovec, Luxturna) that evaluated the efficacy and safety of bilateral sequential subretinal injections to both eyes in patients with LCA.4

The trial with voretigene neparvovec involved 29 pediatric patients older than 3 years with LCA and visual acuity of 20/60 or less. Participants were randomized (2:1) to intervention or control groups. The results of this trial have demonstrated that voretigene neparvovec ameliorated functional vision in RPE65-mediated LCA, and there were no treatment-related serious adverse events. Mild ocular inflammation was reported in only two patients (10%) which was resolved. The authors did not provide details regarding how the ocular inflammation was managed.4

Different vector therapy trials are being conducted for both non-neovascular and neovascular AMD. The safety of subretinally delivered lentiviral EIAV vector expressing endostatin and angiostatin for neovascular AMD has been established with well-tolerated doses, no dose-limiting toxicities, and little to no ocular inflammation.30 Intravitreal injection of AAV carrying aflibercept gene has also shown very promising results in controlling neovascular AMD disease activity.57 Additional studies are being conducted to confirm the potential role and utility of vector therapy, via various approaches, including subretinal, intravitreal, and suprachoroidal delivery, in the management of AMD.

Suprachoroidal delivery of an AAV vector carrying an anti-vascular endothelial growth factor (anti-VEGF) fab segment is being evaluated for diabetic retinopathy without central involving macular edema in a phase I clinical trial.58 A clinical trial is also evaluating an intravitreally delivered AAV vector coding for aflibercept for diabetic macular edema.59

Leber hereditary optic neuropathy (LHON), an inherited mitochondrial optic neuropathy related to retinal ganglion cell death, is most commonly linked to ND1 (G3460A), ND4 (G11778A), and ND6 (T14484C) gene mutations.60 As delivering genes into the ganglion cell mitochondria is difficult, allotopic expression strategy (mitochondrial gene expression in nucleus) has been developed.61 Different trials have demonstrated the safety and efficacy of gene therapy using an AAV vector, delivered through an intravitreal route, for LHON.6264

Gene therapy can be administered into the eye via different ways such as intravitreal, subretinal, and suprachoroidal routes. Each mode of delivery has its own advantages and unique effects on how the immune system reacts to the vector, which in turn affects the phenotype of ocular inflammation. Different types of intraocular gene delivery are illustrated in Figure 1.

Figure 1 Images showing different methods of intraocular gene delivery: (A) intravitreal, (B) suprachoroidal, and (C) subretinal.

The intravitreal route is the traditional route used by ophthalmologists to deliver most intraocular medications into the eye, such as anti-vascular endothelial growth factors (anti-VEGFs), antibiotics, and steroids. The intravitreal route is a convenient choice; it can be administered in office settings and requires fewer instruments and equipment than the subretinal route. In addition, it is surgically simpler, less invasive, and generally safe. Also, this method is more logistically plausible due to its relative ease in delivery. Another advantage of intravitreal gene delivery is its theoretic ability to transduce the whole retinal surface, in contrast to the localized transduction induced by subretinal delivery. Such approach may be beneficial in cases where the targeted cells are not limited only to the macula.65,66

There are two main limitations of the intravitreal route: the inability to transduce outer retina layers and possible immune and inflammatory reaction. The outer retina is the main target of gene therapy for most retinal diseases. Most of the retinal genetic diseases are due to defects in the RPE or photoreceptor cells.67 Vectors delivered via the intravitreal route have limited ability to transduce the outer retina possibly due to the internal limiting membrane (ILM), evidenced by the improvement of outer retinal transduction after removing or degrading the ILM.68,69 However, other studies showed that some specially engineered vectors, via directed evolution, can transduce the outer retina after being injected intravitreally.65,70 If this result can be reproduced, it may revolutionize gene therapy.

Several reports showed that the vitreous cavity may be considered an immune-privileged space.7173 Yet, the intravitreal vector approach has still shown a different and distinct immune response from subretinal vector delivery.74 Studies on humans and NHPs have demonstrated consistently that intravitreal delivery of vectors induces a significant humoral immune response.13,21,75,76 The response is marked by the production of Abs, which may not lead to inflammation, but can significantly reduce the efficacy of treatment by attacking and eliminating transduced cells through the neutralizing antibodies. Intravitreal injection of one eye has also been shown to block vector expression in the contralateral eye when injected intravitreally with the same vector, due to the production of neutralizing Abs.75

Reichel et al directly compared the degree of inflammation between intravitreal and subretinal gene therapy.13 In their study, they found that the subretinal route caused more anterior and posterior segment inflammation than the intravitreal route, although the intravitreal route caused a stronger humoral response. The finding suggests that there might not be a clear association between intraocular inflammation and humoral response,77,78 which is further supported by the work of Bouquet et al79 who showed that neither baseline Abs nor the degree of immune response, defined by increased Ab titers, correlated with the degree of intraocular inflammation.

However, Cukras et al showed that antibody titers were correlated with the degree of inflammation.41 In this phase I/II clinical trial, patients were divided into low dose, intermediate dose, and high-dose groups. No patient in the low-dose group had a significant increase in their neutralizing Ab titers. Ab titers increased significantly in both intermediate and high-dose groups. In this study, anterior chamber inflammation correlated significantly with higher Ab levels. All patients of the high-dose group had high Abs titers for 18 months. It should be noted that, in this study, inflammation in all cases in this study was controlled by topical and oral steroids.

In the relatively recent INFINITY clinical trial that evaluated intravitreal AAV for diabetic macular edema (DME), late onset severe intraocular inflammation was observed. In this trial, patients were randomized to three groups: high virus dose (N=12), lower virus dose (N=13) and aflibercept (N=9) groups. Three patients in the high-dose group developed late onset significant inflammation including panuveitis, which resulted in hypotony. All three were treated with pars plana vitrectomy (PPV), silicone oil (SO) and Retisert implantation. None of the patients in the low dose or aflibercept groups developed hypotony. Most patients in both virus treatment groups developed some sort of intraocular inflammation that required difluprednate eye drops beyond a prophylactic post injection 10 weeks period. Most of the high-dose group required additional medications including steroids administered through multiple routes including oral, periocular, and intraocular. Two patients in the high-dose groups required mycophenolate therapy to further suppress intraocular inflammation. Around 50% of the low dose group required additional periocular or intravitreal steroid therapy.80

Interestingly, the same viral concentrations were administered in the Optic trial for AMD, but no hypotony developed and the reported intraocular inflammation was less frequent and less severe, and all incidences were successfully treated with topical steroids only.81 This clearly suggests a role of the underlying disease in the development of inflammation in addition to the route and dose. Inflammatory processes are known to be integral in the pathogenesis of diabetic retinopathy,82 and this might explain the difference in rates of intraocular inflammation between eyes with diabetic retinopathy and those with AMD, despite being treated with the same vector and concentration.

Subretinal vector delivery requires pars plana vitrectomy. After completion of the vitrectomy, a macular retinotomy is done via a small gauge cannula. Detachment of the macula is achieved by injecting balanced saline solution followed by vector injection in the preformed bleb.14,83

Using the subretinal approach to deliver vector therapy is well established as it has many advantages. It ensures transduction of outer retinal layers through direct vector delivery. The efficacy of transducing the outer retina by injecting vectors through this route has been reported extensively and consistently.4,14,29,8486 The subretinal space itself has a special immunological response, which will be discussed below. As mentioned previously, voretigene neparvovec, the only FDA approved ocular gene therapy, is delivered through this approach.

The main disadvantage of this approach is the surgery itself. Traditional vitrectomy complications such as cataract, IOP rise and retinal tears, as well as subretinal injection-related complications such as a macular hole.4,87,88 The technique itself requires significant surgical experience. Ochacovski et al89 have shown that subretinal injection, in NHPs, can cause mild thinning of the outer layers of the fovea in comparison with an intravitreal injection of the same vector.89,90 However, the difference was not clinically significant. Photoreceptor damage was also reported in the phase I trial for the same gene therapy.

The subretinal space is immune privileged and has a deviant immune response. Immune responses to antigens in this space can be similar to anterior chamber associated immune deviation (ACAID); immune responses are suppressed by activating T helper 2 cells.19,91,92 Many studies have shown minimal to absent humoral response to antigens delivered to this space.13,74,75 Furthermore, Anand et al reported suppression of pre-existing cellular immune response to certain antigens after injecting them into the subretinal space.19 Other studies also found that gene transduction was achievable if injected in the subretinal space even if the subjects have neutralizing antibodies.74,92 This beneficial immune response has raised the question of whether it is better not to use steroids with a subretinal injection, as this would theoretically negate the good suppressive nature of that deviant immune response.13,19

As mentioned above, few studies found that subretinal route can induce more inflammation compared to the intravitreal route.13,77,78 One may consider this secondary to the surgical technique itself rather than the immune response to the vector; however, Reichel et al showed that subretinal delivery of a vector caused more inflammation than just performing the same surgical procedure without injecting a vector.13 Nevertheless, to our knowledge, none of the studies that evaluated the subretinal gene delivery have reported devastating panuveitis with loss of vision similar to the above mentioned case that was associated with intravitreal delivery.

Another infrequent but potentially severe immune/inflammatory response to subretinal injection is the poorly understood phenomenon of intraretinal hyperreflective foci, found on optical coherence tomography, following subretinal injection which has been reported in several studies. It was reported at least in two human subjects in two different studies: one study had a subject who suffered from irreversible photoreceptor and vision loss despite steroid use, and another study demonstrated the adverse event in one subject but fortunately resolved following oral steroid treatment.14,93 It was also reported in NHPs, but resolved and the retina returned to baseline.13 To our knowledge, it has not been reported with voretigene neparvovec. It is possible that this reaction represents a unique side effect of a special type of vector, but it was reported with the use of both AAV2 and AAV8 subtypes, suggesting it may not be vector specific.

With both intravitreal and subretinal routes having their disadvantages, suprachoroidal route was studied to overcome these challenges. The suprachoroidal route is less invasive than the subretinal route. It also has the potential of a weaker immune response than the intravitreal route, leading to lower levels of produced antibodies.78 It can also deliver the vectors to the outer retina, which is a main limitation of the intravitreal route.78 This route is also being investigated for delivering non-viral vectors with promising results in animals.94

Different techniques are being used for suprachoroidal drug delivery. It can be done via a microcatheter,9597 hypodermic needle,98 or microneedles.99,100 Microcatheters require a sclerotomy that requires visualization with a surgical microscope. Cautious dissection of the sclera is done until the scleral-choroidal junction has been reached. The blunt-tipped catheter is then inserted and directed toward the posterior pole, using a light pulp at the tip of the catheter to aid in visualizing its position. The hypodermic needle technique requires merely inserting the needle at an oblique angle through the sclera until a release sensation is just felt. Because it is a somewhat blind procedure, it may lead to choroidal or retinal penetration. Another technique utilizes the microneedle which is a very short needle that is applied perpendicularly into the sclera. A large clinical trial employed this method with no serious side effects.99

Yiu et al have shown that humoral response to suprachoroidal gene therapy was weaker than the response to the intravitreal route, with levels of neutralizing Abs being significantly lower.78 To our knowledge, this is the only published study that compared antibody production between the two routes. Although the sample size was small, and the study was on NHPs, it is very encouraging. This study has also shown that suprachoroidal delivery was associated with widespread transduction of RPE cells, in contrast to the subretinal delivery in which the transduction is localized to the macular bleb.

However, there are issues with the suprachoroidal route as well. There are inconsistent reports about its efficacy in infecting photoreceptors. Two studies involving NHPs showed conflicting results in the efficacy of photoreceptor cell uptake.78,101 This may be due to the difference in AAVs capsid or promoter sequence, but further studies are needed. Studies on animals other than NHPs showed that the suprachoroidal route can be used effectively to infect photoreceptors.95,101 Another issue is the non-sustainability of gene expression via this route, which can be gradually diminished over 3 months.78 Such non-sustainability may be due to the high flow of the choroidal circulation, with a stronger immune response.

Safety of the suprachoroidal route is also an issue. Yiu et al had inadvertent subretinal injection twice by a microneedle when they changed the site of injection from 4 to 10 mm posterior to the limbus.78 Other human clinical trials did not report this adverse event.99,100

Inflammation can also occur secondary to the suprachoroidal route. Different degrees of posterior segment inflammation following delivery of the same antigen via intravitreal, subretinal, and suprachoroidal routes have been reported. While the intravitreal route did not cause significant posterior segment inflammation in the form of chorioretinitis, both suprachoroidal and subretinal routes elicited it.78 There has been no evidence of a deviant immune response in the suprachoroidal space.

The key differences between intravitreal, subretinal and suprachoroidal modes of delivery are listed in Table 2.

Table 2 Key Differences Between Different Types of Modes of Delivery of Gene Therapy

Electrotransfection is a non-viral gene therapy modality that uses high voltage short electrical pulses that increases cell membrane permeability to naked genetic material. To our knowledge, there are no published data regarding safety of electrotransfection in human eyes. In different studies performed on rabbits and rodents, there were no reported safety issues.33,102104 There were no histological or functional (electroretinogram) toxicities following electrotransfection. Postoperative inflammation could not be accurately assessed as the studies were done on animal models of intraocular inflammation. However, the studies demonstrated that electrotransfection was effective in decreasing ocular inflammation in these models.33,102104

Timmers et al have shown that the site of ocular inflammation following intravitreal injection varies according to the presence of the viral genome and/or capsid.16 They demonstrated that inflammation in the anterior segment is dependent on the presence of the genome while viral particles with no genome (empty capsids) did not induce an anterior segment reaction. Contrarily, both full viral particles and empty capsids induced vitreal inflammation. Empty capsids induced vitreal inflammation at a lower level than the full particles, implying that capsids induced vitreal inflammation only, while the genetic material induced inflammation in both anterior and posterior segments. The investigators also found that Abs were generated regardless of the presence of the genome, meaning that it is mainly generated by the capsid.

Pre-clinical and clinical studies have indicated that gene therapy with AAV can induce dose-dependent innate and adaptive immune responses. This was true in both subretinal and intravitreal deliveries, although the same viral dose induced lower immune responses when delivered via the subretinal route.91,105107 For example, Cukras et al found a dose-dependent response of ocular inflammation.41 They evaluated the safety of AAV8 as the vector for delivery of RS1 gene in patients with XLRS caused by RS1 gene mutations in a phase I/II an open-label clinical trial. They administered three increasing doses of 1109, 11010, and 11011 viral particle/eye of AAV8 to nine patients through intravitreal injections. The authors found that ocular inflammation was dose-dependent, but it resolved with administration of oral and topical corticosteroids. There was also a dose-dependent increase in the serum level of systemic antibodies against AAV8.

Another clinical trial on the safety and efficacy of subretinal AAV2 injection in patients with LCA with RPE65 gene deficiency showed comparable findings. Le Meur et al administered low (1.222 1010) or high (3.274.8 1010) viral genomes of AAV2 to nine patients.108 Although no clinical abnormality was observed, a mild increase in anterior chamber protein flare was seen, indicating ocular inflammation, in only three patients who received the highest dose. The inflammation was minimal and resolved with no consequences after 14 days with local and systemic steroids. In the aforementioned INFINITY trial, rates and severity of ocular inflammation were higher in the high-dose group. Three patients developed severe hypotony in the high dose (6 1011) group while none of the low dose (2 1011) group showed such complication. The OPTIC trial, which used the same vector type in neovascular AMD patients, did also show a dose dependent inflammatory response but much less in severity when compared with INFINITY trial, implying that the underlying disease should also be considered a factor when assessing the risk of inflammation.80,81,109

Few studies did not show this association between the inflammatory responses and the viral doses. In an open-label phase I/II randomized clinical trial, Bouquet et al79 assessed the link between immune response and intraocular inflammation in 15 patients diagnosed with ND4 LHON undergoing ocular gene therapy with rAAV2 vectors. The authors introduced four increasing doses of 9109, 31010, 91010, and 1.81011 viral genomes per eye through intravitreal injections. Following the injections, mild inflammatory reactions were noted in nearly all patients, regardless of the administered dose. Intensity of inflammation showed no correlation with dosage, and it was also not associated with baseline immune responses and antibody titers. Similarly, Guy et al evaluated the efficacy of AAV2 at two escalating doses of 5109and 2.461010 vector genomes in LHON patients.64 Their results indicated that only 14% of the eyes showed ocular inflammation over a one-year follow-up, which was not associated with vector dose. One can explain the absence of the dose dependent ocular inflammation in these studies by the small number of patients, which might not have been enough to detect the relationship.

As mentioned, Timmers et al16 found that the relationship between the dose and the inflammation may be dependent on the site of intraocular inflammation.16 No or weak correlation was found between the dose and degree of anterior segment inflammation (which was incited by the capsids only), while a strong correlation was noticed with vitreal inflammation (incited by both the genome and capsid).

Steroid administration through different routes has been shown control ocular inflammation following viral vector delivery in most cases. Many studies reported that the resultant ocular inflammation was mild, transient, and controlled by systemic or even topical steroid therapy.4,13,14,29,41,79,87 Such control was reported regardless of vector type/subtype or mode of delivery.

Russel et al used perioperative oral steroids at the dose of 1 mg/kg/day, up to 40 mg/day, as a prophylactic method against postoperative inflammation after subretinal delivery of AAV vector.4 In their study, only 10% of the patients developed mild transient inflammation, which resolved in all patients. Bouquet et al have not used perioperative steroids in their trial which involved an intravitreal injection of AAV vector.79 Most patients who developed postoperative vitreal inflammation were controlled by topical steroids. Oral steroids were used effectively in 2/11 patients who did not respond to topical therapy.

On the other hand, the results of the INFINITY trial clearly show that ocular inflammation following gene therapy does not always respond well to steroids. As mentioned before, some patients responded poorly to intravitreal steroids and required surgery as well as mycophenolate therapy to ameliorate the inflammation.

In such cases where ocular inflammation is significant and can lead to permanent visual loss, aggressive management with zero-tolerance to inflammation should be a rule of thumb to avoid vision threatening complications. It should be noted that the inflammation can develop lately up to 20 weeks following an initial inflammation-free period. Follow-up should be done with due diligence to avoid such late onset, devastating complication.

Gene therapy can be delivered via viral or non-viral vectors. The mode of delivery of gene therapy as well as the underlying ocular pathology influence the postoperative inflammatory and immune responses. While there is no clear evidence of weaker or less inflammatory reactions of the subretinal route when compared with the intravitreal one, immune responses with antibody formations are clearly stronger in the latter. The dose of delivered viral vectors plays a factor in the development of immune and inflammatory responses, and high dose viral vectors were associated with sight threatening ocular inflammation. In general, although the inflammation associated with gene therapy of all routes of delivery has proven to be usually mild and often controlled with steroid therapy, intravitreal route may be associated with late onset sight threatening inflammation.

Suprachoroidal delivery is a potentially simpler and safer approach to deliver gene therapy, but further studies need to determine how unique it is regarding the immune and inflammatory responses. Non-viral gene therapy is also potentially a safe alternative, but its use for inherited diseases can be limited by the short-term expression of transduced genetic materials.

AAV, adeno-associated virus; Ab, antibody; ACAID, anterior chamber associated immune deviation; AMD, age-related macular degeneration; Anti-VEGF, anti-vascular endothelial growth factor; AR, autosomal recessive; AV, adenovirus; DME, diabetic macular edema; DNA, double-stranded deoxyribonucleic acid; EEC, ectrodactyly-ectodermal dysplasia-clefting; EIAV, equine infectious anemia virus; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; IOP, intraocular pressure; LCA, Leber congenital amaurosis; LHON, Leber hereditary optic neuropathy; MPS, mucopolysaccharidosis; NHP, non-human primates; PPV, pars plana vitrectomy; RHO, rhodopsin; RNA, ribonucleic acid; RP, retinitis pigmentosa; RPE, retinal pigment epithelium; RPGR, retinitis pigmentosa GTPase regulator; siRNA, small interference RNA; SO, silicone oil; SS, Sjogrens syndrome; USH2A, Usherin2A; XLRS, X-linked retinoschisis.

There is no funding to report.

Diana Do reports grants from and consultancy for Regeneron during the conduct of the study and grants from and advisory board for Genentech outside the submitted work. Quan Dong Nguyen reports grants and personal fees from Genentech, Novartis, and Regeneron, and personal fees from Rezolute, outside the submitted work. The authors report no other potential conflicts of interest in relation to this work.

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Ocular Gene Therapy: Immune and Inflammatory Responses | OPTH - Dove Medical Press

MUNICH, Germany, April 06, 2022 (GLOBE NEWSWIRE) -- ViGeneron GmbH, a next-generation gene therapy company, today announced a target-specific strategic collaboration and option agreement with Regeneron Pharmaceuticals Inc. (Regeneron) to develop and commercialize a gene therapy product based on ViGenerons novel engineered recombinant adeno-associated virus vectors (vgAAVs) to treat an inherited retinal disease (IRD).

Under the terms of the research collaboration, Regeneron and ViGeneron will create and validate vgAAV-based therapeutic candidates for one undisclosed IRD target. ViGeneron receives an upfront payment and research funding. Regeneron has an option for an exclusive license to develop, commercialize and manufacture the vgAAV-based product for the specific target. ViGeneron is eligible to receive an option exercise fee, development and commercial milestone payments, plus royalties on net sales.

ViGenerons vgAAV vector platform is designed to overcome the limitations of existing adeno-associated virus (AAV)-based gene therapies. To date, therapeutically impactful targeting of photoreceptors relies on subretinal vector delivery, which harbors substantial risks of retinal detachment and collateral damage, often without achieving widespread photoreceptor transduction. vgAAV vectors could potentially enable the efficient transduction of target cells via intravitreal injection that allows lateral spreading and minimizes the risk of retinal detachment caused by conventional subretinal injection.

We are delighted to work with Regeneron to potentially provide an intravitreally delivered gene therapy for patients suffering from an inherited eye disease, said Dr. Caroline Man Xu, Co-founder and CEO of ViGeneron. This agreement with Regeneron further validates the potential of our vgAAV platform, which is excellent for us and also delivers a deal value that contributes financing for our platform and proprietary program development activities. Furthermore, it fits into our strategy of developing proprietary programs for selected retinal targets through clinical trials, while maximizing our technology platforms for additional collaboration programs in retinal diseases, CNS and other disease areas with bellwether biopharma. Our aim is to overcome the current limitations of gene therapy and to bring a novel therapeutic approach to patients in need, she added.

About ViGeneron

ViGeneron is dedicated to bringing gene therapy innovations to people in need. The company is advancing its proprietary gene therapy pipeline to treat ophthalmic diseases, while partnering with leading biopharmaceutical players in retinal diseases, CNS, and other disease areas. ViGenerons two novel next-generation gene therapy platforms are geared towards addressing the limitations of existing adeno-associated virus (AAV)-based gene therapies. The first, vgAAV vector platform, enables a superior transduction efficiency of target cells and is designed to overcome biological barriers, thus enabling novel, less invasive routes of administration such as intravitreal injections. The second, REVeRT (REconstitution Via mRNA Trans-splicing) technology platform, allows efficient reconstitution of large genes (>5Kb) in various tissues such as retina, brain, heart, liver, and skeletal muscle. Privately-owned ViGeneron was founded in 2017 by a seasoned team with in-depth experience in AAV vector technology and clinical ophthalmic gene therapy programs and is located in Munich, Germany. For further information, please visit http://www.vigeneron.com

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ViGeneron signs gene therapy strategic collaboration and option agreement with Regeneron for one inherited retinal disease target - BioSpace

Key MessageWhat is already known on this topic

Electrophysiological assessment of eyes with choroidal detachment, a common postoperative change of glaucoma surgery, has not been reported previously.

In the absence of choroidal detachment, rapid functional improvement was observed in the first, second and third order retinal neurons within several days of glaucoma filtration surgery.

Glaucoma, an irreversible disease, is characterised by the loss of retinal ganglion cells (RGCs) and their axons in the retina, with progressive optic-nerve damage and characteristic visual-field defects.1 2 It is the second most common cause of preventable blindness in the world.3 In 2020, 3.6million people over the age of 50 worldwide lost their vision because of glaucoma.4 Visual-field loss typically becomes detectable only after a large number of RGCs are lost.5 RGC damage can be detected by measuring retinal nerve fibre layer (RNFL) thickness using optical coherence tomography (OCT) to capture morphological changes in the early stages of glaucoma.6 The reversibility of some glaucoma-related changes, such as optic disc cupping, lamina cribrosa displacement,7 vessel density and ocular blood flow,8 following intraocular pressure (IOP) reduction in patients with glaucoma has been reported.

The photopic negative response (PhNR), an electroretinographic (ERG) component, is an objective parameter that can be used to estimate RGC function.8 9 It consists of a slow negative wave that follows the positive b-wave of the ERG and is derived from the inner retinal layers, specifically the RGC layer.8 The PhNR amplitude and PhNR/b-wave ratio, defined as PhNR divided by the b-wave, have been reported to worsen in glaucoma.8 9

Investigations of the function of RGCs810 as well as of their microstructure6 11 12 have contributed to the understanding and diagnosis of the pathophysiology of glaucoma. Interestingly, several studies have shown that the PhNR amplitude is significantly lower in glaucomatous eyes than in normal eyes.8 9 Niyadurupola et al10 and Tang et al13 reported that lowering the IOP led to electrophysiological RGC improvement. These studies reported improvements in PhNR in ocular hypertension and glaucoma after several months of IOP-lowering treatments, including eye-drops, laser therapy and surgery. However, there is no information on how early this functional RGC improvement occurs after IOP reduction following glaucoma filtration surgery. Further, there has been no electrophysiological assessment of eyes that developed choroidal detachment (CD), a common postoperative change of glaucoma surgery.14 15

In this study, we evaluated RGC function in the early postoperative period in glaucomatous eyes undergoing filtration surgery using full-field ERG and skin electrodes. Further, we compared these changes in eyes with and without CD.

Patients who underwent glaucoma filtration surgery and preoperative and postoperative ERG recordings at Saitama Medical University Hospital between September 2020 and June 2021 were included. All patients underwent a comprehensive pre-and postoperative ophthalmologic examination, including visual acuity testing, a slit-lamp biomicroscopy and IOP measurement with Goldman applanation tonometry. The most recent preoperative values were used to assess visual acuity. Visual-field tests were performed within 3 months preoperatively. Standard automated perimetry was performed with the Humphrey Field Analyzer (Carl Zeiss Meditec, Jena, Germany) using the 24-2 Swedish Interactive Thresholding Algorithm standard threshold. We measured the axial length (AL) and central corneal thickness (CCT) (Optical Biometer OA-2000, Tomey, Nagoya, Japan) within 3 months preoperatively. All participants underwent cross-sectional imaging to measure the circumpapillary RNFL thickness at each visit using spectral domain OCT (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany).

Glaucoma was diagnosed based on: (1) glaucomatous changes in the optic nerve head (ONH) observed with fundus photography, such as a vertical cup-to-disc ratio 0.7, rim notch with a rim width 0.1 and/or an RNFL defect (with its edge at the ONH margin greater than that at a major retinal vessel) diverging in an arcuate or wedge shape; (2) glaucomatous visual field defects that met at least one of the Anderson-Patella criteria, that is, a cluster of 3 points in the pattern deviation plot in a single hemifield (superior/inferior) with p<0.05, one of which must have been p<0.01; a glaucoma hemifield test result outside the normal limits, or an abnormal pattern deviation with p<0.05.16 The included patients had manifest glaucoma deemed to require glaucoma surgery owing to high IOP or evidence of progression in the visual field. All glaucoma subtypes and treatment modalities were included. Patients with visual acuity 20/200 were included in the study, whereas those with diabetic retinopathy, and insufficient ERG quality (described in detail below) were excluded. No exclusion criteria were applied for AL, refractive errors, CCT or past ocular surgery history if the patients fulfilled the inclusion criteria. The patients were divided into two groups according to the presence or absence of CD after glaucoma filtration surgery. The presence of CD and CD grading were determined using ultra-widefield fundus photography (California, Nikon, Tokyo, Japan) and grading criteria as previously reported.17

Full-field ERG was recorded using the RETeval system (LKC Technologies, Gaithersburg, MD; Welch Allyn, Skaneateles Falls, New York, USA), a portable ERG device that uses skin electrodes. The pupils were dilated with topical 0.5% tropicamide and 0.5% phenylephrine hydrochloride. The patient adapted to the background light prior to testing. Sensor strips of skin electrodes were carefully placed 2mm below the lower eyelid margin after cleaning the skin with an 80% ethanol-impregnated solution and connected to a lead wire. The stimuli consisted of a red flashing light (intensity of 1.0cd-s/m2, stimulus duration of 4 ms) on a stable blue background light (10cd/m2). Two hundred flashes were delivered at a frequency of 3.4Hz, which has been reported to achieve a good balance between testing time and signal quality.18 Signal acquisition was performed at a sampling frequency of 2kHz.

The recording time was 220ms, including 100ms of prestimulus recordings. The implicit times and amplitudes of the ERGs were automatically analysed using the software integrated into the RETeval system. The a-wave amplitude was measured from the average pre-stimulus mean baseline to the a-wave trough. The b-wave amplitude was measured from the a-wave trough to the b-wave peak; the a-wave and b-wave peak times were measured from the time of the flash to the peak of the wave.19 The PhNR was selected as the most negative trough appearing behind the b-wave according to the standard of the International Society for Clinical Electrophysiology of Vision.8 Its amplitude can be measured in various ways; in this study, it was measured from the b-wave peak to the PhNR trough (PT) (as shown in online supplemental figure 1). We also analysed the PT/b-wave amplitude ratio; the PT amplitude and PT/b-wave amplitude ratio have been reported to be highly reproducible.20 These indices were analysed using the well-recorded ERG waves that had a stable recorded baseline. When the last point of the recorded waveform deviated from the baseline level before recording by 3SD or more of the noise amplitude, it was judged that the baseline of the recorded waveform was unstable and defined as an ERG wave with insufficient quality. The fluctuation range of the baseline before recording was regarded as the noise amplitude. It was measured in 10 randomly selected eyes according to the manufacturers instructions and was measured to be 1.30.9 V. Therefore, the reference value was defined as 5.1 V. Preoperative ERGs were recorded the day before surgery, and postoperative ERGs were measured within 2 weeks.

The significance of the differences within the groups was compared using the paired t-test and that between the groups was compared using Students t-test. Pearson 2 and Fishers exact test were used for categorical variables. We analysed the relationship between the change in PhNR amplitude and various structural and functional factors such as age, AL, CCT, preoperative and postoperative IOP, preoperative mean deviation (MD) values by HFA 24-2, past surgical history, presence or absence of postoperative CD, change in visual acuity and self-reported systemic diseases. Decimal visual acuity was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Variables with p<0.10 in the univariate analysis were used for multivariate analysis. In addition, to confirm the intersession reproducibility, we randomly selected 15 patients and measured the preoperative and postoperative PhNR amplitudes and implicit times in the non-operated eye and calculated the coefficient of variation (CV) values. Statistical significance was set at p<0.05 based on a threshold two tailed. Distributed variables are reported as mean (95%CI), except for age, which is reported as the median (quartile). We used the JMP Pro V.16 software (SAS Institute) for the analyses.

Figure 1 shows a flow diagram of the study patients. Seventy-four patients were initially enrolled in the study. Seventeen patients were excluded because of poor visual acuity (five eyes), diabetic retinopathy (five eyes) and insufficient ERG quality (seven eyes; three eyes had insufficient quality preoperatively, two eyes had insufficient quality postoperatively and two eyes met the criteria for insufficient quality in both preoperative and postoperative measurements). Among the 4 eyes that showed insufficient ERG quality and IOP of less than 10mm Hg, 2 eyes showed CD (2 eyes out of 11 eyes: 18.2%), and the other 2 eyes had no CD (2 eyes out of 46 eyes: 4.3%), and there was no significant difference. Thus, the data of 57 patients were included in the analysis, including those of 46 patients without CD and 11 with CD. Table 1 summarises the characteristics of the two groups. There were no significant between-group differences in age, gender distribution, preoperative best-corrected visual acuity, preoperative mean deviation, preoperative IOP, distribution of glaucoma subtypes and whether cataract surgery was concomitantly performed. As expected, the postoperative IOP value was significantly lower in the CD group (6.4 (4.6 to 8.1)mm Hg, mean (95%CI)) than in the non-CD group (9.7 (8.6 to 10.7)) mm Hg (p=0.003). Other factors such as age, gender distribution, preoperative IOP, preoperative MD value, CCT, AL, self-reported systemic diseases and past ocular surgery history were not significantly different between the groups.

Patientcharacteristics

Flow diagram of study patients. CD, choroidal detachment; ERG, electroretinography.

Figure 2 shows three eyes of the representative cases from the non-CD group. Compared with before glaucoma surgery, IOP decreased and PhNR amplitude improved after surgery in all three cases. Figure 3 shows two eyes of representative cases from the CD group. In both cases, transient CD (grade 2) occurred after glaucoma surgery, and PhNR amplitude deteriorated compared with before surgery. CD recovered spontaneously and disappeared after 1month and the PhNR amplitude also improved.

Representative cases from the non-CD group of preoperative (left column) and postoperative (middle column) electroretinography results and widefield fundus photography (right column). Case 1 was an 84-year-old man. His IOP was 23mm Hg preoperatively. The day after the surgery, his IOP decreased to 11mm Hg and his PhNR amplitude improved. Case 2 was a 64-year-old man. His IOP was 28 mm Hg preoperatively, and on the seventh day of surgery, his IOP decreased to 7mm Hg and his PhNR amplitude improved slightly. Case 3 was a 72-year-old man. His IOP was 20mm Hg preoperatively, and on the third day of surgery, his IOP decreased to 9mm Hg and his PhNR amplitude improved slightly. CD, choroidal detachment; IOP, intraocular pressure; PhNR, photopic negative response.

Representative cases of the CD group preoperatively (left column), early postoperatively with CD (middle column), and postoperatively after spontaneous recovery of CD (right column). Case 4 was a 74-year-old woman. Six days after surgery, the IOP decreased to 7mm Hg, and a grade 2 CD was confirmed by wide-angle fundus photography. PhNR amplitude had also worsened. One month later, the CD recovered spontaneously and the PhNR amplitude improved. Case 5 was a 73-year-old woman. The preoperative IOP was 28mm Hg. On postoperative day 4, the IOP was 10mm Hg, but wide-angle fundus photography showed grade 2 CD, and the amplitude of the PhNR also deteriorated. One month later, the CD recovered spontaneously and the amplitude of the PhNR improved. CD, choroidal detachment; IOP, intraocular pressure; PhNR, photopic negative response.

The changes in ERG parameters preoperatively and postoperatively for each group are summarised in table 2. The scatter plots in figure 4 show the changes in the PhNR implicit time and amplitude and the PhNR/b-wave amplitude ratio.

Scatter plots showing the change in PhNR implicit time and amplitude and the PhNR/b-wave amplitude ratio. Scatter plots of each PhNR parameter pre -and postoperatively. The x-axis shows the preoperative values, and the y-axis shows the postoperative values. In the plot, the circle indicates the non-CD group and the cross indicates the CD group. (A) PhNR amplitude. (B) PhNR/b-wave amplitude ratio. (C) PhNR implicit time. CD, choroidal detachment; PhNR, photopic negative response.

Comparison of full-field ERG parameters before and after the operation

In the non-CD group, the PhNR amplitude, PhNR/b-wave amplitude ratio and PhNR implicit time significantly improved after surgery. The PhNR amplitude changed from mean (95%CI) 17.3 (15.6 to 19.1) V to 18.7 (16.7 to 20.6) V (p=0.008). The PhNR/b-wave amplitude ratio changed from 0.86 (0.84 to 0.89) to 0.90 (0.87 to 0.93; p=0.002). The PhNR implicit time changed from 75.3 (72.6 to 78.0) to 72.3 (70.4 to 74.3) ms (p=0.039). In addition, the a-wave and b-wave implicit times significantly improved after surgery. The a-wave implicit time changed from 14.8 (14.4 to 15.2) ms to 14.3 (14.0 to 14.7) ms (p=0.027). The b-wave implicit time changed from 32.2 (31.5 to 32.9) ms to 31.4 (30.9 to 32.0) ms (p=0.004).

In the CD group, the PhNR amplitude significantly deteriorated after surgery. The PhNR amplitude changed from 17.0 (12.4 to 21.5) V to 11.4 (7.7 to 15.0) V (p=0.002). In addition, the a-wave and b-wave amplitudes significantly deteriorated after surgery. The a-wave amplitude time changed from 4.9 (6.0 to 3.8) V to 3.1 (4.2 to 2.0) V (p=0.001). The b-wave amplitude changed from 19.1 (14.5 to 23.8) V to 13.3 (9.3 to 17.3) V (p=0.001). The PhNR/b-wave amplitude ratio, PhNR implicit time, a-wave amplitude, and b-wave amplitude did not change significantly.

Figure 5 shows the distribution of change in the PhNR amplitude in the CD group and the non-CD group. The postoperative change in PhNR amplitude was significantly lower in the CD group than in the non-CD group (p<0.001). Table 3 shows the results from the univariate and multivariate models investigating the relationship between the change in the PhNR amplitude and related factors. Postoperative IOP (p=0.031) and postoperative CD (p<0.001) were significantly associated with change in the PhNR amplitude in the univariate models. We separately examined the presence of postoperative CD and postoperative CD gradings with two different multivariable models. In the multivariate analysis, the presence of postoperative CD, CD grading 1 (p=0.048) and 3 (p=0.004) were significantly correlated with change in the PhNR amplitude.

Association between change in PhNR amplitude and ocular variables: univariate and multivariable analysis

Distribution of change in the PhNR amplitude in the CD group and the non-CD group. CD, choroidal detachment; PhNR, photopic negative response.

The CV values were 12.4% (95% CI 7.5% to 17.4%) for the PhNR amplitude, 2.4% (95% CI 1.1% to 3.7%) for PhNR/b-wave amplitude ratio and 6.0% (95% CI2.6% to 9.5%) for PhNR implicit time.

In this study, we demonstrated the rapid improvement in RGC function within several days after glaucoma filtration surgery by measuring PhNR using skin electrodes in the same eye preoperatively and postoperatively. The PhNR amplitude worsened after glaucoma surgery in patients with CD because of overfiltration.

Interestingly, the a-wave, b-wave and PhNR improved after glaucoma filtration surgery. This suggests the possibility that the reduction in IOP may be related to changes in blood flow in deeper layers. Deep macular microvasculature alteration in glaucomatous eyes has recently been reported.11 21 Further studies on whether this deep circulatory impairment can be improved by lowering IOP would provide an answer. Using OCTA, we recently reported microcirculatory disturbances in the macula before and after glaucoma surgery.22 23 The foveal avascular zone area was significantly reduced at 3 months after surgery. We concluded that capillary circulation may improve to a level detectable with OCTA. IOP, microcirculation and physiological improvements in function are considered closely related and act together quite early in the postoperative period.

RETeval is a relatively new ERG recording system that uses skin electrodes and is less invasive.24 RETeval PhNR is simple, reproducible and carries a low risk of infection when observing acute functional changes in the dense perioperative period.24 25 Using this method, it was possible to observe retinal function 2hours after vitreous injection26 and several days after vitrectomy.27 In this study, we showed that skin electrode ERG can be used to evaluate retinal function in the early postoperative period, even in eyes after filtration surgery that cannot tolerate contact lenses and DTL electrodes.

Another notable finding of this study is the significant association between the presence of CD soon after postoperative glaucoma filtration surgery and changes in retinal function observed using skin electrode ERG. In some situations, mild CD is difficult to detect. Objective diagnosis of the presence or absence of CD in the early postoperative period is practical and could help decide on further management.28 This study showed that the behaviour of the ERG components recorded in the early postoperative period strongly correlated with the presence of CD. The a-wave, b-wave and PhNR waves deteriorated in the CD group. First, choroidal function may play a role. Miyake et al15 analysed the electrooculogram of eyes with rhegmatogenous retinal detachment (RRD) and found that the preoperative values were significantly lower in eyes with CD than in those without. Choroidal dysfunction may affect outer retinal layer function, leading to changes in the a-wave and subsequently in the b-wave and PhNR. Second, another explanation is that the inner protrusion of the retinal surface caused by CD may have reduced the response of the ERG because of unequal stimulus light exposure. The fact that the amplitude deteriorated but the implicit time was relatively maintained is consistent with the latter explanation. Third, the effect of IOP on ERG changes should be considered. Miyake et al29 used ERG to monitor retinal function during scleral buckling surgery in eyes with RRD. They observed a marked decrease in retinal function immediately after subretinal fluid drainage, but it improved with increased IOP caused by buckling. Therefore, the authors stated that the functional reduction was attributed to the effect of low IOP. In this study, eyes with CD also had a lower IOP than those without. However, rapid IOP reduction does not always cause reduction in the ERG response, as shown by studies of electrophysiological monitoring during intravitreal injection.30 31 Further studies are required to validate this mechanism.

Recently, Shin et al reported on CD grading using wide-angle photographs.17 The widespread use of wide-angle fundus photography has enabled objective interpretation of the degree of CD. In this study, we showed a significant association between CD grading and PhNR amplitude change. They showed the risk of CD was associated with pseudoexfoliation glaucoma, older age, and previous cataract surgery. Though there was no statistically significant difference between the two groups in this study, the results were consistent with the past reports by Shin as the CD group was older, had more cases of pseudoexfoliation glaucoma, systemic hypertension and diabetes, and previous cataract surgery.

The limitations of this study include its retrospective design, small sample size and lack of long-term postoperative data. It is possible that the deterioration of the PhNR amplitude may improve with the improvement of CD, and it is unclear how long the improvement of the PhNR amplitude will persist. Further studies with longer follow-up periods will clarify these associations. Second, it can be argued that the improved PhNR after surgery could be a result of improved media factors rather than the recovery of retinal function. Preoperative corneal oedema and combined cataract surgery may influence ERG quantitative measurements. In this study, the proportion of patients with a history past ocular surgery history was similar in the groups. Simultaneous cataract surgery was performed in 22 out of 46 eyes (47.8%) in the CD group and 3 out of 11 eyes (27.2%) in the non-CD group, and cataract surgery may have affected the postoperative changes in ERG. Tanikawa et al32 conducted a detailed study on the effects of cataract surgery on ERG. They reported a significant increase in the a- and b-wave amplitudes, but not in PhNR, after cataract surgery. In addition, after excluding eyes with preoperative IOP higher than 30mm Hg (five eyes) from the analysis, the results were similar (online supplemental table 1). Thus, the impact of media factors on PhNR, if any, may be considered inconsequential for the results of this study. Third, the influence of the hypotonic state on the ERG quality may be a cause of concern for selection bias. The comparisons of the ERG parameters between CD and non-CD groups should be interpreted with caution; however, the incidence of the excluded eyes due to insufficient ERG similar in the groups (data not shown).

In conclusion, even in the early postoperative period within several days, the PhNR amplitude increased with IOP lowering following filtration surgery, and showed rapid functional recovery. However, the appearance of CD identified by wide-field fundus photography suggests that CD may arrest functional recovery, at least temporarily. The present results enhance understanding of the structural and functional recovery after glaucoma surgery and the role of postoperative CD.

Data are available on reasonable request. The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Consent obtained directly from patient(s)

The present study was part of a prospective longitudinal study approved by the Ethics Committee of the Saitama Medical University (No. 15138) and conducted in accordance with the tenets of the Declaration of Helsinki. The detailed design of this longitudinal study has been described previously. The Ethics Committee of Saitama Medical University approved the present study and waived the requirement of additional informed consent due to the retrospective nature of the study (No. byou2021-074).

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Early changes in photopic negative response in eyes with glaucoma with and without choroidal detachment after filtration surgery - British Journal of...