m
Recent Posts
Connect with:
Monday / April 15.
HomemiophthalmologyThe Premature Thief of Sight

The Premature Thief of Sight

Retinopathy of Prematurity (ROP) is the leading cause of blindness in infants in both the developed and developing world. It has affected the entire lives of greats that include Stevie Wonder and Australia’s own 2011 Senior of the Year, Ron McCallum.

Sydney based research scientist, Dr. Tailoi Chan-Ling’s findings have influenced the classification system developed by an international committee of specialists to measure the disease progress. Her findings will impact future treatment of infants with ROP.

Ophthalmologists have described ROP as the third epidemic on a global scale. Babies born prematurely are most at risk – and that’s no small matter. The World Health Organisation estimates that approximately 12.9 million babies are born at <37 weeks gestation every year. 92 per cent of these births take place in low to middle developed countries where access to high level neo-natal intensive care is limited.

Globally, at least 50,000 of the 1.4 million children born every year are born blind from ROP. In middle income countries across Latin America and Eastern Europe, a massive 50 per cent of all childhood blindness can be attributed to ROP.
The disease, which is characterised by uncontrolled growth of blood vessels in the developing retina, was first seen in the 1940s.

Back then premmy babies were placed in incubators with high oxygen to support the growth of their brains and lungs. While this saved many babies from brain damage and assisted their lungs to develop, the adverse consequence was that many babies became blind.

Too much oxygen can be pathological, too little oxygen can be pathological, and there’s a constant battle between the needs of the brains and the lungs and the needs of the retinal blood vessels

According to Dr. Jeremy Smith, a VMO at The Children’s Hospital at Westmead, while neonatal incubators and oxygen therapy reduced infant mortality, morbidity increased with increased
rates of blindness;

“Kate Campbell, a Melbourne paediatrician, was the first to report the association of oxygen therapy and the epidemic of blindness – she noted increased rates of blinding eye disease in infants who were given oxygen therapy compared with those who were not given supplemental oxygen. ROP assumed epidemic proportions in the 1940s with10 per cent of surviving infants with a birthweight <1500g sufferring blindness, now attributed in large part to the unrestricted use of oxygen in neonatal management,” he said.

High oxygen levels were the reason. Within the high oxygen environment of an incubator, the retina is flooded with all the oxygen it needs to develop. The chemical signal that stimulates blood vessel growth – vascular endothelial growth factor (VEGF) – is switched off. The blood vessels of the retina stop growing while the retina itself continues to mature.

“As the retinal neuronal maturation proceeds, metabolic activity increases and relative hypoxia replaces the preceeding hyperoxaemic state,” said Dr. Smith.

Finally, once the baby is strong enough to be removed from the incubator and placed in a normal environment, the retina becomes starved of oxygen because the rate at which retinal blood vessels normally grow has been delayed.

“An abnormal increase in VEGF arises and this stimulates aggressive and abnormal retinal neovascularisation which is accompanied by fibrous scar tissue. This contracts creating retinal traction and potentially total retinal detachment – or Stage 5 ROP – the blinding outcome of severe ROP,” explained Dr. Smith.

A Delicate Balance

These days more is known about the effects – positive and negative – of oxygen levels, however getting the balance right between too little and too much oxygen is still a concern.

“I’m always asked how much oxygen to give – if only I knew,” said Dr. Chan-Ling. “Too much oxygen can be pathological, too little oxygen can be pathological, and there’s a constant battle between the needs of the brains and the lungs and the needs of the retinal blood vessels. Its very complex and every baby is different.”

Experts say management of ROP requires a coordinated approach between the ophthalmologist, the neo-natologist and the neo natal intensive care unit, with constant monitoring as the disease status can change within a short time frame.

The trick is close control of oxygen levels and very good ophthalmological care to ensure early intervention. “Around the 32WG period appears to be a critical time for intervention but that said, ROP can spontaneously regress so it’s difficult – we can’t tell which babies are most likely to deteriorate. But if we don’t intervene with laser or cryotherapy, and more recently with anti-VEGF compounds, you can reach retinal detachment or the blindness that’s the end stage of the disease,” she said.

One Step Forward,Two Steps Back

With improvements to science, knowledge and equipment, over the past few decades, ROP has been increasingly well managed in the western world.

However, along with increased ROP management capabilities, improvements in modern neonatology and neonatal care have made it possible for babies to survive when born at gestational ages and birth weights previously thought non-viable. Between 1990 and 2002 for instance, the survival rate of babies born in Australia weighing under 500g increased by around 25 per cent from 105 babies to138 babies. Over the same period, the survival of babies weighing between 500 – 749g increased by around 80 per cent.1 The greater incidence of survival has brought with it a renewed incidence of ROP. As smaller babies survive, more severe Rop is increasingly being encountered, known as Aggressive Posterior ROP (AP ROP).

In developing nations, it’s a slightly different story. Whereas just a decade ago, most premature babies simply died, increasing access to basic levels of neonatal care, has resulted in a greater incidence of survival. However, the skills and equipment are not in place to prevent ROP.

According to Dr. Sjakon Tahija from the Klinik Mata Nusantara in Jakarta, despite the economic troubles in Indonesia, there have been significant advances in private health care fuelled by a growing middle class. While in most areas of the country, babies born with a birth weight of 1500g or lower do not survive, in a few private hospitals it is common for babies with a birth weight of 1000g to survive. Some born with a birth weigh of 800g are also being saved. However, the success of saving babies with low birth weight and very low birth weight has not been coupled by an awareness of the need to prevent ROP.

Ophthalmologists are usually consulted once the disease has commenced.

Dr. Tailoi Chan-Ling says that increasingly in developing nations, there appear to be other contributing factors to ROP. “Its not just the tiniest premature babies that have the disease – in China, for instance, we’re finding that babies born at 30 – 32 weeks gestation may suffer the more severe stages of ROP.

According to Dr. Tahija, some full term neonates in Indonesia, who would not typically have been at risk of ROP, are acquiring the disease. Most of these babies are in care in government facilities where the main focus is on saving lives. They have acquired the disease as a result of high and unmonitored concentrations of oxygen levels administered to manage illnesses such as septicemia.2

Experts worldwide are now considering the possibility of geographic and genetic links as well as the need to provide more training to specialists working in these areas so that they understand the potential consequences on the eye of interventions aimed at optimising the health of these premature infants.” In recent years, she and a team of international ROP experts have run conferences in developing countries the include Lithuania and India aimed at educating on the pathogenesis of the disease as well as ROP management and treatment.

Development Classification

The progress of ROP has traditionally been observed and measured against the International Classification of ROP (ICROP), which refers to the disease progressing in circular zones that extend across the retina. The staging uses three descriptive variables: the location in terms of zones one, two and three (where zone one is the inner most and zone three the outermost); the extent, which describes the clock hour positions of the ROP observed from stages one – three and the suffix ‘plus’. The ‘plus’ stage is the most ominous prognostic sign that denotes vascular tortuosity and dilation of vessels observed in the posterior segment.

Treatment Options

Ophthalmologists and neonatologists have relied on the ICROP classification to help determine when to intervene with laser, cryotherapy, or anti-VEGF therapies, However, having studied the processes of human retinal vascular development, Dr. Chan-Ling says her team has determined that the ICROP theory was based on an incorrect assumption that retinal blood vessels in the human infant grow with a circular topography. Rather than developing in even, concentric circles, she says, the clinical presentation of ROP develops in a butterfly shape.

Dr. Chan-Ling said the finding will make a difference to the way clinicians are trained to grade ROP which in turn will impact the way patients are managed and treated. “We showed that the blood vessel is shaped like a butterfly – its not circular at all. When the ROP zones were circular, babies were incorrectly classified as either zone 1 or 2 ROP and that led to under and over treatment. This new mapping will create greater accuracy in the number of patients classified in each zone and therefore more refined treatments.”

Shedding New light

Dr. Chan-Ling’s research has also shed new light on the reasons why laser and cryotherapy treatments have had little success in controlling the progression of ROP in zone one – the most severe form of ROP.

In collaboration with Professor John Flynn at the Harkness Eye Institute, University of Columbia, she has discovered that zone 1 (affecting the posterior pole of the eye) versus zone 2 (affecting the peripheral parts of the retina) ROP correlates with two phases of vessel development in the retina: vasculogenesis (first stage) and angiogenesis (second stage).

In zone one, ROP is located on the posterior retina and involves the entire circumference of the developing vasculature. “The vessels in this area are of vasculogenic origin and therefore insensitive to VEGF – which is why laser or cryotherapy treatments have little effect,” she said. “Whilst trials have not been conducted, anti-VEGF drugs are also unlikely to help in Zone 1 ROP, as it is not mediated by hypoxia-induced VEGF signalling.”

Avastin now under consideration

According to a multi-centre clinical trial of 150 babies conducted by Dr. Helen Mintz-Hittner of University of Texas Health Centre in Houston, and published in the New England Journal of Medicine, a single injection of Avastin into premature babies’ eyes was vastly superior when compared with laser. The study showed that among the 75 infants who received Avastin and whose retinopathy was in zone one (the zone of the retina closest to the optic nerve), just six per cent had a recurrence of retinopathy of prematurity compared with 42 per cent treated with laser surgery.

While this study appears to be good news for those babies suffering end stage ROP, Dr. Smith says the trial was too small to determine the long term effects of using the drug on infants.

“There are concerns surround the systemic absorption of the drug and the injection into the eye which can cause intraocular infection, haemorrhage, retinal tears, retinal detachment and cataract,” said Dr. Smith.

“Approximately one in 900 adults who receive intravitreal drug injections are at risk of endophthalmitis (intraocular infection), retinal detachment or cataract formation and we think it would be fairly similar for the neo natal eye.

“We are particularly concerned about the potential effects of Avastin and neurological and pulmonary disease and the other organ development in preterm neonates. In the ‘Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity’ (BEAT-ROP) study there was a worrying increase in the mortality with bevacizumab (6.6 per cent) than with laser (2.2 per cent), which appeared to be related to hypoxia and respiratory disease. There may be an increased risk of cerebral palsy and other neuromotor disease of infancy with avastin treatment of ROP. The BEAT -ROP investigators pointed out that the study numbers were insufficient to comment on ocular and systemic safety.

“We also know that VEGF is required for retinal neuronal differentiation and survival, which could be compromised by bevacizumab. Without larger randomised controlled prospective studies, that provide accurate data on ocular and systemic outcomes, Avastin should only be considered for treatment in Aggressive Posterior ROP (APROP), severe zone one or posterior zone two disease or after failed laser. In general it is not recommended as first line treatment of choice in ROP.”

Future May Obviate Need

While Dr. Chan-Ling Is pleased to observe progress in ROP management, she hopes to obviate the need for laser, cryotherapy or Avastin treatments in the near future. In her laboratory in the heart of Sydney University, her team has its focus on a treatment that is non invasive, inexpensive and could quite easily be implemented I developing countries.

“We’re putting the finishing touches to our research report now, then its up for peer review. Subject to that, and obtaining the necessary funding, we hope to move into clinical trials within the next year.”

“Our treatment, if it works, will stop the horse before it bolts, whereas all other treatments are treating to block the end stage,” she said.

Let’s hope that within the next decade, Dr Chan-Ling will have succeeded in putting an end to this extraordinary disease that steals the sight of babies permanently from the very moment they enter the world.

References:
1. Retinopathy of Prematurity: Two Distinct Mechanisms That Underlie Zone 1 and Zone 2 Disease. John T. Flynn MD and Tailoi Chan-Ling, PHD
2. Proceedings of the Third International Symposium on Retinopathy of Prematurity; an update on ROP
from the lab to the nursery (November 2003, Anaheim, California)