Sick and visually impaired?

Recently I caught sight of Asa, and the way the light was falling on him made him look to me, for the first time, like the sort of children we sometimes see in hospital waiting rooms – Completely bald from chemotherapy.  And unwell.

This struck me, because for the most part, Asa doesn’t seem sick to us these days.  He’s so lively, so playful and happy that we often forget about his illness.

Of course, his hair has almost disappeared.  He sometimes looks pale. And he still sometimes needs an NG tube to get his medicine in.  But that’s about where the resemblance to a sick child ends.

Asa & granddad Clive

Sometimes friends ask how Asa is doing, saying “We heard he’s very sick.”  

It can produce an odd look from us, because it’s both true and untrue.

The end of chemo

During the 5th cycle of chemo, Asa was on a lower dosage (50% Vincristine), and the side effects were milder.  His appetite declined early on, but soon he was eating more or less normally again, and his energy levels were high.  He had none of the discomfort we’d seen during the 1st and 4th cycles. He needed a transfusion of platelets in the second week, but his haemoglobin level remained in the normal range throughout.

As the cycles of chemo have progressed, we’ve gotten more relaxed.  Whereas a couple of months ago we were keeping him confined to a few designated safe areas in the house, these days he roams widely (most of the time, on two feet), and he’s made the place his own.

Tomorrow, if all goes well, Asa will receive his last dose of chemo. 

It will take about 3 weeks to work its way out of his system.  After that, we hope we may be able to relax even more.

The latest on Asa’s eyes

The latest news we have on the cancer, from an examination 3 weeks ago, is this:

The large tumours in both eyes are inactive, and in the process of becoming calcified. 

But there are 50 to 100 seeds (small, beginnings of tumours) in the retinas of each eye; and in the left eye there are 2 vitreous seeds – seeds outside the retina.

Whereas before chemo both retinas were detached, the retina of the right eye has now become attached again.

Sporting shades after an eye exam, April 2012

The prospects of the retina re-attaching in the left eye are lower – As a doctor told us, if the retina hasn’t attached by the 4^th cycle of chemo, it’s unlikely to do so afterwards. 

This is important for a couple of reasons.  For one, a detached retina impairs vision.  For another, a class of therapies including laser and cryo aren’t possible if the retina’s detached (they can detach it even further).

Because the retina in the right eye has re-attached, laser therapy could be performed on the subretinal seeds in the right eye at Asa’s last session.  But nothing was done to the left eye.

So what are the options for the left eye? 

If either the seeds or the large tumours in the left eye become active again, then the first recourse might be intra-arterial chemotherapy (intra-arterial melphalan, or IAM), delivered directly to the eyeball rather than to the whole body.

And although the doctors haven’t mentioned it recently, there remains a possibility that if the therapies don’t work, the eye might need to be removed.

We hope and pray that won’t be necessary. 

Implications for vision

What does all this mean for Asa’s vision at present? 

With the retina detached in the left eye, the doctors infer that Asa can only see “light and dark” out of that eye.  And because of the size and position of the tumours in the right eye, they assume he has only limited vision there. 

But there’s a weird disconnect between the doctors’ judgments, based on examining Asa’s eyes under anaesthetic, and our observations of his behaviour from day to day.

First of all, he gets around, makes eye contact, snatches things from us, and generally behaves just like any other child.  There’s no obvious visual impairment at all.

Second, when Selam breastfeeds him, Asa often has one eye at least partially covered, as he lies sideways on her lap.  In this position, she’s able to test his vision in each eye by proffering things (her necklace, a mobile phone, and so on) and seeing whether he reaches for them. 

Selam’s impression, based on many such tests, is that Asa sees better with the left eye than his right.  He’s more likely to reach for stuff when his right eye is covered than when his left eye is. 

Which is precisely the opposite of what we’d expect from what the doctors tell us.

One interpretation of this is that the “light and dark” he gets from the left eye is better even than the partial vision he gets through the right eye (where the tumours are more centrally located). 

Since he doesn’t cooperate when people try to patch one eye (he protests and tries to rip the patch off), it’s difficult to test him formally.

But he’s clearly using what vision he has to the max.

Next month, after the last cycle of chemo is finished, we’ll have a follow-up vision test at the Royal London Hospital.  Perhaps then we’ll get a better sense of how well he’s seeing, with each eye. 

For the moment, it remains a daily wonder to see him roaming and playing, and defying anyone to call him sick or visually impaired. 

Rb in Ethiopia / Cycle 4

Chemo cycle 4 has been hard, as Asa struggled to tolerate a raised dosage of one of the chemo drugs, and was hospitalized for four days over Easter.  I was in Ethiopia during much of this.

At the beginning, Asa was relatively happy in the daytime, but during the nights he was clearly uncomfortable. Paracetamol did nothing to relieve his discomfort, and Codeine worked only for brief periods.  Saddest of all to see, he wanted desperately to breastfeed, but as soon as Selam’s nipple was in his mouth, he would be overcome with nausea and retch or vomit. 

The dosage of Vincristine had been raised from 50% to 75%, and it’s an indication of how powerful this drug is that an additional 0.19 mg. should make such a massive difference in terms of side effects.  Our experience with the lower dosage had made us feel pretty confident about chemotherapy – “We can handle this!” – but this cycle put us back on the defensive again.

That was the state of play when I left for Ethiopia on the Sunday before Easter. 

It was a great relief to hear, after I arrived, that Asa had stopped vomiting and was breastfeeding again. 

Housekeeping

One of the jobs I had to do in Ethiopia was to gather things from the apartment in Addis Ababa that we’d left in January.

Since we left, Selam’s aunt Birritu had moved our stuff to another apartment, and when I got there I was surprised to find that she’d arranged the new apartment exactly like the old one – everything down to the fridge magnets and the books on the shelves was in its place.

A note on the fridge.

It was moving to be surrounded by those things again, and it reminded me of how incredibly easy life had been for us – even if we hadn’t fully appreciated it – before Asa’s diagnosis.

Rb in Ethiopia

Another job was to see Dr Abonesh, the ophthalmologist who’d first confirmed Selam’s suspicion of Retinoblastoma, and to learn more from her about Rb in Ethiopia.

I met Dr Abonesh at the private practice where she works, and we chatted for a half hour as several patients waited outside her door.

Dr Abonesh estimated that she’d seen 10 cases of Rb per year during the 8 years that she worked at Menelik II Hospital, the country’s main referral centre for eye problems.  The children came from all over the country, she said.  Most arrived with proptosis (protruding eyes), and when parents were told that the eyes should be removed, they would often disappear in denial, sometimes coming back when there was a protruding mass that needed to be cut out, but more often not returning at all.

Dr Abonesh knew of only two success stories – children who’d been diagnosed relatively early, and who’d traveled to Kenya for surgery.  Both had had their eyes removed, but were doing well since. 

So the short answer to our question, “What would have happened to Asa if he’d been in Ethiopia?” is that he too would have had his eyes removed.

When I told Dr Abonesh that we were interested in helping children diagnosed with Rb in Ethiopia, she suggested something we hadn’t thought of before. 

In the UK, there are several organizations that provide accommodation and transport services for families whose children need urgent medical treatment – the Sick Children’s Trust, which accommodates families from out of town whose children are receiving treatment in London; and CLIC Sargent and a government benefit scheme, which help with transport costs.  But in Ethiopia, where the challenges for families are so much greater, we don’t know of any equivalent. 

Contributing to a transport fund for families who need to travel to Addis Ababa for treatment would be one way to make their burden lighter. 

Of course transport and accommodation aren’t the only things that are needed.  Raising awareness among regional medical personnel and improving doctor-patient communication would be helpful too.  Not to mention making available the drugs that Asa’s receiving. 

But transport is at least an area where one could make a difference with a small investment. 

The day after I met with Dr Abonesh, I took a bus to Jimma in southwest Ethiopia, where I’d done my PhD research.  The cost of the ticket from Addis to Jimma is 100 Birr (about $6) – Not much to us, but a considerable sum to many Ethiopians.

Addis Ababa central bus station at dawn

Asa’s trials

While I was in Jimma, Asa came down with a fever and was admitted to hospital in Colchester.  He was placed on antibiotics, and over the following 3 days he had transfusions of red blood cells and platelets when his counts dipped below the danger thresholds.

He’d been admitted on Good Friday, and when I arrived home on Easter Monday he was close to being discharged.

He’d eaten almost nothing during the entirety of my time away, surviving on cow’s milk delivered through his NG tube and breastmilk, and an occasional slice of orange or spoonful of vitamin syrup.

His hair, which had thinned out somewhat in previous cycles of chemo, was reduced to a sort of tennis ball fuzz, and his eyebrows had almost disappeared.

Staying positive

The good energy we’ve received from family and friends has helped us stay strong as Asa goes through all this.

Last month some dozens of friends sent us photos of themselves bearing good wishes for Asa (see here!). 

To them we send the following message:

As we reach the last days of cycle 4, Asa’s appetite is starting to revive.  On Wednesday he ate a full meal (his granddad’s chicken and veg) for the first time in more than 10 days, and since then he’s accepted small amounts of food by mouth.  This morning, with much cajoling and patience on his mum’s part, he finished his breakfast.

But even when he’s not eating, Asa’s liveliness is extraordinary.  Despite all the poisons in his bloodstream, and the negligible nutrition he gets, he somehow mobilizes great energy for exploration and play. 

As we sit on our bed, writing this, he is crawling all over us and biting random parts of our bodies.

Much love from us and our balding but lively 14-month-old to you all.

RB genetics ... What would happen in Ethiopia?

Retinoblastoma is a complicated business. It’s not uncommon for us to ask a question of a doctor, only to be told, "Ah, that's a question for Dr X."

The team that manages Asa’s treatment includes ophthalmologists, oncologists, and geneticists – each of whom contributes a piece of the puzzle.

As it turns out, some of our questions about the causes of Rb and its long-term implications are questions for geneticists.

Genetics is relevant here because, given that both Asa's eyes are affected, there's a very high likelihood that it’s due to a mutation in a gene known as RB1. 

Dr Rosser, a geneticist at Great Ormond Street Hospital, helped us understand how this mutation might have arisen, and what its implications are.

Since neither Selam nor I have relatives with Rb, the most likely way Asa got the mutation is through a random change in the sperm or egg that made him.

As Dr Rosser explained: "Every time a cell divides, 40,000 genes get copied.”

“All of us have 20-50 mistakes in every gene, but most don’t matter.

“His matters."

It’s kind of a relief to know that genetic mutations are common – that we all have them.  And that they’re not always bad news.

But obviously some are more important than others.

How does Asa’s matter? 

How (not) to build a retina

One of the major jobs genes do is to give instructions on how to build a body.  Genes have relatively specialised tasks, and the job of the RB gene is to issue the command, "Stop growing, retina." When there's a mutation in this gene, the "stop" command doesn’t register, and cells keep dividing in the retina area, more than are needed. (Retinoblastoma literally means growth on the retina – blastos being Greek for bud or growth.)

Eye anatomy, showing the retina (from visionandeyecare.wordpress.com)

Since the retina does most of its developing by age 5 – and most of that during the first two and a half years – Asa will be at greatest risk from Rb during the first 5 years of his life.  After that, according to Dr Rosser, he will have about a 6% chance of other tumours, e.g. in bones, muscle or skin, with the risk peaking in his teens or early 20s, and declining thereafter.

There are two other corollaries of RB mutation: it may be accompanied by other mutations, and it can be passed on to children.

 

Sometimes when the RB gene isn’t working, it’s the first sign that there are other abnormalities: neighbouring genes could also be faulty, and these could lead to other problems in development.  We will have to keep an eye out for developmental oddities in Asa.  The fact that he’s developing normally so far (he started walking independently this week!) bodes well.

There’s a 50:50 chance that Asa’s children might inherit the RB mutation.  Knowing this, however, means that any child he might have could receive prompt evaluation and, if necessary, treatment to nip tumours in the bud.

How common is Rb?

For some reason, the copying mistake that leads to the RB mutation happens at a fairly predictable rate across human populations.  The figure that's often cited is 1 in 20,000 (50 in a million). 

The universality of this phenomenon can be difficult to believe, because almost everything you see on the internet (and we’ve spent some months searching) is related to Rb in Europe and North America.

In Europe, we learned recently, there’s some variation, with slightly higher incidence rates in the north than the south (MacCarthy et al. 2006).

But if it occurs at roughly the same rate all over the world, how come we don’t hear more about Rb in Asia, Africa, and South America?  

Some possible answers are that high child mortality from infectious diseases in the developing world makes cancer a marginal concern; there are a lot more resources available for cancer treatment in the West; and the internet is Eurocentric.

Still, we wonder.  Are there really thousands of children born with Rb in the developing world?  What happens to them?

What would Asa’s chances of survival have been if he was in Ethiopia?

Rb worldwide

This month, a review was published in the Lancet by a team of physicians in Canada and Kenya (Dimaras et al. 2012).

Their review doesn’t confirm the 1 in 20,000 incidence rate, but it does show that there’s a lot of Rb in other parts of the world.

In Kenya (one of the few countries in Africa where there is a dedicated treatment centre for Rb) more than 70% of children with Rb die from it. The mortality rate from Rb is surely higher in places where there are no treatment centres.

What happens when Rb goes untreated is quite horrific.  The Lancet article includes a photograph of a child with a very large tumour that has burst out of the eye socket.

Ethiopia is one of the places that lacks a treatment centre.  While we don’t know how many children in Ethiopia have Rb, the ophthalmologist in Addis Ababa who first diagnosed Asa, had referred patients to Kenya. 

And as the second most populous country in Africa, Ethiopia usually comes close to the top of the list when cases of disease are tallied up.

So given what we know about the genetic basis of Rb, and its regular incidence rate, it seems likely that there are scores of children being born with Rb in Ethiopia, most of whom will die of it.

Selam and I would like to help families there whose children have Rb get treatment. Next week I’m going to Ethiopia, and I’ll try to find out more about how we might do this. 

Sources:

A recent article documents the commonness of genetic mutations, and suggests that most do not have any major consequences for health (MacArthur et al. 2012, Science 335, 6070:823-8; news item here). 

 

Incidence of retinoblastoma higher in northern than southern Europe (MacCarthy et al.2006, European Journal of Cancer 42, 13: 2092–2102)

Lancet review of retinoblastoma (Dimaras et al. 2012, Lancet 2012, doi:10.1016/S0140-6736(11)61137-9)

Thanks to Charlotte Kvasnovsky for letting us know about the Lancet review.

"What's the prognosis?"

The examination under anaesthetic last week revealed that the tumours in Asa’s eyes have halved in size in the left eye and more than halved in the right eye since he began chemo.

Retina scans showing tumours before and after the first two cycles of systemic chemotherapy.

The retcam images show how the tumours have shrunk, and also changes in texture from diffuse blobs to gnarly, calcified masses.

 

This is encouraging, but there’s still a lot of cause for concern.

For one thing, systemic chemo has its greatest effects in the first cycles.  So unfortunately we can’t expect this rate of shrinkage to continue through the remaining 4 cycles of chemo. As the ophthalmologist told us, the remaining chemotherapy is to prevent relapse.

The other cause for concern is seeding. 

In the images, the constellations of little spots around the tumours are “seeds”: tumours-in-the-making that, if they’re not attacked, will grow bigger.  These are a worry because (a) they’re so many of them and (b) they’re not well supplied by blood vessels, the way the big tumours were, so they won’t respond as well to systemic chemo, which relies on the circulatory system to deliver the drugs.

The seeds can be attacked in a variety of ways, including laser and cyrotherapy.

But there’s a delicate balance to be struck between the benefits these treatments can bring in terms of destroying the seeds, and the collateral damage they can cause in the process.  Aggressive use of laser, for instance, might inactivate the seeds, but could also further detach the retina, which would cause problems of its own.

This is part of the reason why, after this first course of chemotherapy ends, Asa’s going to need to be examined under anaesthetic every month or 2 months for the next few years.  The doctors will be trying to keep these seeds under control, using an appropriate level of focused therapy.

Where we are now

The day after the examination under anaesthetic, Asa received his third dose of chemo.  

Now we have three down; three more to go.

Asa and parents at the new Royal London Hospital, in Whitechapel

Last week Asa's blood counts -- specifically, his neutrophil count -- didn't return to normal in time for him to undergo his eye exam and begin the 3rd round of chemo. Our medical appointments were pushed back a week, and in the meantime we've enjoyed a lull, waiting things out, and hoping the neutrophils are climbing, but also getting more time and space to reflect on life than we've had for the last couple of months.

The first time Asa’s neutrophils fell below 1.0, during the first cycle of chemo, we were thrown into a panic, and half expected him to break out in spots or immediately develop a fever.  Since then we’ve learned that the danger is manageable.

Neutrophils are one component of white blood cells, which indicate your body's ability to withstand infections.  The chemo drugs Asa is taking inhibit his ability to produce white blood cells, and consequently his immune system is seriously depressed for a while after each dose.  During the first cycle they plunged after 9 days, and then returned to normal by day 20 or so. This time they fell more rapidly and stayed down for longer. 

The implications for our day to day life aren't all that great: We've been taking precautions to protect him from infections, and we don't get out much: an excursion to the shops every now and then or a walk in the countryside when the weather's fine is about as adventurous as we get.

One of the precautions we take – keeping Asa (and sometimes Selam) penned in

This has become our normal routine now, so we're used to it.  And so far we've been lucky this time around -- no fevers, no scary coughs, no inflammation around the Hickman line.…

The downside of up

At first, the absence of crisis was a bit difficult to deal with.  When you've been putting out fires for weeks on end, it feels weird not to have an emergency on your hands.  And the first week or so after Asa's appetite returned, when he seemed to be pulling back and was acting (as he still is now) pretty much like any other toddler, saw us struggling much more than we'd expected, with worries bubbling up.  Your mind goes strange places under these circumstances -- you start wondering how long all this treatment is going to last.  How you’ll get your own career back on track.  How nice it would be to return to Ethiopia.  And what it would be like if Asa were really to lose his sight….

We started searching for more information from other families who had children with Rb, and how things had worked out for them. 

This has been a sobering exercise, and the stories make difficult reading.  The first 6 months of chemo are never the end of the road, at least in the cases we've heard about.  There are long periods when children are getting regular eye exams under anaesthetic, doctors are spotting new tumours, and children are receiving focused therapies like cryo, laser, and radioactive plaque… 

And sometimes, after all this, removal of one or both eyes is necessary.

The blog that we've learned most from is Fintan Tadgh's.  Maintained by his parents James and Fiona, it tells the story of their journey from Fintan’s diagnosis in 2007, when he was 6 months old, through an EUA last week, at the age of 4.

Fintan and his family have been through a lot, and learned a lot, over the years.  Following them through this, reading a year's worth of posts each evening last week, we empathised as they took a roller coaster ride through periods when it looked like Fintan’s cancer was on the ebb, through times when it was resurgent, and through many and various treatments, all of which they suffered with great strength and dignity.

At the moment, we can’t tell how closely Asa’s story will resemble Fintan’s.  We expect we’ll get more information when we see Mr Reddy, the consultant ophthalogist at the Royal London Hospital on Wednesday.  And while we’re hoping for good news on how the chemo’s working, we know that this won’t be the final judgment, and there are likely to be more surprises ahead.

For the time being, we’ve attained a certain amount of equanimity, and the past few days have been as good as any I can remember of late. 

Asa's been developing in new and surprising ways: imitating sounds, walking more confidently each day, fussing for our attention (are we spoiling him??), and kissing us (wetly and smack on the mouth).   

And we've felt more lighthearted than we have for a long time, one sign of which is our ability to laugh at things that would have caused us to freak out just a week or two ago -- for example, me tracking dog shit into the house one day… Not a great move at the best of times, but especially not when you've got a severely immune compromised toddler in the house. 

The second cycle

 

Two weeks ago, Asa had his second dose of chemotherapy. So far, the second cycle has been much easier than the first. We’ve managed to stay at home except for short visits to hospital, and we've largely succeeded in controlling Asa's discomfort. 

Part of the reason for this is that we’ve been giving him potassium supplements to head off hypokalaemia, whereas the first time around it was several days before we began using potassium. But a bigger reason is that the dosage of the most potent of the drugs he is on – Vincristine – has been halved.

Halving the dosage of this drug is a big deal, because our most immediate challenge is managing the side-effects of the chemo drugs.

In the first cycle that meant trying to distract him from pain.  This time it's mainly meant trying to get him to eat. 

Asa feeding Jed feeding Asa....  Oranges are the only food he's never refused.

Expecting that Asa might have difficulty feeding, we had a naso-gastric tube inserted just a couple of days after the second dose of chemo.  The tube is useful not only for topping him up with food when he’s not taking anything by mouth, but also for giving him anti-nausea medicines and potassium syrup (which can themselves be nauseating to swallow).

Thankfully, he has been breastfeeding well throughout.

In this way we’ve been able to get him through the rough first few days of the cycle, until his appetite starts to revive.

Blood counts

Next week, we'll learn whether the drugs have been working – whether the cancer is receding.  On Wednesday, the staff at the Retinoblastoma Service in London will examine Asa’s eyes, and assess how much the tumours have shrunk since he began chemo.

For the time being, the main indication we have of how the medicines are working is Asa's blood counts.  These give us an idea of how effectively the drugs are inhibiting the reproduction of fast-developing cells throughout his body (including the cancer). 

The blood components that are most important to keep track of are haemoglobin (red blood cells) and platelets. Haemoglobin carries oxygen to cells, and platelets help the blood to clot.  They’re important not only because they serve as an index of the drugs’ action, but also because if they fall below critical levels, one needs transfusion.

Platelet and haemoglobin counts for cycles 1 and 2 of chemotherapy. 
Cut off points for transfusion are 30 for platelets and 7 for Hb.

Yesterday Asa's haemoglobin levels dropped into the danger zone for the first time, and today he received blood transfusion at our local hospital. 

This is something we'd been hoping to avoid.  But, as with so many other choices we’ve had to make recently, transfusion is much better than the alternative – seeing him become more anaemic, and increasing the risk of spontaneous bleeding.

Who are you calling anaemic?

Asa hadn’t shown any of the lethargy that often accompanies anaemia.  In fact, even during the days when he wasn’t eating, he looked and behaved much like any other toddler, ebullient and energetic.

But it was a pinker, better perfused Asa who emerged from hospital this afternoon, with 200 ml more red blood cells in his system than before.

Taking a walk in the hospital corridor during transfusion

 

In the past week Asa began to stand by himself, and to walk confidently when his hands were being held. 

It’s a source of wonder to us that, despite all he’s going through, Asa should be developing as fast as he is. 

During a week-long stay in hospital last month, he began saying, “Dada”.  He claps his hands and applauds himself when he’s succeeded in stacking hoops onto a pole (one of his favourite games).  And his babbling becomes more florid and melodic each day.

All of this buoys us up, and keeps us optimistic.  

As my mum observed, in some ways it’s easier for those of us who are with Asa day to day than for those who aren’t, because we see the happy times as well as the sad ones.  Those happy moments are in large part what keep us going – them, and the love and support we receive from friends and family.

Many thanks to all who sent birthday wishes to Asa.  And to everyone who's reached out to us.