Pilot Safety Trial of Deferiprone in 10 Subjects With Superficial Siderosis

Michael Levy, Rafael Llinas

https://doi.org/10.1161/STROKEAHA.111.628032 Stroke. 2012;43:120-124

Originally published December 23, 2011

Transcript of a Webinar by Dr Levy gives more comprehensive details of Superficial Sidersis & related problems.

Slide 1

Hi, my name is Dr. Michael Levy. I'm an assistant professor at Johns Hopkins University in Baltimore and a neurologist. I see patients with Superficial Siderosis of the nervous system. This webinar was really a joint effort with my patients on Facebook, who recruited me to present a twenty to thirty-minute overview about Superficial Siderosis. Today I'll go through just kind of the broad strokes of the pathophysiology of the disease, at least the parts we understand. We'll work out the treatment options that are available.

First, what is Superficial Siderosis? In broad brush strokes, Superficial Siderosis is an iron overload condition of the brain and spinal cord. Patients with Superficial Siderosis do not have an overall iron overload condition. The total body iron levels are normal, but the iron is distributed to the wrong place. There should not be iron on the surface of the brain and spinal cord. It is toxic in those locations, and that is the basis of the disease. I'll get into more about how the disease occurs biologically in a future slide

The condition is defined as a slowly progressive nerve-degenerative condition. Slow, I mean that it takes years between the time that patients have their first bleed, and the time that they have their first symptoms of Superficial Siderosis. It could be ten, twenty, thirty years, in one case forty years before the bleeding catches up with the symptoms and once the symptoms begin, the course is also very slow, so year by year the patient will notice that the hearing loss and the balance is getting worse. But it's not suddenly worse, and it doesn't go up and down. It's not a relapse and remitting condition and progressive really speaks to the course of the diseases. It's continuous, so that year after year you're worse than the previous year.

The triad of symptoms are hearing loss; ataxia, which is balance; and myelopathy, which is spinal cord dysfunction. The hearing loss can occur usually in one ear and then the other. It tends to involve higher pitched sounds first, and then lower pitched sounds later and it eventually becomes complete so patients at the end of this process will become deaf. The ataxia, or the balance trouble, is often second. Sometimes it's the presenting symptom, and it mostly is obvious in walking. The patients tell me that they bump into things, or that they fall more often. Rather than the fine motor tasks of the hands, it more involves the balance of the trunk, the balance of staying upright. Especially walking and running. The myelopathy is more of a heterogeneous process. Myelopathy just means spinal cord dysfunction. The spinal cord is involved in strength, sensation, bladder function, autonomic function. There are many different symptoms that can result from myelopathy, including

weakness, numbness, pain, spasticity, urinary retention, urinary incontinence, constipation. All those symptoms can be due Superficial Siderosis.

Slide 2

Superficial Siderosis is incredibly rare. It's one of the rarest conditions in the world. We estimate that there are approximately one hundred patients in the U.S. The incidence may be climbing a little bit because MRI is widely available in the U.S., and it's the basis for making the decision. Worldwide it may be harder to make that diagnosis because MRI is not as available, and so we estimate that the incidence is approximately one in three million people. Again, worldwide we don't know if those numbers are higher or lower. The incidence between men and women is approximately the same, and the age of onset tends to be in the later years, mostly because it takes ten to twenty to thirty years before symptoms begin. So if you have your traumatic even in your teenage years or in your twenties, it may be until you're fifty when you finally present with hearing loss.

Slide 3

What causes Superficial Siderosis? What's really the biology underlying this disease? It starts with the concept of spinal fluid. Spinal fluid is produced deep in the brain, and it's forced out of the brain through these small channels. The spinal fluid then circulates around the entire brain and around the entire spinal cord. The cause of the disease is bleeding into the spinal fluid. The bleeding can take place anywhere. It could be this part of the brain, it could be down to the spinal column. Wherever the bleed occurs, the spinal fluid will then circulate around and deposit those blood products all around the brain and spinal cord.

There are many different potential etiologies. Trauma is the most common, trauma to the spine. That can occur in car accidents, diving into pools, falling off ladders, and getting kicked by bulls. There are a lot of different reasons people have trauma, and the basis of the traumatic event is not that there's a one-time bleed, but that there is a tear in the lining around the spinal cord that does not heal completely, and tears and re-tears over and over and over again such that the bleeding persists or is intermittent over the course of years and years. That doesn't typically happen after trauma, and that is why there are only a hundred patients in the U.S. with this condition cuz most of the time you heal well after a trauma, but for one in three million of the time the healing is not complete, or the bleeding remains intermittent, and you develop superficial siderosis.

The next most common cause are tumers. There are some tumers that bleed. The tumers generally lie within, with access to the spinal fluid, so when they bleed they bleed into the spinal fluid. Same problem. There are surgical procedures, very common. It's probably the second most common reason people get Superficial Siderosis. Again, when the neurosurgeon goes in there to remove a tumor, or fix the spine, or do whatever, if there's incomplete healing and persistent bleeding into the spinal fluid, then after years and decades you can get superficial siderosis.

Finally, there are some people with rare causes, such aneurysms, that leak into the spinal fluid, or tears in other parts of the lining that surround the spinal cord and brain that can lead to superficial siderosis.

Slide 4

Now, chronic bleeding into the spinal fluid, what that causes is a breakdown of the blood cells that leak into the spinal fluid. Within those blood cells are compounds that contain iron. The iron is normally used to transport oxygen around your body, and when these compounds break down they release the iron. Iron is very toxic, especially to the brain, and so we've evolved over billions of years to produce a protein called ferritin, and excrete it to bind the free iron and make sure that it's not toxic. That ferritin and iron compound is called hemosiderin, and that's what's seen on the MRI is hemosiderin.

The hemosiderin that floats around the spinal fluid that's shown here in this representative graph, representative picture, it floats all around the brain and the spinal cord, and then by gravity it tends to stick wherever it hangs around. So, if you're laying on your back to go to sleep for eight hours a night, then it tends to deposit here around the cerebellum, where the balance problems come from. When you're upright for the rest of the two-thirds of the time you're alive, the iron tends to deposit by gravity around the spinal column. The nerve that goes through the brain to the ear is particularly susceptible to the floating hemosiderin deposits because that nerve spends most of its life in the spinal fluid, as opposed to any other nerve coming off of the brain. So that's why the hearing is lost, because that nerve is particularly vulnerable.

99.9% of the time the ferritin is actively bound to that free iron. It keeps it from being toxic, but that .1% of the time where it's not actively bound, the free iron escapes and causes damage, and over years and years and years and years of this kind of release and damage, that's how superficial siderosis develops. That's why it takes such a long time. The big question is, if we remove the iron, do the symptoms improve? Or, if we remove the iron, have we, ah, already gone down a pathway that's not fixable. That's really the big question that we're trying to answer, and we'll show you how we're trying to answer that question in the treatment options later.

Slide 5

The primary way we make the diagnosis is by MRI. Here are MRI shots of the brain and um, the brain stem here, identified by that white arrow, the cerebellum identified by that white arrow, and the cortex, identified by that white arrow and what they're all pointing to are these dark, black deposits. That's the hemosiderin that we're talking about. It's unmistakable on the MRI. You don't see these kind of deposits in any other condition, and so if the patient gets an MRI for any reason, for hearing loss, balance problems, whatever, the radiologist should be able to identify this particular pattern and make the diagnosis of Superficial Siderosis.

The lumbar puncture is an important test to see if you're actively bleeding. So, if you've undergone a procedure, for example, to fix the problem, and one patient who had a bleeding tumor had the tumor resected, then add the question, "Is there ongoing bleeding?" The only way to find out is to do a lumbar puncture, and that involves inserting a needle into the lower spine, well below the end of the spinal cord but well within the spinal sack, withdraw spinal fluid and analyze it. Fresh blood can be detected within two to three days of a bleed. Blood products, those breakdown products, will remain floating around in the spinal fluid for up to two months. So if you do a lumbar puncture, you can detect any bleeding that occurred within the past two months. A clear spinal tap suggests that you haven't had a bleed within the last two months. It doesn't mean you're not bleeding ever. It just means you haven't bled for the past two months.

Slide 6

Ok, I mentioned the majority of people have Superficial Siderosis through trauma, and the trauma is mostly in the spine, in the back, and in the neck. In fact, in the recent Mayo study 70% of patients had a spinal malformation that leads to bleeding, and by far the most common is what's called a dural tear. The dura is the orange membrane around the spinal cord. The orange membrane surrounds another membrane called the subarachnoid tissue, which surrounds the spinal cord itself. The dura is really a membrane, it's as tough as leather, that does not heal well, so if you tear your dura, which is very difficult to do, but if you tear it what happens is your body tries to heal it by bringing in new blood vessels, new cells. The immune system goes in there and really tries to do its best to heal that tear and keep any spinal fluid from leaking out. The problem is that the recruitment of those small blood vessels and the inflammation really doesn't do the job well, and instead that weak healing process just leads to more bleeding over time as you tear and re-tear over the course of years.

How do we know if the bleeding is coming from the spine? The best clue is to look at the brain MRI. If the hemosiderin deposits are equal on both side of the brain, it almost certainly came from below, and, as I mentioned, by gravity the iron deposits layer on the bottom of the brain when you lay down. That's how we know the bleeding is coming from the spine. The other way is to do an MRI on the spine and look for the dura that's been torn and displaced. It's not always detectable, and about a third of our patients we cannot find the source of the bleed. The best way to identify the exact precise site of the tear of the dura is to do what's called a CT myelogram. And that’s where, it's like a lumbar puncture, but you don't go in as far, and you inject a dye that travels on the outside of this membrane, and wherever the tear is it quickly travels on the other side. When you see that dye moving, then you know that you found the tear. As I mentioned, sometimes the dura is sealed by the healing process. Even if it's not that good of a seal, the dye can't get across, and so by the myelogram it will normal. You have to actually be bleeding or have a torn dura for the CT myelogram to detect the tear.

I pose here a theoretical question. Does it matter where the bleed is coming from? The reason I pose that question is because if you're on an iron chelator like [ferriprox 00:15:26], which is much better at chelating active iron than it is at chelating hemosiderin, then if you're on ferriprox when you bleed you've pretty much chelated all that blood, and so it doesn't really matter that you can't find the source of the bleed, it doesn't matter that you should be really trying hard to find the source of the bleed if the ferriprox is just going to chelate it. That's something to consider, and we'll talk more about that later.

Slide 7

The typical course of this disease is slow. I put that in caps because there are no emergencies with Superficial Siderosis. Things do get slowly worse over time, and that's concerning to most people, but they get worse very slowly. I mentioned it takes a long time for the disease to progress, but it is progressive, so once you start to get worse, you're going to continue to get worse. Usually, hearing starts first, but sometimes bladder problems start first. Most of my patients have trouble walking, and many of them have bowel or bladder dysfunctions. These tend to occur later. As I mentioned, there are many functions within the spinal cord, including autonomic function. That's blood-pressure control, sexual function that can be affected as well.

Slide 8

I get this question a lot, so I thought I would address it in this presentation the question a lot of patients ask is, does superficial siderosis lead to an early death? We don't know the answer to that. We don't know if superficial siderosis causes an earlier mortality. The reason we don't know that is because we haven't studied enough patients over time to be able to see that. I can give you my personal experience. I've seen at least seventy patients, and so far two have died. Those were men in their seventies. One died of a stroke, and one died of cancer. They were in their seventies. The average lifespan is somewhere around seventy-six to seventy-eight for men, so they were slightly younger than that. Whether or not that's hastened by superficial siderosis, I don't know.

Now we have had three strokes in this patient population so far. They were all men, at least sixty years of age with other stroke risk factors. It could be that superficial siderosis is a risk factor for stroke. We haven't seen too many other comorbidities so I can't say that there are any other particular diseases we should be looking for in patients with superficial siderosis that may cause an early death.

The one phenomenon I want to mention is called neurological reserve. Neurological reserve is really the capacity of the brain to handle stress. If you think about a baby who's under stress, it really can't handle it and they quickly lose their neurological function very quickly. Same with older folks. An older person may have an infection and then slow thinking is a result. You treat the infection and the thinking improves. That's really because the neurological reserve in young and the very old is reduced over time. The same is true with superficial siderosis. The neurological reserve is reduced, so when you undergo a stressful or metabolic stressor, you may find that your symptoms are exacerbated. A classic presentation is a patient going under

anesthesia for surgery requiring more time to recover from the anesthesia. That's a classic presentation.

Slide 9

Ok, let's talk about treatment options. The way we used to manage this condition is to just kind of stop the bleeding. We know from patients who bleed all the time, one-time bleeds from trauma or hemorrhages or strokes, that the brain is capable of removing the iron, so we were thinking that if we stop the bleed that the brain would be able to just remove the iron over time and we found that didn't work, and probably the reason it didn't work is because when patients finally presented with symptoms the capacity of the brain to remove more iron was finally overwhelmed, and so stopping the bleeding at that point did not help. So our current approach is really to try to not just stop the bleeding if it helps, but also to remove the hemosiderin and iron that's bound to the ferritin; to try to remove that as well.

Slide 10

So let's discuss how we stop the bleeding. There are three ways that we approach this. The first way is through an exploratory surgery. You may be able to find a neurosurgeon or orthopedic surgeon who can go into your spine, look around, and try to stop the bleeding at the source. Sometimes exploratory surgery identifies the tear or the site of bleeding, but sometimes it does not. There are risks, obviously, going under the knife, but there are potential benefits. If you find a surgeon, who is really keen on finding the leak and can do it and feels confident doing it, give them at least a chance to explain themselves.

Another approach is called direct fibrin injection. This is when we know the site of the bleed. We'll insert a needle between the bones to the space right near the site of the tear or the bleed, and we inject the blood product called fibrin. Fibrin is a glue which seals the membrane that's torn and provides a good seal for at least a few weeks, gives the immune system and the healing process a chance to really try to fix that tear better than without the injection.

The third approach is what's called the blood patch. Blood patch is where we insert a needle into the lower spine. No matter where your tear is the needle goes into the lower spine, blood is injected from your arm, blood is taken out, and then re-injected back into your body through this needle, and the blood goes on the outside of the spinal cord and pushes that lining around your spinal column and triggers an inflammatory reaction. The blood there keeps the dura in place, triggers an inflammatory process that really gives the dura a chance to heal. Sometimes it works, sometimes it doesn't. The blood patch is by far the safest of all the approaches, followed by the fibrin injection, then followed by the surgery after that.

Slide 11

Ok, the approach we've taken recently is to use what's called an iron chelator. This is a molecule that binds the iron. Very simply, the goal here is to try to remove the iron that's on the surface of the brain and spinal cord, and to see if the brain and spinal cord can heal once the iron is removed. The reason that we use Deferiprone or Ferriprox is because it's the only iron chelator that gets in the brain. There are three or four or five other iron chelators on the market, but none of them get in the brain. So they circulate in the blood, but they won't get in the brain.

We performed this study of ten subjects with Ferriprox using the drug over three months and followed them by clinical measures and by MRI, and we found that in four of the ten subjects the MRI improved in as little as three months. So then we extended it out as an observational study to thirty-seven subjects, following them for two years to see if we can detect a clinical benefit, and what we found is that most subjects take at least two years to really see that improvement on MRI. Almost everyone had improved, at least by MRI, and what we really need now is to see what happens after that iron is gone.

So in many of these patients, as the iron disappears, can we then detect a clinical benefit? Is there a healing period that's required? We don't know. Does all of the iron have to be gone before the healing can begin? We don't know. We do know that in the first two years as the iron is being chelated there's no real clinical benefit. We don't see patients getting much better, at least initially, because the iron is still there, and it's still being toxic, and so the healing process is really limited early on. What we really need to see is, when that iron is finally gone, then can we see a clinical benefit?

Slide 12

Here are the alternatives, tested and untested. There are copper chelators that get in the brain. They do not work. Less common is Triamterene. It doesn't work for Superficial Siderosis, although it is a weak iron chelator. There are other iron chelators, as I mentioned, available on the market, but they don't get in the brain. One example is Exjade. There's no point in taking Exjade because it's just going to chelate the iron in the rest of your body. What you need is to chelate only the iron in your brain and spinal cord. People have thought, well if you're bleeding into the spinal fluid can you shunt that spinal fluid out into the body instead of letting it circulate around? It's a good thought. The truth is, though, is that you need spinal fluid to buffer your brain, and so you can't shunt all of it. Shunting part of it, it delayed the onset of disease, but it doesn't change the progression of the disease. Doing nothing is not an option. Doing nothing means that you're going to progress. We were hoping that some patients, that they maybe could stabilize and maybe do fine in the long term. That doesn't happen. Everyone progresses.

Here are some untested alternatives that I personally do not have experience with, but my patients brought to my attention. One is Inositol Hexaphosphate. It's a vitamin, IP6, that apparently gets in the brain and apparently is an iron chelator. That's the combination we're looking for. I don't have any experience with it, but if other people do I'd love to hear from you. Curcumin is a derivative from turmeric, and it's been purported to be an iron chelator and get in the brain. And we are aware of new iron chelators that are being developed by pharmaceutical companies, that have penetration into the brain. Those are maybe promising.

Slide 13

As I mentioned before, our ongoing research is really to look at these patients who are on an iron chelator for a long time. Because again, what we really want to know is, once that iron is gone does the clinical benefit fall out? We know we're good now with removing the iron. The question now is, does that provide a clinical benefit?

So I would like to acknowledge my patients who set up this group in the U.K. called The Silent Bleed. They've been helping raise money for research, which we've been using towards these clinical trials.

That's the end of this webinar. You can always reach me at [email protected]. If you have any personal questions, I'd be happy to answer them. Thank you very much for paying attention

There are 2 different types of Superficial Sideroses, one is Superficial Siderosis "of the central Nervous System", and the other is "Cortical" Superficial Siderosis, commonly seen in Cerebral Amyloid Angiopathy patients. If you're interested in the latter, you'll find ressources in the attached RG project ; Imaging biomarkers of hemorrhagic small vessel disease. Best regards 

Thanks Gregorie.  My main interest is in CNS-SS.  However cSS is of interest as I have had contact with people who have had bleeds which resulted in CNS-SS who have also had strokes.

I am particularly interested in:

What type of MRI scan or scanner is best for diagnosing SS initially; 

How CNS-SS or indeed cSS is best monitored following the initial diagnosis;  

Treatment options such as currently being investigated by Dr Levy of Johns Hopkins Baltimore; 

How decisions on what degree of Siderosis should be treated or simply monitored; and

If monitoring is the preferred option, how often should monitoring MRI scans and other tests such as hearing and balance be done.