Dr. Jennifer Harris at the 2023 Cedars-Sinai Intracranial Hypotension Conference
Dr. Jennifer Harris, assistant professor of neurology and director of vascular neurology fellowship at Cedars-Sinai, presented this talk on superficial siderosis at the 2023 Cedars-Sinai Intracranial Hypotension Conference on July 8, 2023. The conference was hosted by Cedars-Sinai with generous support from the Spinal CSF Leak Foundation in Kohala Coast, Hawaii.
Transcript
[00:00:12] Hello everybody. Thanks so much for having me. Again, my name is Jen Harris. I am a vascular neurologist at Cedars Sinai. I’m also the director of the vascular neurology fellowship program there, and I’m going to talk a little bit about superficial siderosis. I have nothing to disclose.
[00:00:28] This is a little outline. We’re going to briefly touch on what is superficial siderosis, pathophysiology, epidemiology, how do these patients present, diagnosis, and management. So superficial siderosis is rare. Actually, matter of fact, when I was a resident at Beth Israel Deaconess in Boston, or even as a fellow at Columbia, I saw superficial siderosis in relation to CAA, cerebral amyloid angiopathy, meaning like supertentorial superficial siderosis, but I’ve never seen a case or heard about infratentorial superficial siderosis until I started at Cedars and Dr. Schievink had asked me to see a couple of his patients. So it’s pretty rare. It’s the result of hemosiderin deposition in the subpial layer of the brain, cranial nerves, and spinal cord. And this is actually one of our patients. It’s an MRI SWI sequence and you see the hemosiderin deposition around the brainstem and the cerebellum.
[00:01:20] It’s thought to be due to an insidious low volume, chronic leak of red blood cells into the subarachnoid space, and it’s often due to a spinal defect. This is just a schematic in regards to the pathophysiology. Essentially, the thought is, if you have or if you have a patient with a dural defect, that the red blood cells can leak into the subarachnoid space, and there they are broken down to heme.
[00:01:43] And this triggers the microglia to produce hemoxygen as one, which breaks down the heme into ferrous iron, which is toxic, which in turn triggers the Bergmann glia to produce ferritin, which binds that ferrous iron and produces the hemosiderin that we see on imaging. And the thought is that over time, when you have this chronic leakage, that the ferritin system is overwhelmed and you have all this free iron, which is neurotoxic and it produces the symptoms that we see in our patients.
[00:02:11] Now, this is very important. Okay, there are different subtypes. We have cortical superficial siderosis, which I already touched on, which is basically a localized form of superficial siderosis. It’s asymmetric. It’s focal areas of hemosiderin and the supratentorial cerebral convexities. And in the elderly, it’s often associated with CAA, which can present with cognitive impairment.
[00:02:32] But this talk is about infratentorial superficial siderosis, and there are two types. Type one is the classical one, and it’s essentially hemosiderin deposition predominantly in the posterior fossa, and it’s in patients with no overt source or history of hemorrhage. And it’s most commonly attributed to some form of spinal defect such as a CSF leak from prior neurosurgery, trauma, osteophytes, connective tissue diseases, to name a few.
[00:02:57] We also have intratentorial superficial siderosis type 2, which is the secondary type, and as the name implies, it’s usually attributable to a history of prior intracranial hemorrhage. Again, it’s pretty rare. Prevalence is estimated to be one in a million. In the U. S. in 2020, there were an estimated 200 diagnosed cases, which is actually double from 2014.
[00:03:20] And the thought is that, you know, you have better imaging and more awareness, so it’s increasing now. Patients with iSS often present in the fourth to sixth decade, because again, it’s a slowly progressive disease, and there’s a higher prevalence in males, and this is thought to be due to just higher incidence of trauma in males.
[00:03:38] Circa 27 percent are bed bound at 1 to 37 years from the first symptom due to either cerebellar ataxia, myelopathic syndrome, or both. When you see these patients in clinic, the cardinal symptoms are usually progressive sensor neuronal hearing loss, ataxia—so oftentimes these patients are actually misdiagnosed with cerebellar ataxia— myelopathy.
[00:04:00] And this table is actually a table from Dr. Levi, where they looked at the most common presenting symptoms. And again, hearing loss, 81%; ataxia, 81%; myelopathy was 53%. And then we have some non classical symptoms such as anosmia, bowel and bladder symptoms, cranial nerve palsy, and headaches, which is oftentimes a intracranial hypotension headache due to the CSF leak.
[00:04:21] One thing I didn’t put on the slide, but the median latency from presumed traumatic event to onset of first symptoms in one series by Wilson was around 19 years. And when we actually looked at our patients at Cedars, we looked at our patients with symptomatic intracranial hypertension and followed them to see if they develop iSS [infratentorial superficial siderosis].
[00:04:39] And for us, it was a latency of 126 months. The diagnosis, you diagnose it usually with an MRI brain. And again, you will see the hemosiderin deposition in the cerebellum and brainstem on iron sensitive sequences such as SWI or GIE. And then on spinal imaging, you can sometimes see, Dr. Stoodley also pointed, out there’s a hypointensity, this rim of hypointensity around the cord on T2-weighted imaging.
[00:05:09] But the next question you have to ask yourself, where was the blood coming from? And again, since most of the time it’s due to some kind of spinal defect, we usually start with MRI of the neuraxis. In this case, like if you look for a spinal leak, obviously MRI of the brain, of the spine, oftentimes this will not show you anything.
[00:05:23] So the next step is an MR myelogram, like as Dr. Maya pointed out, we often use the a heavily T2-weighted one because it doesn’t require any injections, but at one point they will need some form of dynamic either CT guided myelogram or digital subtraction myelogram.
[00:05:43] This is just a nice algorithm that I like that basically summarizes a diagnostic pathway, but essentially if you have a patient with superficial siderosis, and it’s basically summarizing what I just said, but superficial siderosis, and it’s mostly infratentorial and they didn’t have any recent like trauma or like ICH, then it’s Probably iSS type one, a classical one, and the next thing would be an MRI of the spine and followed by some form of CT or MR myelography. And if you find something, you refer them to people like Dr. Schievink.
[00:06:13] Treatment options. Again, because oftentimes you usually deal with like some leak, so you can do a blood patch where you just take some blood and squirt it into the epidural space. Obviously it’s not permanent and sometimes doesn’t work. You could do a fibrin injection, direct fibrin injection if it’s accessible, but really the most permanent and probably best option is surgical repair of the leak. But however, surgery arrests the bleed, but you still have all this hemosiderin in your brain and in the cord.
[00:06:40] So what we often use at Cedars is a Ferriprox or Deferiprone, which is an iron chelator, it’s FDA approved actually for thalassemia and sickle cell. But we use it off label. It crosses the blood brain barrier. It has like variable clinical and radiological improvement.
[00:06:55] It’s usually used at 30 mg/kg per day, orally given, two or three doses. It’s overall thought to be safe, but however, it can have some pretty significant side effects such as anemia, neutropenia, neutropenic sepsis, and agranular cytosis. So it requires frequent monitoring. I actually have one patient on it right now and we get weekly white blood cell count, we get like monthly LFTs and like ferritin levels.
[00:07:21] This was one of the first studies that looked at the safety of Deferiprone and this was a study by Levy. It’s a small study only used 10 subjects, but they treated these 10 subjects with 30 mgs/kg per day and followed them for 90 days, and over the 90 day period, actually, these patients actually didn’t have any adverse effects on hematologic, liver, or neurological function.
[00:07:42] They did some MRI assessments afterwards of the brain and it indicated that there might have been a reduction in hemosiderin deposition in some of these patients, and they concluded that overall, it was thought to be safe in this population. Later Martin et al. did a systematic review of the effect of Deferiprone on infratentorial superficial siderosis, and they included 11 papers with 69 patients, and out of these 69 patients, 25 percent discontinued the drug and the most encountered adverse effect was anemia at 21.7 percent, neutropenia was observed in 8.7, and agranulocytosis in 5.8 patients. The clinical response varied, and stability improvement was seen across six studies, and five studies showed like a mixed response. And on imaging 28.9 percent of patients improved, 53.3 at least were stable, and 17.8 deteriorated.
[00:08:36] In regards to prognosis, superficial siderosis, really it depends on like the underlying source and if you are able to arrest the bleed. And then also, it depends on at what stage the patient came to you, right, because surgery is not going to reverse anything. So, oftentimes the patients, when we see them in clinic, they already are left with permanent deficits.
[00:08:58] This is actually a pretty short lecture right now because, you know, there’s not much update on superficial siderosis, but Dr. Stoodley made me aware that one thing I forgot to mention is like, what kind of type of CSF leak is most commonly associated with iSS. And actually when we looked at this at Cedars, which I forgot to include here, but we found that in these patients that we looked at with SIH and a development of iSS, we found that the ventral leak was the most common one, and this has to do with the anatomy of the leak.