Dr. Deborah Friedman at the 2023 Cedars-Sinai Intracranial Hypotension Conference

Dr. Deborah Friedman, neuro-ophthalmologist and headache medicine specialist, presented this talk on medical treatment for rebound intracranial hypertension at the 2023 Cedars-Sinai Intracranial Hypotension Conference on July 9, 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] I’m going to talk a little bit about treatment of intracranial hypertension. There are no FDA approved medications for this purpose. And much of the content about treating intracranial hypertension is unfortunately not evidence based. It’s based on experience. So what I’d like to cover is the differential diagnosis a little bit but you really heard about it and a rational strategy for it.

[00:00:36] And I’d like to start with a case. So this is a 46 year old woman who had a history of orthostatic headaches for about 10 years, and they would come on later in the day, about six or seven hours after she was upright. She rated them a seven out of 10 in severity. They were at the top of her head, sharp pain with some neck pain; associated with photophobia, constant tinnitus, and pulsatile tinnitus in the morning. The headaches were daily. The pain was constant. The only thing that made them better was sleep and being at high altitude.

[00:01:09] And she also had some occipital pain and some pain between her shoulder blades, along with the neck pain. When recounting her history, she said, you know, the weirdest thing, about a year before she saw me, she woke up two days in a row with what she said was a wet ear. And there was a halo of blood and liquid on her pillowcase, and her headaches got worse after that. She got evaluated for a skull-based CSF leak, which was negative. And she was started on topiramate for headaches.

[00:01:39] Five years before she saw me, she was actually worked up for IIH. She had a lumbar puncture that showed a normal opening pressure. A CT myelogram showed multiple perineural cysts, but no leak. And she got a non targeted blood patch that lasted about a month. So this is her imaging from two years before she saw me, coming in with low pressure symptoms. And you can see that she doesn’t have anything that looks like low pressure symptoms or low pressure, but she does have pituitary flattening, and she has a little bit of extra fluid around her left optic nerve sheath, or within her left optic nerve sheath.

[00:02:16] Past history: Ehlers Danlos syndrome. She’s a little overweight. You know, I look in everybody’s eyes, no matter what, and she had normal optic nerves with spontaneous venous pulsations, a normal neurologic exam, but she did improve somewhat in Trendelenburg. She did have multiple perineural cysts, and we decided to target this big one down there at T10, which also gave her short-lived relief.

[00:02:42] She came back and she saw my nurse practitioner at the time who said, you know, if we think you have low pressure, maybe you shouldn’t be on topiramate. Maybe that’s not the right choice for you. So she took her off topiramate and the patient would come in every month or two and get blood patches, which gave her relief.

[00:02:59] However after her last blood patch, she developed a different kind of headache. Like Peter mentioned, worse when lying flat. And then she went into this pattern of waking up every morning with a headache that lasted about 10 or 15 minutes after getting out of bed, then she’d be okay for a while. And then about four hours later, she would develop her initial orthostatic headache.

[00:03:24] It turns out that stopping the topiramate might not have been the greatest idea, because she gained 30 pounds after stopping the topiramate. And oh, by the way, I’ve had these episodes of transient visual loss all my life. So now I look in her eyes, and her fundi are not normal anymore. She’s got bilateral papilledema, a little worse in the right eye.

[00:03:46] And her venous pulsations went away. So, I’m not going to talk a lot about the diagnosis, you’ve just heard it, but rebound intracranial hypertension can occur anywhere from immediately to several days after the blood patch. Most commonly, it’s either frontal or retro orbital. The orthostatic component disappears. This may be worse on awakening. Patients are unable to lie flat.

[00:04:10] Now, I’ll tell you that with de novo IIH, we don’t really hear about this reverse orthostatic component. I think it’s very unusual. But with RIH, it is very common. So why does it occur? Did we just over-correct? Did we disrupt spinal fluid absorption because of that blood patch and the blood adhering to the dura?

[00:04:31] Maybe? Is the brain making more CSF? I doubt it. Or was the primary problem that the patient had unrecognized intracranial hypertension and self decompressed by having a leak? And that leak can be anywhere, right? It can be in the optic nerve sheath, at the sella, at the skull base, or in the spine.

[00:04:52] Now these patients often don’t have papilledema, and this came up before. So why might you not have papilledema in the setting of high pressure? Well, maybe the patient had previous papilledema and it went away before you saw them. Maybe it was just mild and it resolved on its own. Maybe the patient did have optic atrophy.

[00:05:10] Now my mentor always told me that dead axons don’t swell. So when you look in the eyes, you might not see papilledema. But there was recently a presentation at the neuro ophthalmology meeting a few months ago, showing that optical coherence tomography can show subtle elevation in the nerve fiber layer in those patients who appear to have optic atrophy with recurrent IIH.

[00:05:35] Maybe you saw them very early in the course of the disease, or maybe they are leaking. There’s a lot of literature about IIH causing skull base leaks, and the folks that fix skull base leaks I think are pretty aware of this now. There was a nice retrospective study of 117 patients who underwent endoscopic repair for CSF rhinorrhea.

[00:05:58] They looked at the preoperative MRI and found that 90 percent of their patients had an empty or partially empty sella prior to having their skull base leaks fixed. And they, a lot of those patients also had other findings that look like what we see in patients who have IIH, but fewer than half had symptoms of IIH and only about 20 percent of them had papilledema.

[00:06:23] Now this is risen to the point of awareness in the skull-based leak community that there is an international consensus statement that was put out. Just, it was published in 2021, basically saying that if you’re going to fix somebody’s skull-based leak, you should ask them about symptoms of high pressure. I’m not going to go through all of them.

[00:06:43] And in the long term management after their leak is closed, they need to be aware that some of these patients are going to develop high pressure again, because maybe that was the initial problem. Well, what about spinal leaks? There’s a lot of anecdotal experience, and I’m just curious, like, how many people have seen this? People who have had blood patches, it turns out the initial problem was IIH. Okay. They’re not reported in the literature.

[00:07:09] So there’s a case from Duke that was presented earlier this morning, so I’m not going to go through that one again. But then there’s also a case series that was published quite a while ago of 26 patients with IIH per the IHS, which is now the ICHD criteria.

[00:07:25] Interestingly, 15 of them were men, which is pretty unusual for IIH. They presented with orthostatic headache or spontaneous subdural effusions or subarachnoid hemorrhage. And they had myelography and found leaks and had blood patches anywhere from one level blood patch to multi level blood patches.

[00:07:45] And most of them had improvement after their blood patches, but there was no mention of RIH. So what was the initial problem? And how do we pick this up? So first of all, if the patient has a previous diagnosis of IIH, that makes it a little easier. If they have a history of obesity or recent weight gain, other risk factors for IIH, undiagnosed or untreated sleep apnea, a history or symptoms of a prior skull-based leak. And that’s, I think my patient did. I think the otorrhea she had was a symptom of a prior leak that was just not detected. Or other IIH symptoms in the past, like pulsatile tinnitus or, in her case, transient obscurations of vision.

[00:08:30] If they have previous or current imaging signs of increased intracranial pressure. And in Wouter Schievink’s paper that was just mentioned in the last talk, he looked to see if the transverse venous sinus stenosis on MRI was a predictor of whether people would develop RIH. And in fact, it was, as was female sex. But what we’re looking for, of course, is the opposite of what we see in SIH, and Peter described that very nicely, with no other evidence of brain sag. The only reason I show this again is to say that none of these findings are really specific for IIH, and you can’t make a diagnosis based on an MRI alone.

[00:09:12] We’re seeing a lot of this in neuro ophthalmology. Patients are being misdiagnosed left and right, they’re being overdiagnosed, because they have a headache, somebody does a scan, and they find things that sort of look like SIH. So this is from studies that came out of Emory, and they’re part of a group of three different papers that they wrote. And I encourage you to read them. But they took almost 300 patients who were undergoing an MRI for various reasons. They sent a very industrious medical student down to the MR suite with a fundus camera. And they looked at all the results of the MRIs, and they also looked at the results of the fundus photography.

[00:09:53] The reasons for the MRIs were kind of all over the place, but fewer than 10 percent were getting an MRI for headache. And only less than 2 percent had a previous history of an ICP disorder. About a third were having surveillance imaging for a previous brain neoplasm. And they found that of these 300 patients, almost 50 percent had at least one sign that we think of as being associated with IIH. And there was a previous slide that was shown yesterday with the numbers, also from the Emory group, showing the, you know, incidence of empty sella that’s just, you know, found incidentally on an MRI scan. It was about 20%. They found it in 33%. Followed by enlarged Meckle’s cave, increased perioptic CSF, and you can see the rest of them. Only about two thirds of the patients had an MRV because they were just getting this for clinical care, and only 3 percent had bilateral transverse sinus stenosis.

[00:10:49] Five had papilledema. So of the five that had papilledema, two had the history of IIH with worsening headaches, so you would expect that. Two had a glioblastoma. So you would expect that. And one patient had temporal lobe seizures from a meningoencephalocele. And as the number of MR signs increased, the likelihood of having papilledema increased.

[00:11:10] But the bottom line is, only five patients out of 300 had papilledema. And 50 percent out of 300 had these MR signs that we think about with II h. So their conclusions were that MRI signs were very common but rarely associated with papilledema, and incidentally detected signs don’t require a lumbar puncture unless there are concerning symptoms present.

[00:11:35] So let’s move on to treatment for intracranial hypertension. You know, the easy thing to do initially, first of all, I tell my patients to restrict their salt. Sleeping reclining, sleeping sitting, elevating the head of the bed. Tea: I know that Dr. Schievink likes dandelion tea. The only article I found out about tea, and there was one, it was not specific to dandelions. But somebody prescribed for their patients drinking eight cups of caffeinated tea per day for their rebound intracranial hypertension, which I find interesting because we use caffeine to treat hypotension right after spinal tap. So, I guess the diuretic effect in this case outweighs the vascular effect.

[00:12:23] Other things we can think about, and I’ll talk about medical management, therapeutic lumbar puncture. A lot of patients in my experience are reluctant to have this. They don’t want anything stuck in their dura again, they’re done with that. But let’s talk about some medical management. So the first choice is usually acetazolamide. This is the only medication that’s ever been shown in a randomized trial to be helpful for IIH. The starting dose is usually 500 milligrams twice a day for IIH. I would say probably similar, 500 once or twice a day for RIH.

[00:12:55] And in the clinical trial, we titrated up to four grams of acetazolamide a day in people who could tolerate that. If your patient doesn’t tolerate acetazolamide, but they’re not allergic to it, you might want to try methazolamide. I find that it is actually much better tolerated. The starting dose is 25 milligrams twice a day, and you can ramp it up to a few 100 milligrams a day as needed. Third choice after that. is furosemide, which also works by decreasing the secretion of CSF from the choroid plexus. Bumetanide, there’s no real evidence for it. It’s never really been studied, but the advantage of Bumetanide is that you can give it IV. So if you have a patient in the hospital and you want a diuretic, you could try Bumetanide. Acetazolamide can also be given IV.

[00:13:44] Fourth choice. It’s sort of up to you, whatever you like. If you have an allergic patient who’s truly allergic to acetazolamide, not just to sulfa antibiotics, because they’re different sulfa groups, and usually there’s no cross reaction. You could try either triamterine, spironolactone, or ethacrynic acid. Just be careful if you’re combining diuretics because people can get very hypokalemic.

[00:14:08] Then if you need to, that’s treating the pressure, right? Does treating the pressure work? Well, for most people it does. For most people they get better. But if your patient has prolonged headaches, then we’re going to think about treating the headache. So, we tend to treat according to the phenotype, whether it’s migraine, whether it’s tension type headache, whether it’s a unilateral headache like hemicrania continua.

[00:14:31] So as far as the symptomatic treatments, a lot of different things we can use, anywhere from anti-inflammatories to acetaminophen; indomethacin in particular has, there’s evidence that it lowers the intracranial pressure. Now, it’s a tough drug to take. It’s hard on your stomach, but you can try indomethicin. There are a lot of other medications that we can use for people who have a migraine phenotype, including the triptans, ditans, the newer medications, gepants, dihydroergotamine. And you know, many of these patients with not only with leaks, but also with IIH, have a prior history of headache.

[00:15:08] It’s extremely common, much more common than in the general population. So there, there may be a component of central sensitization for these people that have prolonged headaches. I would say avoid opioids, avoid butalbital, and use antiemetics as needed. Now if the headaches really won’t go away and they persist after weeks, and you wanna think about maybe adding a preventive, we usually consider adding preventives for people who are having headaches at least once a week.

[00:15:36] And of the generic orals, which I’ll go through in a sec, we usually start at a low dose and gradually work up. For CGRP antagonists, the only one that’s been studied thus far and published is erenumab, which was studied by the group in the UK, and they found that it was helpful in their patients who have IIH.

[00:15:54] We also did a retrospective study, looking at all the different injectable CGRP antagonists and found that actually they did help for many people. Just if you’re thinking about the old orals, consider that many of them cause weight gain, which is probably not what we want to do.

[00:16:10] So some of the medications we can think about topiramate, zonisamide. Again, if you’re thinking that maybe the primary problem was high pressure before the patient developed low pressure, I think it’s a good choice. I actually use a lot of topiramate in my IIH patients as well. Then just other things that we use for headache prevention. Low-dose tricyclics, indomethicin, if the patient could tolerate it. Naproxen can actually be taken every day. If their headache sounds like chronic migraine, you can consider onabotulinumtoxinA. SNRIs, SSRIs; calcium channel blockers I tend to avoid, because they can cause peripheral edema. You know, almost anything you can think of that we use for migraine or tension type headaches. We don’t really know about devices. We don’t really know or have great evidence for cannabinoids.

[00:17:01] So, back to the case. We started her on acetazolamide. She hated every minute of it. She couldn’t think straight on it. She was just miserable. And then she ended up having to, like, take low doses every couple of hours. She was waking up in the middle of the night to take azetazolamide. We changed to methazolamide; it was better tolerated, but it didn’t work as well. Then we added furosemide. She had several therapeutic LPs after some negotiation, which helped for a little while, and she was pretty distraught.

[00:17:28] So then we considered, well, maybe your problem actually was you had IIH to begin with. So we talked about the options: shunting, stenting, fenestration. There was really no indication to do an optic nerve sheath fenestration. She had good vision and really minimal papilledema. I, no offense to the neurosurgeons in the room. I try to, you know, keep your life happier by not sending you patients who have IIH for a shunt. But she didn’t want to have a shunt either because she didn’t want something poking in her dura. And also she had Ehlers Danlos, so she’s concerned about that. So we ended up stenting her. And She she did well.

[00:18:06] This was her numbers before and after stenting. So she had a gradient of 21 before, and less than five after the stent. And there’s her post-stent. She had this weird little kind of a fenestration in her sinus. So.

[00:18:20] In summary, RIH, it’s different from IIH. It’s a different kind of headache than these patients are used to. And the transverse sinus anatomy may be a predisposing factor for them. Often a therapeutic lumbar puncture is enough to relieve their symptoms, and most people do well, okay?, most people do not have underlying IIH. But I think it’s something to think about in patients who have a prolonged course, that maybe we just missed something way back when, and maybe their IIH was never really manifested in the typical way because they decompressed themselves. Headaches are usually self-limited. First line treatment, acetazolamide or methazolamide. And I would say surgery should be saved as a last resort in case patients don’t respond. Thank you very much.