Advances in fluorescein-guided techniques for brain tumor and vascular neurosurgery

Recorded webinar from May, 2020

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Prof. Dr.med. Karl-Michael Schebesch

Department of Neurosurgery, University Hospital, Regensburg, Germany


Summary

Prof. Dr. med. Karl-Michael Schebesch talks about improved brain tumor and vascular neurosurgery treatments using fluorescein-guided techniques

In this recorded webinar he explains the theoretical operating principle of using fluorescein sodium in neurosurgery and why intraoperative visualization of brain tumor is so important. He shares his vision on how to increase the quality of tumor resection while also explaining the usage of fluorescein sodium treating cerebral metastases.

Answers from Prof. Dr. Schebesch to questions asked during the live webinar

Fluorescein Sodium

Which pharmaceutical companies are providing Fluorescein Sodium?

In Germany it's Alcon. In the rest of the world I don't really know, but I am absolutely sure that it is available, because as I said, in ophthalmic surgery it is used everywhere for decades. So it must be available and we take the same product as they provide for ophthalmic surgery.

What is the cost for Fluorescein Sodium for one surgery?

In Germany it is below 10 € and the filter, of course, for the microscope.

What is the maximum dose which can be applied to a patient?

There are some reports in literature coming from Asian centers from the 1990s and the early 2000s and they have administered 20 milligram per kilogram bodyweight. The two reports on intraoperative blood pressure drop were with that high dosages. So, I would not recommend to take more than 5 milligram per kilogram bodyweight. When you have the filter - this is crucial - then you can decrease the dose even down to 2 or 3 milligram per kilogram bodyweight.

What is the maximum dose per day, if it is repeated and after which time can it be repeated?

I cannot really answer this question. I don't know. We rarely need more than one injection once, so I cannot answer this question. I am very sorry.

Can you explain the dynamic of Fluorescein Sodium?

The dynamic: As in vascular procedures you have seen that it is circulating very intensively, immediately staining the endothelium and then accumulating in the next minutes in the disrupted blood brain barrier and for the next, let's say 30 minutes, it is contaminating the blood, the CSF and it accumulates in the blood brain barrier but after it is circulating, it is washed out and then; and I hope this is the answer to the question; Then the dynamic is slowing down and then you have a stationary accumulation of fluorescein sodium for the next hours.

Do you have any experience in using fluorescein under white light and without the yellow filter?

No. There are first reports under white light. Fluorescein Sodium then must be administered in much higher dosages, like 20 milligram per kilogram bodyweight. Then you can even have an effect under the white light, yes. But I think that it is not really dangerous, but I don't have an experience with that high dose, so I would be very cautious and careful.

Do you have to adjust the dose of fluorescein according to the glomerular filtration rate?

We always check the renal function with the laboratory findings and when we have a normal or a slight pathologic, but not a severe failure then we administer it. I am not sure but maybe there are some reports on the glomerular filtration rate and possibilities, but I am very sorry, I don't know.

What kind of side effects have you obtained?

We have never obtained side effects. But you have to remember, and this is something that I have forgotten to say in fact, that there are of course some limitations to the use of fluorescein sodium. Thank you very much for this question.
The first of course is a known anaphylactic reaction to former use of fluorescein sodium like in ophthalmic surgery and the most important thing is that you don't administer it in patients with severe renal and hepatic failure. So, this is a very important thing to remember. Because fluorescein sodium is eliminated renally after a couple of hours. During that time the urine becomes very yellow and sometimes very slightly the skin also becomes a little bit yellowish. But no other side effects have ever been encountered with the dosage of 5 milligram per kilogram bodyweight. There are two reports in neurosurgical literature from Asian centers with very high doses. Like four times higher than we have for study purposes. So I think I can say that when you remembered the exclusion criteria you don't have to fear any adverse events.

Did any patient develop anaphylaxis in your experience?

I'm absolutely honest, we have never seen anaphylactic reactions.

Does 5-ALA or Fluorescein Sodium have side effects on the brain?

Not on the brain, but 5-ALA can cause severe skin reactions, very rarely, when exposed to very intensive light and fluorescein sodium is eliminated renally completely after a while. So, it doesn't accumulate in the brain and it is washed out and after 12 hours, I think, it is eliminated completely. So, it doesn't accumulate in the brain and stays there.

Dr. Schebesch, do you have experience in using fluorescein sodium with a Blue 400 filter?

Yes. The first publication, from the Besta Institute in Milan, Italy, which I have shown in the presentation is with the Blue 400 filter and fluorescein sodium. You don't have that brilliant imaging that you have with the Yellow 560 filter, but you can of course use it. It has not the similar but comparable wave length and yes you can use the blue filter for fluorescein sodium visualization.

Have you ever used 5-ALA and Fluorescein Sodium simultaneously?

Yes, we did. But I was not convinced that this is beneficial. There is one publication from the Münster group. They have concluded the fluorescein sodium and 5-ALA combination under the blue filter. Fluorescein sodium is enhancing the environment, but 5-ALA is enhancing the tumor, so this can be beneficially used. But in my experience it was not a really reliable visualization of the surgical field.

Are you using Fluorescein Sodium for epilepsy surgery ?

No. Simply because we don't do epileptic surgery in great style here.

Tumor

For tumor resection, do you inject the dye? What is the timing for the application?

Yes we inject it. Now we inject it during induction of anesthesia. After the central venous line has been established and this is here in our hospital something like 30 - 45 minutes prior to skin incision. Let's say after 60 minutes we have the craniotomy performed, we have the Dural opening and then we can have the effect of fluorescein sodium as an accumulation in the disrupted blood brain barrier for at least two to three hours of surgery unproblematically.

What is your surgical strategy to get the most resection in grade II gliomas?

Again, very important question. Grade II gliomas are really challenging. And to be honest, I cannot really identify, or we are not able to identify patients eligible for fluorescein sodium guided resection properly. However, as I said when you have a strong metabolic activity which you can nowadays visualize with a FET-PET then I think in those selected patients you can beneficially use fluorescein sodium to guide your resection even in low grades. Even in grade II tumors which are not enhancing contrast gadolinium at all.

What the percentage of cases of grade II glioma will enhance on fluorescein

Difficult question. Good question but very difficult. Normally grade II gliomas have very heterogeneous entities and some of them they have very slight contrast enhancement. Some of them have a higher metabolic activity and in those selected cases but to be honest, really I don't know the percentage, fluorescein sodium can be a helpful adjunct, but these cases have to be identified in future. So, at the moment I cannot really answer this question properly.

Can we use Fluorescein Sodium for pituitary micro adenoma?

To be honest: I don't know. I have never evaluated and I'm not sure about that or I don't remember a group or a publication focusing on the benefit of fluorescein sodium guided surgery in pituitary adenomas, but this has to be evaluated. But I don't know to be honest.

Is fluorescein useful in producing adenomas?

Yes, that is a question from before. I think you mean pituitary adenomas and I really don't know it. It has to be evaluated. I'm not sure whether some colleagues have already tested it but I don't have any information on this.

Do you have experience in pituitary surgery? In particular microadenomas and cavernous sinus invasions?

To be honest: No, I don't have an experience on the use of fluorescein sodium in pituitary adenomas. This is a very important question, but again I don't have an experience. I can not say something concerning this.

Did you use Fluorescein Sodium for cavernoma surgery?

I did two or three times, but cavernomas normally do not enhance properly with gadolinium and you don't have a dedicated disrupted blood brain barrier. So it can work, but it is not that it is reliably effecting cavernomas.

What do you think about the use of Fluorescein Sodium in pre-operative embolization of tumors?

Once a tumor is embolized preoperatively by glue or coils or whatever, then you have sever changes of the perfusion of the vascular leakage and I have no experience on the possibility of the use in fluorescein sodium in pre-embolized tumors.

What is your experience with cystic tumors?

Cystic tumors are intensively enhancing once the marker gets into the cyst. I haven't shown pictures, but I have very impressive pictures of cystic tumors. Especially of metastasis with complete enhancing cyst.

Can Fluorescein Sodium be used for brain stem glioma resection?

Yes, it can be used and especially the colleagues from Turkey, Talat Kırış, he has a huge experience on the use of fluorescein sodium in brain stem surgery, tumor and vascular. He's always saying that you can very nicely have the visualization of the surgical field especially, concerning the tiny and perforating arteries of the brain stem.

What is the advantage of using fluorescein in meningiomas specifically?

This is a good question. So, to be honest, I don't use it myself in meningiomas. But the colleagues from Turkey have focused on that and they have found out that you can nicely visualize the Dural tail, for example, which can be sometimes challenging to identify intraoperatively under white light. In meningiomas invading the superior sagittal sinus, for example or the transverse or sigmoid sinus, it can also be very nice to have it. Because then you can easily identify the spreading of the Dural invasion in meningiomas.

Has there been any work aiming at hybrid compounds with fluorescein to target normal tissue such as cranial nerves in vestibular schwannoma?

There are some publications from a couple of years ago from I think Southern America, Brazil or Argentina, in a few acoustic neuromas in order to identify the cranial nerves the vestibular part of the cranial nerve but I have also administered it in such cases and I was not convinced that this could really help in the small surgical field for cranial nerve identification. So, I don’t rely on this in this special case.

What is the structure/ substance (like inflammatory cytokines) that fluorescein binds/target in brain and make the tumor be visible?

I don't understand it properly, but I will try to answer as well fair and good as I can. Again, fluorescein sodium is not binding to the tumor. It is not metabolized; it is a vascular leakage permit. Originally it has been designed as a vascular dye just like gadolinium. We have a similar molecular weight. Both dyes are vascular dyes. Leakage parameters are not specifically turned over in tumors. So, it accumulates in the disrupted blood brain barrier.

You seemed to have done everything possible with fluorescein and brain tumors! Do you think there are questions still left to answer or is it ready to roll out for clinical use?

There are still questions of course - always. The most important one nowadays is the quantification of the intensity of fluorescein signaling. So, there are some groups approaching this very sophisticated idea. Is it that we can have a different kind of intensity of the fluorescence staining and does this correspond to the tumor entity or to the part of the tumor you're working at? But this is something which we have to wait for. I think at least some years before we can answer it properly. But I think, and this was the most important part of this question, that it is ready to roll out for the clinical use - Yes, it is.

Vascular

Please clarify the timing of dye for Aneurysms.

It's just in the same way as ICG is injected from the anesthesiologist via the central venous line in a very low dose. You take one milligram per kilogram body weight and it has to be administered after you have dissected the aneurysm. Then you switch to the filter and then inject. A couple of seconds later you have the visualization of the aneurysm. Of course not before, but after clipping in order to confirm the accuracy of the clip and the patency of the parent vessel.

How to differentiate pre and post clipping of aneurysms, after injecting Fluorescein Sodium?

Only after of course. But I've shown the videos in order to have the most well illustrative cases shown. But of course I would not administer it before, but only after clipping.

What dose do you recommend to aneurysm and AVM surgery taking into consideration the endothelium staining. Can you use repeated doses?

Of course, you can repeat after a while. You have to wait, in my experience, at least 10-15 minutes. But in that time, even with a very low dose, like we have experienced one milligram per kilogram body weight, you have a severe staining of the endothelium, which doesn't allow a second or third injection immediately after the first one. So please wait 10-15 minutes and then you can repeat the injection.

In cerebral aneurysms, what is the advantage of using it prior to clipping? Is it not better to use it as a post-clipping transoperative angiography?

Yes, it is of course. But when you start to evaluate a technique like this, it is sometimes even for illustration purposes and for assessment. Just to have the dye evaluated before the clipping in order to see how the aneurysm is stained. But I agree totally that it its only helpful in order to have the confirmation of the clip accuracy and of the patency of the parent vessel of course.

In our experience we use 0.5 ml of a 10% solution and we found that the dose can be repeated without much endothelium staining.

Yes, that's great. I think yes, I have experienced some cases. I don't know why some patients or is it the thickness of the arteries of the endothelium? Whatever, with a very low dose like 0.5 milligram, yes, you can be very lucky, when you can repeat the injection immediately after the first one. But in my experience with our dosage of 1 milligram per kilogram we wait 10-15 minutes before we repeat it.

General

Are there any limitations in the pediatric population?

First of all, it is off label in adults and in pediatrics. You have yet the written inform consent from parents but there are no exclusion criteria despite severe renal or hepatic failure and of course any known anaphylactic reactions of a former use of fluorescein sodium like in ophthalmic surgery. But we have not encountered one severe anaphylactic reaction in our patients - adults and pediatrics - with a dosage of 5 milligram per kilogram body weight. The only two reports coming from Asia, decades ago, with very high doses and they had an intraoperative drop of the blood pressure which was fully reversible. There are only two reports in literature.

What about the pediatric age group?

Yes, it can be used very beneficially with a very, very low dose of fluorescein sodium administered intravenously in the same way. Like 30 - 45 minutes prior to surgery in various kinds of pediatric tumors and we have used it and I would always recommend because it is not sure that 5-ALA is working in children in the variety of pediatric tumors.

How can I get training?

I think you have to be trained. This is a very brief training but a very intensive one. Maybe Sebastian you can answer it.
Sebastian: We from Zeiss we offer trainings - when we don't have a Corona Pandemic going on - we offer training twice a year in Regensburg together with Prof. Schebesch and his team where you learn all the important details about this filter and dye and then we also offer twice a year a training in Milan in the Besta Institute with Dr. Acerbi. Now to register the best is to reach out to your local sales organization and then they can manage to take the steps which are needed.

Has confocal laser micro endoscopy been able to identify brain-tumor interface ex-vivo?

Yes. It has been capable of identification of brain tumor interfaces but still under scientific evaluation we hope that we can publish the first results in the near future, but we have to wait until we can legally start the study.


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