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My name is Richard Kim, a headache specialist with Premier’s Clinical Neuroscience Institute located in Miami Valley South in Centerville. I am also an assistant professor in Internal Medicine and Neurology with Wright State University School of Medicine.

Today, I will be reviewing the guidelines for migraine treatment and some just recently FDA-approved medications and devices. I have no disclosures. I will be discussing off label uses of medications, and I will be reviewing the guidelines for both acute and preventative treatment for migraine. I just want everyone to remember that our guidelines are based on the available evidence at the time they are written. Some of the older medications may not have enough funding to do a large clinical trial, which may affect recommendations.

Here are my objectives for today; I would like to review the diagnostic criteria for migraine and chronic migraine. I think it is important to have an accurate diagnosis before starting treatment. Also review the guidelines for acute and preventative migraine treatment and then discuss some recently approved FDA therapies and devices for migraine.

The diagnostic criterion for headache disorders comes from the International Classification of Headache Disorders and is currently in the 3rd Ed. Beta version. The diagnostic criterion for migraine is that the patient experiences at least five attacks fulfilling criteria B through D. So the headache attacks last anywhere from 4-72 hours, and it's important to realize that this is an untreated or unsuccessfully treated headache attack. Sometimes if the patient takes an over-the-counter medication for headache that may not progress, and they may not see all these symptoms or meet criteria.

The headache has at least two of the following four characteristics; unilateral, pulsating, moderate to severe in intensity, and aggravated by or causes avoidance of routine physical activity. During the headache at least one of the following are experienced by the patient; either nausea and/or vomiting or both light and sound sensitivity. So the patient does not have to experience all these symptoms, and classically when patients think about migraine they think they are nauseous and vomiting, but they don’t really need to experience those either.

The diagnostic criteria for chronic migraine include patients who experience headaches on at least fifteen days a month for the past three months. They have to have a prior history or diagnosis of migraine, and on eight or more days per month for the last three months, the headaches have to meet criteria for either migraine with aura or without aura. Or the headache attack must be believed by the patient to be migraine at the onset and relieved by migraine specific medications, such as triptan or ergot.

In 2015, the American Headache Society published an evidence assessment of the Abortive Treatments for Migraine. The Level A recommendation for medications proven to be effective include analgesics and combination medications; such as acetaminophen high dose at 1000 mg or the combination of acetaminophen, aspirin, and caffeine, brand name Excedrin. These seemed to be more effective for milder headaches. Also included in Level A recommendations are ergots, dihydroergotamine, both nasal spray and pulmonary inhaler, although the pulmonary inhaler is not FDA approved yet as they have been having some issues with manufacturing. There are several NSAIDs or nonsteroidal anti-inflammatory drugs that are proven to be effective. These include high dose aspirin, diclofenac, ibuprofen, and naproxen. All the triptans are Level A recommendations, as well as the opioid butorphanol nasal spray. However, it is generally not recommended to use opioids as first line, as they have an addictive potential and overuse can lead to medication abuse headache, which I will touch upon later.

Next, I will be discussing the triptans. I made this table to try and include clinically helpful relevant information. In the column labeled “dose and max dose,” the numbers prior to the slash are available strengths per dose. The max dose is the maximum dose in 24 hours. The triptans are seven different triptans, some of which have multiple routes of delivery.

Sumatriptan is the first triptan I will be discussing; available in three different routes. The subcut sumatriptan is available in doses ranging from 1-6mg with 12 mg the max for 24 hours. It has the fastest onset of action of all the triptans, starting at about 10 minutes. It's not able to be used with MAOIs and is pretty expensive, even for the generic STATdose pen.

Oral sumatriptan is available in three different doses; a little bit slower than the subcut sumatriptan, but still pretty quick. It is much cheaper than the injectable. Nasal sumatriptan also comes in three different doses. It is very quick as well, starting to work in about 15 minutes, but this has a very horrible taste and a lot of people cannot tolerate it very well. Even for a generic medication, it is still relatively expensive.

Naratriptan has a longer half-life of about six hours, but it also has a slower onset of action, as well.

Almotriptan is available orally, has an intermediate half-life, and in some people it seems to work pretty quickly in about 30 minutes. In other people, it takes a little bit longer up to two hours.

Frovatriptan has the longest half-life of all the triptans, the onset of action is the slowest at about two to three hours. Although it is a generic, it is still pretty expensive at about $55.00.

Rizatriptan is another oral triptan and it does work pretty quickly in some people (as quick as 30 minutes) and other people a little slower (up to two hours). It is another triptan that is not able to be used with an MAOI, but it is pretty cheap at $2.00.

Eletriptan is another triptan, with a slightly longer half-life but works pretty quickly in about 30 minutes but relatively expensive.

Zolmitriptan comes in two routes of administration. The oral form works in about 45 minutes. The nasal spray works in about 15 minutes. So of the triptans, the sumatriptan nasal spray and zolmitriptan nasal spray are the two quickest triptans available outside of using subcutaneous sumatriptan. Zolmitriptan cannot be used with MAOIs and it's still relatively expensive.

Next, we will go to Level B recommendations or medications found to be probably effective for acute treatment of migraine. This includes a class of medications called antiemetics. Of them, chlorpromazine, droperidol, metoclopramide, prochlorperazine have been found to be probably effective. Droperidol is not used very much anymore because it does have a black box warning of QTc prolongation and torsades.

DHE IV, IM, and subcutaneous is included in this category, as well as the combination of ergotamine plus caffeine. There are several other NSAIDs listed under Level B; flurbiprofen, ketoprofen, and Ketorolac. Magnesium sulfate is probably effective in patients with migraine with aura as opposed to migraine without aura. There are some combination medications; acetaminophen with codeine or Tramadol, but again it's not recommended to use opioids as a first line therapy for acute treatment of migraine.

Level C recommendations are medications found to be probably effective and include IV valproic acid, ergotamine, phenazone, which is an NSAID. Other opioids are in this category; IV dexamethasone, butalbital and butalbital containing medications, and intranasal lidocaine. I don’t prefer to use butalbital because there is a high risk of medication overuse headache with this medication. Also, it can be associated with a dangerous withdrawal syndrome, as well.

Next, we will talk about some pearls for acute treatment of migraine. Remember to choose a specific therapy based on effectiveness, contraindications, side effect profile, and patient preference. Some patients may really be needle phobic and want to avoid injecting sumatriptan. Use an adequate dose. I see this pretty frequently where a patient comes to me; they are on 25 mg of sumatriptan and say it doesn’t work for them. I will increase it to 100 mg and it does work for them. So using an adequate dose is important before giving up on the medication.

Treat the headache early in the attack; within 60 minutes from onset and when the pain is still mild. Studies show that if patients get cutaneous allodynia, which is tenderness in the scalp, the triptans are just not as effective. And that happens usually about 60 minutes from the onset of headache. Use a stratified care approach to treatment and match treatment with attack characteristics. I generally recommend an NSAID for mild to moderate headache and then a triptan for a severe headache. If they have nausea and vomiting, adding an antiemetic is also helpful.

Consider the route of administration. If they do have significant nausea and vomiting, using a non-oral route would probably be best so subcutaneous sumatriptan or nasal sumatriptan or zolmitriptan. Also if they have a quick onset headache, then using subcutaneous sumatriptan or nasal sumatriptan or zolmitriptan would be good options as well.

Although opioids are probably effective, it’s not recommended to use regularly. Again, they can get into medication overuse headache. Medication overuse headache can make headaches more frequent, more severe, or make other medications not as effective as they should be. This can happen with using simple analgesics like acetaminophen or ibuprofen or triptans just ten days a month. For opioids, it’s even less, eight days a month, and butalbital even less than that, four days a month. The other bad thing about opioids is that it can leave glutamate out on the synapses, and this is an excitatory nerve transmitter on the trigeminal nerve, which can make headaches worse.

If a patient is on propranolol and they’re prescribed rizatriptan, they should be given half the maximum dose, so 5 mg instead of 10 mg per dose.

Medications that can be used with an MAOI are naratriptan, almotriptan, frovatriptan, and eletriptan.

Some patients don’t tolerate sumatriptan very well. In that case, they may tolerate naratriptan or almotriptan better. Some patients may respond well to a triptan, but their headache may come back later that day or the next day. In these patients, trying frovatriptan might be a good option as it has the lowest recurrence rate for the headaches. Rizatriptan does have the best efficacy at two hours for the oral triptans, but it does have a higher recurrence rate. As I mentioned earlier, zolmitriptan nasal spray is a good, rapid acting alternative to injectable sumatriptan. If a patient is prescribed eletriptan and they’re on a cytochrome P450 3a4 inhibitor, the eletriptan dose should be decreased to half.

I included a couple of questions in this presentation just to highlight some important key points. So which of the following medications are FDA approved for the prevention of migraine? Valproic acid, topiramate, and propranolol; topiramate, propranolol, amitriptyline, lisinopril; valproic acid, topiramate, propranolol, timolol, and atenolol; or valproic acid, topiramate, propranolol, and timolol. So the answer is valproic acid, topiramate, propranolol, and timolol. And this often surprises audience members as far as the number of medications that are FDA approved for the prevention of migraine as well as which beta-blockers are FDA approved.

So treatment goals for the prevention of migraine, we want to decrease the attack frequency, intensity, and duration of the headaches. We want to improve the responsiveness to acute treatment so the medications have less of an uphill battle to start working. We’d like to improve function and quality of life. Reduce the need for abortive medications thereby reducing and/or eliminating medication overuse. And this is an important point, it’s not no headaches.

Although we’d like to get the headaches to go away completely, it’s often not realistic. There’s no cure for migraines at this point. And having a discussion with a patient regarding realistic expectations, I think is key to improving treatment success.

So in what situations might we consider starting a migraine preventive medication? The US Headache Consortium guidelines in 2012, lists a couple recommendations. They recommend starting a preventive in migrainers with six or more headache days a month or if they have four or more headache days with some degree of functional disability or if they have three or more headache days per month resulting in severe disability. There are some other instances you might consider starting a preventive; if the patient has failed or has contraindications to or troublesome side effects to abortive medications, if they’re overusing acute medications, or if their headaches are increasing in frequency.

So there are multiple societies that have published guidelines for the prevention of migraine, The American Headache Society, Canadian Headache Society, and the European Federation of Neurological Society. They all come to slightly different conclusions, but it’s all based on the same body of evidence. Why is that? Each society takes into consideration slightly different criteria. The American Headache Society/American Academy of neurology guidelines are based on efficacy alone. The Canadians also take into consideration benefits and harms of treatment, and the Europeans also take into consideration expert opinion. Although the guidelines vary, there are some areas of agreement in the four medications with the highest level of efficacy are divalproex, metoprolol, propranolol, and topiramate.

So I’ll be discussing the American Headache Society/American Academy of Neurology guidelines published in 2012, and their recommendations for Level A, or those medications shown to be effective, are divalproex sodium, valproate, and topiramate. In the third column, I did list a studied or target doses, and it’s important to try to get your patients up to this dose and have them stay at that dose for an adequate time. For divalproex sodium, it’s 1000 mg a day. For topiramate, it’s 50 mg twice a day. There are three beta-blockers, timolol, propranolol, and metoprolol with Level A recommendation.

Level B recommendations, or those medications found to be probably effective include some antidepressants, amitriptyline and venlafaxine, and some other beta-blockers, atenolol and nadolol.

Level C recommendations, medications found to be possibly effective, include lisinopril, although I see a lot of people in my clinic already on lisinopril before they come to me. And I don’t use this very much because I personally don’t think it works that well. Candesartan is Level C. There was a study that came out about two or three years ago that was positive for candesartan so I do use this occasionally. Clonidine and guanfacine are also Level C as well as carbamazepine, nebivolol, and pindolol. Cyproheptadine is a medication I sometimes use in pregnant patients because it is FDA a Category B for pregnancy.

Here’s another question. Which of the following are FDA approved for the prevention of chronic migraine? Topiramate, propranolol, onabotulinumtoxinA or Botox, valproic acid, topiramate and Botox, topiramate, propranolol, and Botox. So Botox is the only FDA approved medication for the prevention of chronic migraine.

Another question, which have the best evidence for efficacy for the prevention of chronic migraine? And the answer choices are the same as the slide before. Topiramate and Botox have the best evidence for efficacy for chronic migraine prevention.

The preempt one and two trial were the landmark trials that were used to obtain FDA approval for Botox for the prevention of chronic migraine. And I present data here in both the double blind phase as well as the open label phase. The double blind phase lasted 24 hours, and they compared placebo to Botox group. And you can see at about four weeks, the Botox group starts pulling away from placebo. Both groups did have improvement in their headaches, although some would argue that the placebo group started leveling out near the end of the 24 weeks.

The open label phase ran from 24-56 weeks, and the placebo group received Botox at that point. And you can see both groups continue to get improvement in their headaches. The original placebo group seemed to try to catch up to the original Botox group but not quite. The 50% responder rate at 24 weeks was about 47% in the Botox group compared to 35% in the placebo group. There does seem to be a cumulative effect though. And the longer the patients were on Botox, the more improvement they did receive. So at 56 weeks, the 50% responder rate was about 69% in the original Botox group and about 62% in the original placebo group. So the placebo group did try to catch up to the original Botox group but not quite.

The injection paradigm for Botox is 155 units in 31 injections, and these are in the corrugators, the procerus, the frontalis, temporalis, occipitalis, cervical paraspinal muscle groups, and the trapezi. And it’s five units per injection every 12 weeks.

So tips on migraine prevention, start low and go slow. We like to try to avoid side effects, and the longer patients can tolerate it, the more likely that we can get them up to an adequate target does. We want to titrate up the dose until they achieve a therapeutic response or the target dose is achieved or the patient experiences side effects. Again, adequate duration is important. We’d like the patients to be on an adequate dose or a target dose for at least two or three months. I have a lot of patients that come in, have tried an appropriate medication but quit after one or two weeks because they’ll say it didn’t work. They just were not on it long enough. So oftentimes, I’ll place these patients back on the original medication, keep them at the target dose for a couple of months, and they do seem to get better.

Try to get a twofer. If they have multiple comorbidities and you can treat all of them with one medication, that’s great. If they have depression, anxiety with migraines, trying a tricyclic antidepressant or venlafaxine might help. If they have anxiety or high blood pressure, trying a beta-blocker might be helpful. Topiramate, at doses over 200 mg a day can decrease the levels of oral contraceptive pills, and this is important in our migraine population as most of the patients are younger women in their childbearing age. So keep this in mind as a lot of medications including topiramate can cause birth defects.

We’ll switch gears to some newer treatments for migraine including treatments that have been reformulated and are delivered differently as well as some of the newer modulation devices. So current treatments delivered differently are old wine in new bottles. A lot of them are injectable sumatriptan as well as a different form of an intranasal sumatriptan. And then I’ll talk briefly about the sumatriptan iontophoretic patch.

There are several different sumatriptan auto-injectors. The picture in the top left is of the generic STATdose sumatriptan injectable. It’s a little cumbersome to use and a lot of steps. There’s a pen that is housed in the small circular pole in the container and then two syringe cartridges next to that. So when a patient is in the midst of a severe migraine, they’re vomiting, lying in the dark, they have to get this out, take the pen out, screw it on the syringe cartridge, inject themselves, put the syringe cartridge back into its housing, unscrew the pen off, and then house the pen again. It’s a lot of steps. There’s a needle-free sumatriptan injector, and this may be used in patients that are really needle phobic, but it uses air to drive the medication. And it’s actually more painful than the needle injections, and it leaves a pretty significant bruise. So many people don’t tolerate it. There is an EpiPen like sumatriptan auto-injector, but they have been out of stock for a long time. And I’m not sure if it’s coming back.

There are three newer prefilled auto-injectors, and two of them are available in the 6 mg doses and one available in a 3 mg dose. They’re all much easier to use, fewer steps. The steps are a little different for all three so I’d recommend that you and your patient go to the website and watch the videos on there.

We’ll talk about Zecuity very briefly as there may be some patients that have a couple patches left over floating around. So Zecuity is a sumatriptan iontophoretic patch that used a battery and an electric current to drive sumatriptan through the skin. However, in June of last year, the FDA announced that it is investigating reports of serious burns and scarring from the device. So about a week after that, the manufacturer pulled the device from the market. I haven't heard anything else from them yet so I’m not sure if it’s coming back or not.

This is a unique device, sumatriptan breath powered dry nasal powder, also called Onzetra Xsail. It’s unique in that it’s not your typical liquid nasal spray. It’s a dry form of sumatriptan. The patient places the nosepiece in their nose and blows through the mouthpiece. And what it does is it blows the powder in the nasal cavity, disperses it better than a liquid nasal spray, and at the same time as they’re blowing, it closes the soft pallet so they don’t swallow the medication avoiding much of the bad taste that’s often experienced by patients with a usual sumatriptan nasal spray. On the right is data from their study, and just briefly, in migraine studies, pain freedom is where a patient goes from moderate to severe pain to no pain whereas pain relief is moderate or severe pain to mild or no pain.

And so in the top chart, you can see that the Onzetra starts working in about ten minutes and then is better than oral sumatriptan at 100 mg up until about two hours when the oral sumatriptan catches up. And then sustained pain relief is about the same for both. Similar results for pain freedom, starts working in about ten minutes, better than oral sumatriptan up until about two hours, and then oral sumatriptan catches up. This is better tolerated than sumatriptan, and patients do have less side effects.

Switching gears, here’s another question. Which neuromodulation device is FDA approved for the prevention of migraine? Single pulse transcranial magnetic stimulation, transcutaneous supraorbital neuro stimulation, noninvasive vagal nerve stimulation, or noninvasive caloric vestibular stimulation. So the answer is transcutaneous supraorbital neuro stimulation. I’ll be talking about the two devices listed here. The last two devices are not FDA approved yet and so maybe that will come in the future.

The first device I’ll be talking about is a single pulse transcranial magnetic stimulator. This is for the acute treatment of migraine with aura, also called Spring TMS. Here they did a study, a randomized trial, for the acute treatment of migraine with aura where they compared two pulses of the device versus a sham given within one hour of the onset of aura. You can see here that the device was better than the sham at all points, at two hours, 24 hours, and 48 hours. And this was for the proportion of patients with pain freedom. In the UK they did an open label study on 29 patients where they did pulses twice a day as well as PRN pulses to treat acutely. And they went 12 weeks. And you can see that there was a reduction in number of acute treatment medications needed as well as a reduction in migraine days.

So to review the level of evidence for single pulse transcranial magnetic stimulation, it’s Level B for the acute treatment of migraine with aura. It is FDA approved. But this is based on one class one study. It is a minimal risk device, and the FDA does have a lower threshold of approving minimal risk devices. For the prevention of migraines, Level U. There’s been four randomized trials, but the data has been conflicting. There’s only been one positive trial and three negative trials. So further research does need to be done on this.

Next, we’ll talk about transcutaneous supraorbital neuro stimulation for the prevention of migraine, also called Cefaly. There was a randomized trial in 67 patients where they wore the device for 20 minutes a day. The endpoint of decrease in migraine days at the third month was actually nonsignificant, but the 50% responder rate was significant at about 38%. It is a little expensive, about $350.00 plus shipping, and then electrodes cost extra, each lasting about 20 sessions. It can be returned within 60 days for a refund, but it can take up to three months to work so they may be returning it before they got a full chance for it to work. It is also approved on this one study, since it is a minimal risk device back in 2014. It’s also approved in Canada and in Europe. In those countries it has three settings actually, for acute, prevention, and relaxation. In the US right now, it’s just for prevention but the company is considering doing studies on the acute treatment of migraine as well.

So to review the evidence and summary for the Spring TMS, it’s Level B for the acute treatment of episodic migraine with aura and Level U for prevention of migraine. And for Cefaly, it’s Level B for the prevention of episodic migraine.

And this is my last talking point. When might you refer a patient to a headache specialist? Consider referring the patient if they fail two or more typical migraine preventative medications at an adequate dose and duration, they fail two or more typical migraine abortive medications, they have contraindications to two or more preventative or abortive medications, if the patient experiences side effects to the medications, if a diagnosis is uncertain. Some patients have more than one or two headache types, and this could cloud the diagnosis, or if the migraine headaches are worsening.

The next several slides here are on the other levels of evidence just for completeness sake that you can refer to. I hope you found this presentation useful, and I appreciate your attention. Thank you.

My name is Tracy Eicher. I am going to spend the next 20 or 30 minutes discussing multiple sclerosis and some of the concepts that we use to take care of multiple sclerosis patients in the year 2017. We’ll go over the basics of MS, including how the immune system affects the brain and spinal cord. We’ll discuss demyelinization, but, beyond this, what multiple sclerosis does to the grey matter of the brain. We’ll discuss models of disease, and the different perspectives that have changed over the years in how we view multiple sclerosis. We’re going to review advances in disease modification and the therapies that have changed over the years, as well as how we use the therapies. We’ll discuss vitamin D and its importance in keeping disease under control. We’ll also discuss shifts in how we view MS care and how we take care of MS patients today.

Multiple sclerosis comes from the immune system. It is not a disease that starts in the brain or spinal cord. The problem is actually in the immune system itself. The immune system is a very complex system made of cells and fluids and other chemicals that helps your body rid itself of things that should not be there. The immune system is made to identify what is foreign and attack it and get rid of it. The immune system needs to be strong and healthy in order for us to combat viruses, bacteria, and other things that should not be in our body. But when the immune system begins to attack the brain or the spinal cord or the optic nerve, it is called multiple sclerosis.

In order for the immune system to attack the brain or spinal cord, it has to cross the blood brain barrier. It’s a very complex process, and there’s a lot that we still today don’t understand. But we’ve developed a lot more understanding in the last five to ten years than we ever had. As we’ve developed more understanding of the immune system, our approach to therapies have advanced and expanded. All of our medications to combat multiple sclerosis take different approaches to balancing the immune system. We used to focus on the immune system’s attack of white matter. The white matter of the brain and spinal cord is called myelin, and we used to discuss this as a demyelinating disease.

But beyond this, it also attacks the nerve body itself, and that’s the grey matter. So grey matter has very much become a focus in MS as well. MS symptoms are varied and are different in every patient. This is because the immune system can attack anywhere in the brain or spinal cord, and it can attack the optic nerve. So symptoms could include vision loss out of one eye. It could include dizziness, balance problems, difficulty swallowing. Could be cognitive or it could be motor difficulties or sensory changes. There could be bowel and bladder changes and sexual dysfunction. All of these things are very common in MS patients, but not any one MS patient is going to experience all of these symptoms. And every MS patient will have their own unique set of symptoms and patterns based on where their immune system has attacked.

We sometimes say that every patient’s MS is like a thumbprint in that it’s unique and different, and their pattern of attack is very different. So it is very difficult for us to tell one patient what they will experience over the following five years or ten years. It’s very difficult for us to discuss with them what they will experience as a relapse, and sometimes we have to give them general ideas. And very often the patient just has to call if they feel like they may be having an MS relapse, and they aren’t sure. We used to discuss pattern of MS disease, and we still do focus on this to some extent. But as we’ve developed treatments for MS, I think our discussions have shifted away a little bit from just patterns to focusing more on what we can do about MS.

In the first picture on the left upper corner, this is relapsing-remitting MS. And this pattern depicts a patient who has an attack, and then it quiets down. And then later they have another attack which quiets down. Over time, they often have attacks which do not fully resolve and don’t full go back to baseline. And over time, you can see that stepping up, and that signifies advancing disability. On the right side, upper corner, you see primary-progressive MS. Primary-progressive MS is probably a unique type of disease, and it probably is separate from the other presentations of MS. But these are patients who never really have a noticeable flare or attack. They just very gradually get worse, and they very gradually feel like they’re losing abilities.

Primary-progressive MS is a very difficult disease state to treat. And, in fact, we don’t have any disease-modifying agents today that are approved for primary-progressive MS, although we have one therapy that is under FDA scrutiny right now. In the bottom of the slide, you can see on the left, secondary-progressive MS and progressive-relapsing MS. This is somewhat of a grey zone and identifying which of these patterns is exactly happening with the patient is somewhat of an art form, and sometimes we take our best guess. The important thing, I think, is that all patients who come into the disease with a relapsing-type picture are good candidates for our disease-modifying therapies.

When there are attacks, we know there is an inflammatory component, and our MS medications have shown to do well against the inflammatory part of the disease. Many patients over the years, whether it’s with continued events of relapse in between or a quieting down of relapses, do then begin to progressively worsen. And you can see that in both of these pictures on the bottom of the screen that over time there is a worsening of the disease and then increase in disability. This slide puts a lot of the ideas together into one picture, and this is the most common presentation of the disease. So on the left-hand side of the screen, the patient comes into the disease with relapses, and the relapses quiet down but maybe not going all the way back to baseline.

Over time, not all the relapses recover, and as relapses continue to occur, more disability is obtained. However, at some point in the disease, it’s very common that the relapses quiet down, and there is not so much of an inflammatory picture in the disease and just disability progression starts to prevail. During the time when there is a lot of inflammation, this is when we see the new lesions which I will show later in this slide show, and lesions are the inflammatory attack on white matter. There is also, to an extent, inflammatory attack at the grey matter, though it is more difficult to appreciate on MRI.

But beyond the inflammatory attack and subtlety underneath the inflammatory attack even early in the disease, there is attack at the grey matter. The nerve cell itself is being damaged, and that correlates more strongly with the neurodegeneration or the disability progression over time than even the accumulation of the white matter lesions. We’ve mentioned that we used to focus a lot on the demyelinating part of this disease, and I’d like to also focus on what happens beyond the white matter attack. In this picture, you can see what we call lesions in MS. The lesions are these white globs on the MRIs that you see.

Historically, this was the focus of what we looked at when we treated patients for MS. We talked to them about their lesions. We counted their lesions, and we thought that lesion load was the answer to why disability accumulated. But we realized, even years ago, that there were patients who had fairly extensive disability without extensive white matter lesions and that the lesion load doesn’t always correlate with how much disability there is. This is a picture of the brain that lets us take a look at where the grey matter is and where the white matter is.

The ribbon around the outer edge of the brain is grey matter. There are grey matter pockets deep in the brain, and those are pictured here, labeled basal ganglia. There are other structures deep in the brain that are pockets of grey matter or nerve cell bodies. On the right of the picture, you can see in the spinal cord, the center of the spinal cord, sort of shaped like a butterfly, is the grey matter. And around the outer edges, actually white matter. This is a better picture of the grey and white matter, and this is a picture of atrophy that occurs in MS.

On the right of the screen is a patient without atrophy. You can see that the area in the center of the brain is fairly small. The dark area, which we call the ventricle, is not very big. On the left, if you look at the ventricle in the middle, there is a large area of darkness. That is because atrophy has occurred, and as the brain grey matter shrinks, space is increased. This is another picture of the same thing. The patient on the left having less atrophy, and the patient on the right having more atrophy. In addition to just the increase in the ventricle size, it is a little more subtle, but you might appreciate that the space around the outside edges of the brain is also expanded.

And as we see more atrophy or shrinkage of the brain, we tend to see disability progression in our MS patients. This is a picture of one of the scales that we sometimes use to measure or discuss how much disability there is. This is called the EDSS scale. It’s often used in clinical trials to give numbers to describe how disabled the patient is. We use it a little less often in the clinic.

I’m going to shift focus now and discuss advances in disease modification. Our first MS drug came out in 1993, and it was an injection. Over the next several years, we developed other medications that affect the immune system in ways that improve the outcome of multiple sclerosis. But all of our medications in the early days were injections. At this point, we have developed more therapies, and we have IV therapies as well as oral therapies available. We still use the injections, but the pills have become a good tool for treatment. Patients like the ease of taking pills, and our IV therapies have become a very important tool in controlling multiple sclerosis.

A lot of our IV therapies are considered to be stronger. Often with strength also comes some increased risk. And so when we choose a disease-modifying therapy for a patient, we have to take many factors into account, including risks, tolerability, and how advanced their disease is or how aggressive their disease seems to be. It’s important to understand that all of our medications approach the immune system from a different way, and it’s not as if we were able to put our injectable therapy into a pill and you could take the same medication by shot or pill. These are different medications, and they do different things to the immune system to keep it balanced or controlled. Making the decision as to what disease-modifying therapy we start a patient on takes a review of that patient’s other medical conditions, their other medications, and also their lifestyle, as well as their MRIs and how their disease appears.

This slide is depicting the changes that occur in the immune system cells as they mature. As the cells mature, they develop different receptors, and our newer advances in MS medications are targeting many of these receptors in order to affect the immune cells different ways. In addition to developing better understanding of how we can affect the immune system through medications, we’ve also developed a greater understanding of how vitamin D can impact the immune system. Vitamin D has multiple effects on the immune system that are beneficial. Higher levels of vitamin D result in better outcomes for MS patients, and there are many ways that the vitamin D is affecting the immune system in a favorable way.

We have also advanced our ability to monitor MS patients, though, for the most part, we still rely on MRIs. We are developing the ability to use higher power magnets. We’re developing new technologies with the current MRIs, including double inversion recovery, 3D FLAIR, diffusion tensor imaging, and other research protocols that someday will be more widely available and not just limited to research.

Double inversion recovery allows us to see the grey matter better and to appreciate MS attack at the grey matter. That’s what’s shown in this picture. These are areas that the grey matter is being affected by MS. When we look at a regular MRI, it’s very difficult to appreciate these areas of attack. Diffusion tensor imaging allows us to evaluate the white matter tracts. It is especially useful if we are unable to appreciate discrete lesions in the spinal cord. Sometimes we can see disruption of the white matter tracts on diffusion tensor imaging. Optical coherence tomography is another tool that has been used more in MS clinics recently. This allows us to look at the thickness of the retinal layer. The thickness of the retinal layer may decline as the grey matter layers of the brain decline, and this is a way that we can measure loss of grey matter without directly looking at the brain.

In addition to advancing our abilities in MS medications and imaging, there have been several changes in the approach to care in the MS community. MS specialists are trending towards more frequent MRI monitoring. We are less tolerant of disease activity on MRIs and changes of disability even subtle. We are more likely to consider changing medications. MS specialists are being more aggressive with surveillance of vitamin D and supplementation of vitamin D to help keep the patients controlled. We are using more nonpharmacologic approaches, such as optimization of the abilities that the patient has through physical therapy, occupational therapy, and cognitive therapy. We are treating symptoms of the disease more aggressively and focusing on optimizing the wellness of the patient.

Due to the complexity of taking care of MS patients at the level that has become expected today, many neurologists and primary care physicians are turning to MS centers, and the MS center approach has become more popular. MS centers strive to offer a full spectrum of care, including a neurology team that consists of neurologists, MS nurse navigators, and medical assistants that are well-versed as the MS drugs and insurance approval needs. Physical therapists and occupation therapists are often highly involved in an MS center. Cognitive therapists and neurocognitive specialists are involved in the MS patient care as well. Social works, nutrition, and wellness support, as well as education and support groups are important. And many MS centers are now offering research trials that allow patients to have access to therapies that are otherwise not available.

The MS center approach is being used more widely, although often not all of the above are located in one place. Many times, a specialized neurology team is developed within a neurologist office, and then the therapies are sent out to other locations. However, it is important to develop a strong network with social workers, physical therapists, occupational therapists, and nutritional and wellness support, whether that is all in one location or through a network structure.

As we develop more understanding of MS and complexity of the disease grows, MS centers have become more and more important in being able to offer the level of care that MS patients need. Care of MS patients has advanced quickly over the last five to ten years and continues to advance. This is an exciting field for neurologists but a very difficult field for patients. Hopefully the podcast has been helpful in giving you an understanding of our current assessment of the disease and the disease state.

Good morning. My name is Barbara Phillips. Today, I’d like to give a cannabis update, an update on the use of medical marijuana.

There are many different types of marijuana plants. The two that are most used for medical uses are Cannabis sativa and Cannabis indica. It’s an extremely complex plant with over 500 chemicals. Over 80 of them are cannabinoids. These are the chemicals that will work in the brain. The most common one is tetrahydrocannabinol, and there are 11 types of this. These are found in no other types of plants. They’re considered phytocannabinoids. These work in the central nervous system because there is an intrinsic endocannabinoid system. It is involved with the most abundant G-coupled receptors in the brain.

There are two receptors that are involved with cannabis use: the CB1 receptor which is in the hippocampus association cortices, basal ganglia, cerebellum, dorsal root ganglion and peripheral nerves. The CB2 receptors are in other parts of the body: lymphatic tissue, hematopoietic and immune cells, pancreas, intestine and retinae. There is a low concentration in the CNS.

There is an intrinsic endocannabinoid system in the brain. These involved are the most abundant G coupled receptors in the brain. G proteins are attached to receptors and they modify their firing and, therefore, affect the effect in the brain. The two main ones are CB1 receptors in the hippocampus association cortices, basal ganglia, cerebellum, dorsal root ganglion and the peripheral nerves. CB2 receptors are in other parts of the body predominantly: lymphatic tissue, hematopoietic and immune cells, pancreas, intestine and retinae. There are low concentrations in the CNS.

The brain makes endogenous cannabinoids including anandamide and 2-Arachidonoylglycerol. The metabolism in the brain indicates that they are neuromodulators. They are rapidly synthesized and then rapidly degraded. They are synthesized by neurons after depolarization and increase in intracellular calcium. It is released into the cleft and travels retrograde, binding at the CB1 receptor in the presynaptic neuron. The effect is inhibitory. It inhibits neurotransmitter release opening potassium channels and closing calcium channels. It also inhibits adenylyl cyclase and stimulates the kinase enzymes.

The history of cannabis in western medicine dates back to the 1800s. It has been documented to be used long before that, at least 5,000 years ago. In the late 1800s, a famous paper by Drs. Reynolds and Gower documented a patient who was controlled on bromides which was the major anticonvulsant at the time. He recurred when he stopped taking his bromides. Eventually, with his noncompliance, he stopped responding, even when bromides were reintroduced. The seizures were controlled again with the addition of cannabis oil, which they had been using as an adjunct to bromides in seizure treatments. Unfortunately, he remained noncompliant and was poorly controlled and eventually lost to followup.

In the last one hundred years, the use has been documented in glaucoma, nausea, vomiting, cachexia related to HIV, insomnia, tremors, multiple sclerosis-related spasms, cancer and multiple sclerosis pain as well as HIV-associated painful sensory neuropathy.

The volume of research has exploded in the last twenty years, especially as it’s been used and noted to be effective in the treatment of certain types of seizures. As it’s been more widely used, side effects have been documented, including low testosterone and erectile dysfunction in men. There have been concerns about promoting heart disease and cancer; although that has not been proven to this point. There has also been a recent paper regarding a presentation of increasing numbers of patients to emergency rooms with acute gastrointestinal pain related to marijuana use.

The main chemical is delta-9-tetrahydracannabinol. In the brain, this is a partial agonist at both the CB1 and CB2 receptors. It is only one of three chemicals that work via this intrinsic endocannabinoid system. The other two are cannabinol and THCV, tetrahydrocannabivarin. THC is the principle psychoactive component responsible for the feelings of being high when taking marijuana. With respect to seizures, it has a mixed result. Most people feel that their seizures have been reduced when using this chemical. Others experience a worsening of seizures.

The second most prevalent chemical is cannabidiol. It is the major nonpsychoactive chemical in marijuana. It has a low affinity for CB1 and CB2 receptors in the brain. It is an indirect antagonist of CB receptors and decreases the effect of CB1 activation. It’s a partial agonist of serotonin receptors. It allosterically modifies some opioid receptors. It consistently has anticonvulsant effects when tested.

In looking at preclinical evidence studies involving animal species, THC showed an overall improvement in seizures in 61 percent; whereas 10 percent of the subjects experienced increased seizures. Cannabidiol had twenty-one studies with two species, and 81 percent showed an anticonvulsant effect with no proconvulsive results. Specifically with CB1 receptor agonists, there were fifty-five studies with two species; 73 percent were anticonvulsant and 2 percent were proconvulsant. CB1 receptor antagonist studies involved only five studies with two species; 9 percent were anticonvulsant and 30 percent were proconvulsive. However, that was a small number of studies.

In humans, the studies are limited and mainly anecdotal and retrospective. The products used are varied. There are varied benefits and side effects noted in these studies. It was found that the results tended to be expectation-dependent. That is, if people expected that they would get better, they were more likely to, or if they expended more effort in trying to get the medication, they were more likely to feel that it was effective rather than not effective. I’ll conclude with the statement that more work needs to be done.

A study done in Colorado, “Parental Reporting of Response to Oral Cannabis Extracts for the Treatment of Refractory Epilepsy” in Epilepsy and Behavior in 2015, documented 75 children given oral cannabinoids; this was cannabinoid oil. Fifty-seven percent showed improved control and 33 percent was the responder rate. The responder rate indicates the percentage of patients that get at least a 50 percent improvement in seizures. Only two patients were seizure-free. It was found that if the family moved to Colorado for treatment, the responder rate was 47 percent versus 27 percent for those who were already residents of Colorado.

The responder rate also varied based on the syndrome being studied. Lennox-Gastaut Syndrome patients experienced an 89 percent responder rate. Patients with Dravet Syndrome experienced a 23 percent responder rate, but no patients with Doose Syndrome experienced improvement at that level. Eight responders had EEGs but none of them showed improvement in the baseline EEG. The parents reported a third of the patients improving with respect to behavior and alertness. Eleven percent were reported to improve in their ability to use language, and 11 percent were reported to improve in their motor skills. Eleven of the patients, 15 percent, were discontinued due to lack of efficacy. Adverse events were fairly common at 44 percent. Thirteen percent of the patients had worsened seizures or developed a new seizure type. Twelve percent reported fatigue. Eleven percent had GI side effects. Rarely, there were reported developmental regression, a new type of movement disorder, transient hemiparesis or focal weakness, cholecystitis, opisthotonus and status epilepticus with one death. The perceived benefit, again, was higher in those who had moved to Colorado independent of the result.

Devinsky et. al. in 2015, published a study in Lancet regarding cannabidiol in patients with treatment-resistant epilepsy. This was an open label trial with eleven U.S. centers. It was conducted from January 2014 through January 2015. The majority of the patients had Lennox-Gastaut and Dravet syndrome. There were a few other intractable syndromes. This involved 214 patients, ages ranging from 1 to 30. There were two overlapping groups. They utilized purified cannabidiol oil. Median monthly decrease in seizures was reported to be 36.5 percent. Adverse events included 79 percent in the safety group. Twenty-five percent reported somnolence. Nineteen percent had a decreased appetite. Nineteen percent had diarrhea, 15 percent fatigue and five patients, 3 percent, were discontinued. Serious adverse events occurred in 6 percent of the patients. One patient died related to sudden, unexpected death in epilepsy. Upon evaluation, this was deemed to be unrelated to the treatment.

An Israeli study was reported in Seizure in 2016, “Cannabidiol-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.” There were 74 patients aged 1 to 18. They had all failed more than seven anticonvulsants and 49 had also failed the ketogenic diet or vagal nerve stimulation. Eighty-nine percent reported a decrease in seizures, but 7 percent reported an increase in seizures. There have been interactions reported between cannabidiol and some anticonvulsants.

In 2015, Jeffrey et. al. published in Epilepsia, a study of a small number of patients. Thirteen patients were studied who were on both clobazam and cannabidiol. Clobazam is also called Onfi. There was an average increase in clobazam levels of 500 percent, resulting in side effects. Ten of thirteen patients had to reduce or stop the clobazam due to side effects because of this interaction.

There are two commercial preparations available in this country. Marinol, which is dronabinol, and Cesamet which is nabilone. They are approved for chemo-related nausea and vomiting and age-related anorexia and wasting. Other preparations include nabiximols, called Sativex, which is approved in Canada. It is an aerosolized oral mist which has a 1:1 ratio of cannabidiol and THC. This is approved for multiple sclerosis and cancer-related pain. Epidiolex is currently undergoing trials for refractory epilepsy. It is a purified oil of cannabidiol plant extract and contains no THC. It was recently given orphan drug status by the FDA. Synthetic cannabinoids have been available and include brands such as K2 and Spice. They are a thousand times more binding to CBRs than phytocannabinoids. Side effects have included dizziness and altered mental status, but severe side effects have also been reported including strokes and seizures.

Recently, Rimonabant, which is a CB1 receptor blocker, was being developed as a diet drug. The study was stopped due to complications including depression, anxiety, insomnia, anorexia, suicide and homicide. Another experimental preparation, BIA-10-2474, inhibits an enzyme required to break down the endocannabinoids, thereby increasing the length of their effect. It was being developed as a long acting pain reliever. It was stopped due to complications including six subjects becoming severely ill and one becoming brain dead.

In summary, evidence is promising for medical use of marijuana and its chemicals. This is especially true in epilepsy where certain types of seizures have responded well to its use. Pros as well as cons have been documented. More work needs to be done.

Thank you for joining me for this update in the use of medical marijuana.

Dr. Tayim: Hello, everyone, and thanks for joining me today. My name is Fadi Tayim and I’m the Division Chief of Neuropsychology and Clinical Assistant Professor of Neurology at the Wright State University and Premier Health Clinical Neuroscience Institute. Today, I’m going to discuss the role neurocognitive assessment in the context of presurgical planning. I have no conflicts to disclose.

So I wanted to give you guys an overview about what we’re going to be talking about today. Some of our listeners will have some familiarity with neuropsych testing, which is also called neurocognitive testing, but chances are a majority of you won’t. So along the way, we’re going to cover what neuropsychology is, the different cognitive domains and where they’re located in the brain, what we might see when certain parts of the brain are damaged due to traumatic brain injury or stroke and epilepsy, tumor, you name it. Also, we’ll look at how neuropsychologists use tests for presurgical planning and how we incorporate our test results with neuroimaging like CT, MRI, EEG. And lastly, how neuropsychologists with specialized training like myself use techniques like fMRI and the intracarotid sodium amobarbital procedure, which is also called the Wada, and how we use that to isolate memory and language functions. 

So we have a lot of ground to cover and I know you’re anxious to get started so let’s begin. Our brains are very, very busy. They contain the accumulation of all of our emotional experiences, our education, our ability to remember things current and past, how we speak and read, not to mention all the other cognitive abilities. Yes, our brains are very, very busy. Neuropsychology is the science is the science behind taking all the things that our brains can do, as represented by this fruit bowl, and making sense of it all so it looks more like this; something that’s predictable, measurable, and understandable. Essentially, neuropsychology is the study of brain behavior relationships. A neuropsychologist deconstructs core cognitive functions into measurable parts, similar to what we just did with the fruit bowl. Our brain thrives on making sense of the world and that’s why you can read sentences like this. Essentially, neuropsychology is the study of brain behavior relationships. A neuropsychologist deconstructs core cognitive functions into measurable parts, similar to what we did with the fruit bowl. Our brain thrives on making sense of the world and that’s why you can read these sentences. 

Clinical neuropsychologists assess brain function by measuring an individual’s cognitive, sensory motor, emotional, and social behavior through formalized assessment. A clinical neuropsychologist is a neuroscientist who specializes in the application of assessment and intervention principles across the life span, especially as it relates to normal and abnormal functioning of the central nervous system. 

Patients may be referred for neuropsychological assessment for a number of reasons. An evaluation can provide information about the nature and severity of a patient’s cognitive difficulties, emotional status, personality characteristics, social behavior, and adaptation to their conditions. Information about their cognitive strengths and weaknesses provides a foundation for treatment planning, vocational training, competency determination, and counseling for both patients and their families. Neuropsych assessment is often requested in cases of traumatic brain injury or TBI; cerebrovascular disorders like stroke, epilepsy, tumors, Alzheimer’s disease and related dementing disorders; and other progressive diseases like Parkinson’s disease, Huntington’s disease, MS; and also, with developmental disorders and neurological infections like meningitis, as well as psychiatric disorders like depression, ADHD, anxiety, you name it. 

So today, I’m going to spend a large portion talking about epilepsy, specifically, and how our evaluation plays a role in surgical planning. But before we get to that, it’s important to understand what the cognitive domains are and how they’re assessed.

One of the most important parts of a neurocognitive exam is getting a better understanding of a patient’s longstanding abilities. We do this typically through intellectual assessments, which you guys probably know as IQ tests. For example, some people are much better at verbal skills like basic reading, reading comprehension, analytical tasks, remembering historical facts, and they may even have a very large vocabulary. These are all predominantly left-brain skills. For others, they may have stronger visual skills like perceptual reasoning and visual organization. A neuropsychologist can use these data to paint a picture of that person’s longstanding skills, answering the core question of, “Does this person have greater left than right, or right than left, hemisphere functioning?” If there’s a significant difference, the neuropsychologist will want to know more information such as if this has always been the case or if this is resulting from the patient’s presenting problem; for example, left temporal lobe epilepsy. 

Next is memory – and these go in no particular order. Memory is perhaps the most complex cognitive domain to discuss because of the intricacies. We have sensory memory, long term versus short term, explicit versus implicit, episodic versus semantic, procedural memory, and I’m sure there are more types that I’m forgetting; the irony of which is not lost on me. Most neuropsychological exams will assess short and long term memory, which helps us in several different ways when we’re talking about lateralizing left versus right hemisphere abilities. For most of us – about 95% – our left hemisphere is dedicated to verbal memory while our right hemisphere is dedicated to visual memory. This is grossly simplified, I know; otherwise, I would digress into detail and would spend hours talking about bilateral activation, etc. But for the purpose of this podcast, I just wanted to really make it clear that when we talk left, we think more for verbal skills. When we talk right, it’s more for visual skills. But keeping in mind left hemisphere for verbal, right for visual; neuropsychologists are able to see if a pattern develops of greater left than right hemisphere functioning as could be the case in right temporal lobe epilepsy. I’ll talk more about memory later when we get to the Wada procedure. So for now, this is just a teaser.

Next up is attention and processing speed. Attention and processing speed are routinely part of the neurocognitive evaluation and can be negatively affected in a variety of neurological and psychiatric illnesses; for example, TBI, epilepsy, tumor, schizophrenia, ADHD, and the list continues. Attention, just like memory, can be broken down into more distinctive parts; for example, simple attention versus complex versus sustained attention, or verbal versus visual attention. Processing speed often refers to the speed at which an individual can perform a task or series of tasks. Many processing speed measures involve attention, as well as visual motor and psychomotor processing speed. While these are different skills, they are regularly lumped into the same cognitive construct. What’s important here is that attention is a fundamental part of the neurocognitive assessment as many, if not all, cognitive abilities begin with the intact ability to attend to the task. For example, we would conclude that the left hemisphere; specifically, the frontal subcortical network, is more actively involved in verbal attention while greater right hemisphere involvement would be seen in visual attention. 

Next up is executive functioning. This domain is another one of those complicated constructs since there’s so much that goes into it. For example, this is where we humans have our higher order frontal lobe functions like planning and organizing; judgment and decision-making; and cognitive flexibility, switching between tasks; verbal-visual abstraction; multitasking; monitoring our performance for errors; and even working memory is an executive function as we’re manipulating information so that we can encode it into our brain. Since we humans depend on these higher order abilities for our day-to-day survival, if you will, executive dysfunction is one of the most readily identifiable complaints from patients experiencing a broad range of neurological and psychiatric illnesses. Executive functions truly involve the whole brain and thus, while we refer to frontal lobes often when talking about executive functions, we see activation all over when we use fMRI. Thus, to simplify, our takeaway here is that executive functions are a very dynamic construct and we can’t really do it justice with this limited time.

Next, I’m going to talk about language, which is another broad cognitive construct. But here, I’m just going to focus on receptive and expressive language. Receptive language refers to an individual’s ability to comprehend what it is they’re hearing, seeing, and reading. Expressive language is what’s produced by the person. So that’s their ability to coherently produce speech. A neurocognitive evaluation should contain both receptive and expressive language measures as these provide a context for which the result of the exam may be viewed. For example, if an individual’s receptive language ability is poor, it’s difficult to conclude that any poor test performance was simply a result of misunderstanding the instructions. As I mentioned before, our core language skills are greatest in our – you guessed it – language dominant hemisphere. And for most of us, that’s the left hemisphere. While we know what multiple systems are involved in language, we know that receptive language is housed in the posterior superior temporal lobe. That’s Wernicke’s area. While expressive language is primarily Broca’s area so that’s the inferior frontal lobe. Knowing the neuroanatomy of language is key when I conduct the Wada procedure, as language localization is a primary goal and the other goal, of course, being a person’s memory ability. 

Now, let’s talk about visuospatial skills. Neuropsychologists often administer visuospatial tasks as part of the standard battery, as deficits often present as perceptual distortions or impairment in object or facial recognition, object rotations, spatial memory, navigation difficulties, visual neglect, and how far or close objects are. Processing of visuospatial information involves multiple brain systems though typically, involving posterior areas of the right hemisphere. For example, identification of visuospatial information is heavily reliant on intact right posterior temporal systems, which is the what visual stream. Whereas localization of visual information is dependent on intact right posterior parietal systems. That’s the where visual stream. Thus, if we were to see a patient presenting with right temporal lobe epilepsy, we’d be concerned about misidentification of objects.

Next up is motor skills, which is another helpful domain within the test battery. Typically, a neuropsychologist will assess simple motor speed like finger tapping and fine motor speed and coordination separately for each hand, noting discrepancies between scores. We usually look at differences between the patient’s dominant hand and the non-dominant hand. The motor evaluation can provide valuable information with respect to the possibility of a lateralized deficit. For example, a left hemisphere motor strip deficit would likely result in right hand apraxia. Additionally, neuropsychologists use motor performance alongside other aspects of the assessment to see if any discrepancy between the left or right hand is consistent with the other discrepancies seen between lateralizing measures so verbal and visual skills or verbal and visual memory, specifically.

Lastly, I’m going to acknowledge that neuropsychologists administer performance validity measures to gauge the patient’s effort during testing but I won’t say much else about this. If a patient’s performance on PVMs is poor, then the results are probably not valid and presurgical decisions should not be made off of those results. There’s a whole host of reasons why PVMs may be poor but effort was okay, and that’s a conversation best had with really a forensic neuropsychologist and perhaps Bob Roth, who’s a great guy. He’s really into this kind of stuff.

Okay, so now that you’re all more familiar with the cognitive domains, I wanted to dive right into what neuropsychologists use to help us lateralize deficits. That is, what test results do we use to help us determine which side of the brain is better or worse? You know that the left hemisphere is associated with verbal skills, verbal memory, right hand functions; leaving the left hemisphere to be associated with visual skills, visual memory, and left hand functions. Again, this is grossly oversimplified but it remains true. As I noted in the beginning, a major factor of lateralizing includes look at the discrepancy between longstanding core verbal and core nonverbal skills. If we notice that their nonverbal skills are worse than their verbal skills, we would have to make a note of that. And while we can’t for certain say that this discrepancy is due to something like, you know, left or right temporal lobe epilepsy; we can often make the case for laterality if we see a similar pattern of laterality that has greater left than right hemisphere functioning on other lateralizing measures like memory.

So let’s talk about memory. We know that we have left hemisphere handling a large portion of verbal memory and the right side in charge of visual memory. Again, this is grossly oversimplified, I know. Using our sample patient with left temporal lobe epilepsy, let’s say that on imaging, we see significant left hippocampal volume loss resulting from mesial temporal sclerosis. Knowing the neuroanatomy and the neuroanatomical correlates for memory, we would anticipate that our patient presents with perhaps short term memory problems and likely, long term retrieval difficulties, as well. We would use this information in addition to the VCI-PRI split that I just discussed to make a case for greater left than right hemisphere impairment. Again, we don’t know for certain if they’ve always had weaker left hemisphere abilities like verbal memory but it’s at least something to go off of. And we will continue to gather this kind of information, noting the patterns that we see across the evaluation and we’ll start to formulate our working diagnosis.

Another way we lateralize is by looking at fine and simple motor dexterity and speed. This is a more gross measure of lateralizing greater left or right hemisphere functioning and it isn’t an exact science. I say that because there are a lot of extraneous influences that can negatively affect motor speed and coordination that aren’t necessarily related to neurological disease, like arthritis. Nonetheless, to change things up, let’s say our sample patient had relatively equal motor speed using both hands. That simply tells me that while our patient has greater left than right hemisphere impairment, that doesn’t translate to motor skills, and that likely means that the motor component, you know, wasn’t effectiveaffected. The motor strip is still intact. Now, if we saw worse right hand performance, we would consider this to be consistent with the overall profile that indicates greater left than right hemisphere impairment.

Some neuropsychologists, like myself, have advanced training in neuroimaging, which comes in handy when a large part of my daily activities involve integrating impressions from scans with neurocognitive tests for clinic and research. Neuroimaging is a broad term and covers a breadth of procedures. But for the purpose of neurocognitive assessment specifically, I’ll use it to refer to the procedures that I have the most experience conducting and interpreting, which in this case, is structural and functional MRI. Most often, we’ll use fMRI to help us establish which hemisphere is dominant for language. But we can also get information about spatial skills and motor functioning. The fMRI paradigms that are administered to a patient often tap into the same cognitive construct. Typically, these include measures of visual ability, visual motor integration like finger tapping, performing physical tasks that are on the screen, that kind of thing; and tasks that are done silently; that is, they’re done in your head and not out loud like listening to words being spoken, coming up with words, filling in the blanks on sentences. 

FMRI tasks are excellent in helping us see the level of activation in certain brain regions that correspond to the task. For example, if the person is administered a visual task and asked to only look at the stimulus without moving, then we would anticipate seeing the visual cortex activated more than any other region. It’s why, for language tasks, we would anticipate seeing the greatest level of activation in the language dominant hemisphere. 

As with any procedure, there are certain limitations that have to be taken into consideration when conducting an fMRI. Some of these limitations include understanding that activation in certain brain regions are not critical to the functions being measured, as well as understanding that the opposite is true. A lack of activation in specific brain regions may not be specific to the task being administered. 

So here’s where it gets more interesting – the Wada procedure, which is also referred to as the intracarotid sodium amobarbital procedure, is a deactivating procedure while the fMRI is considered an activating procedure. This procedure is one of the most important procedures when it comes to presurgical planning. The Wada uses amobarbital, which is also called amytal, to effectively anesthetize one hemisphere of the brain in order to measure the contralateral hemisphere’s functioning. Simply put, that means injecting the left hemisphere, putting it to sleep, so we can see how the right hemisphere is functioning and visa versa. The Wada procedure accurately addresses the question of whether cognitive abilities like language and memory can be performed without the contribution of the affected brain regions. Although a specific neurological region may be involved in the task under normal circumstances; for example, the left temporal lobe in verbal memory and the right hemisphere in visual memory, we perform the Wada procedure to determine if the left hemisphere is absolutely necessary for verbal memory. By anesthetizing the left hemisphere, we’re able to measure the right hemisphere’s ability to sustain verbal memory. 

A key component of the Wada procedure is the ability to determine postoperative change, particularly as it relates to memory impairment. As is often the case in left temporal lobe epilepsy, in the event that there is significant left mesial temporal sclerosis requiring a left hippocampal resection, the Wada procedure is key in determining whether the right hemisphere is capable of performing the function that is traditionally reserved for the left hemisphere, which in this case, would be verbal memory.

So I’m not going to run through the entire Wada protocol here but instead, I’m going to discuss the necessary steps that are involved in conducting this procedure. What’s so great about the Wada procedure is how this is a neuropsychological test at its most extreme. This procedure relies on an entire medical staff to perform; beside me, our neurointerventionists, our neuroradiologists, EEG technicians, medical personnel, and my assistants.

To start this procedure, I have to first determine what side we’re going to inject first. The rationale is that if we’re able to obtain results from only one hemisphere, then it’s best to capture the results from the hemisphere that we believe is more impaired. So I use the results from structural and functional MRI, EEG, and neuropsych tests to help me determine the side to inject first. Sometimes we have a clear focal point; oftentimes, we don’t. When we don’t know where the seizures are coming from, I often begin with the left side to inject, given that left temporal lobe epilepsy is the most common. The angiogram and injections are administered by our neurointervention specialists. The procedure begins with catheterization through patient’s femoral artery and an angiogram to determine the correct placement of the catheter within the internal carotid artery. A contrast dye is injected to identify any obstructions within and against the internal carotid arterial wall and to also observe if there’s any crossflow hemispherically. Once safety has been determined, then we proceed with the procedure.

As I mentioned in the previous slide, we use amobarbital, which is injected through bolus administration over the course of three to four seconds. I typically start with 125 mg and that seems to be enough for most patients. However, if we fail to achieve EEG slowing on the ipsilateral side of injection, then I’ll increase the dosage by 25 mg increments up to a maximum of 175 mg. 

Despite the medical setting of this procedure, the tasks that I present to my patients aren’t that different from the tasks that I gave them when they were in my clinic. We make sure that the tasks are similar so that I can make direct comparisons on their performance based on the cognitive domain, which is, in this case, language and memory; though motor is often a part of this procedure, as well. I’ll get into how I measure language and memory on the Wada in just a minute. 

But first, I wanted to mention that the Wada procedure isn’t standardized across medical centers because the protocols are not the same. Thus, we can’t do a direct point comparison between medical centers. However, our tasks are standardized to the protocol and therefore, we use the normal distribution and descriptive ranges that I’m sure you all have seen in neuropsych reports a million times. These are average, high average, superior, very superior, etc. 

With that caveat noted, the tasks on the procedure are analogous to the cognitive constructs that are being measured through traditional paper and pencil assessment. The difference here is that the patient is in a medical environment reminiscent of a surgical suite and not in the traditional outpatient environment. The tasks themselves are designed to work with the surgical environment while still validly measuring core cognitive constructs that are administered in the traditional outpatient setting.

As I mentioned before, there are practically as many different ways of performing the Wada as there are medical centers. However, many procedures include something like showing the patient some objects, having the patient read words or sentences, following instructions, look at visual stimulus, free recall and recognition memory trials, and sometimes grip strength, finger tapping, or other measures of gross motor ability. The procedure that I use here at Miami Valley Hospital is one that I was trained under at Dartmouth Medical School, which has been around for a couple decades, at least. And it originally was brought to Dartmouth by faculty from the University of Pennsylvania.

With the Wada procedure complete, now we’re ready to interpret our findings. As I had mentioned before, the scores on the Wada are standardized specifically to the protocol used and do not directly translate across medical centers who may have their own Wada protocols. That said, when we’re ready to interpret the Wada results, I look at the amount of objects, words, and designs that were correctly identified. I then calculate the amount of false positives that were reported and then I come up with the total score per hemisphere that represents that hemisphere language and memory capabilities. As noted previously, the scores have a descriptor range that are similar to those seen in neuropsych tests including very superior, superior, high average, etc. 

Interpreting Wada results for language is much more straightforward than interpreting results for memory. When we first inject into the left internal carotid artery, if the patient is left hemisphere dominant for language, then we would expect speech arrest that lasts for several minutes with subsequent dysarthria and articulation difficulties lasting for another couple of minutes. In contrast, we would expect no speech arrest when the right internal carotid artery is injected. If, for example, the patient demonstrates adequate slowing on EEG after the left hemisphere is injected but they’re still able to speak, then this patient may be classified as having bilateral language representation or predominantly right hemisphere lateralization for language. 

But bilateral language representation is not typically uncommon; however, it is still considered somewhat rare and problematic if the question of resection involves the language hemisphere. For example, our patient with left temporal lobe epilepsy earned a left hemisphere total score of 4 and a right hemisphere total score of 9. Looking at the standardization for this protocol, I know that a score of 4 is in the moderately impaired range while a score of 9 is in the average range and is, in fact, the highest score possible. This tells me that the left hemisphere is not capable of sustaining memory when it’s compared to the right. Thus, we conclude that with resection of the left hippocampus, we should see minimal to no postoperative change. 

That brings me to my last point. If we’re capable of seeing a well-lateralized temporal lobe dysfunction, this increases the chances of good surgical outcome as it relates to a reduction in the seizure severity, frequency, and duration. In one study, Loring et al found that 89% of patients were seizure free at one-year followup based on MRI hippocampal volume asymmetries and lateralization of memory as concluded by the Wada test alone. 

That brings me to the conclusion of this presentation. Specially trained neuropsychologists like myself are able to integrate neuropsychological testing results, activation patterns on functional MRI paradigms, and Wada results to correctly lateralize language and memory functions, identify focal neurological deficits, and estimates of postoperative change. Using these tools, we’re able to provide detailed information to the patient’s clinical team and provide the best patient care possible. Thank you all for listening.

My name is John Terry. I am a neurologist and  Associate Professor inat the Department of Neurology. I am a neuro-interventionist, neuro-intensivist and stroke neurologist so a lot of my day consists of dealing with stroke patients. Today, I’d like to speak about the management principles for spontaneous intracerebral hemorrhage. 

There have been multiple iterations of guidelines for management of this disease, the most recent of which was in 2010 when the American Heart and Stroke Association published their guidelines for the management of this disease. I will be referring back to this particular document as we go along to point out some of the major recommendations and also the updated recommendations. 

We really know probably the least amount about spontaneous intracerebral hemorrhage which is a type of stroke. If you look back historically in 1999, there was an iteration of intracerebral hemorrhage guidelines and at that time there were only five small randomized medical trials and four randomized surgical trials dealing with acute intracerebral hemorrhage. 

What I would like to do is review the epidemiology of this disease, talk about the pathophysiology and the treatment options. The blood supply to the brain varies by location. There are several areas that are fed predominantly by very small blood vessels that branch directly off of the larger blood vessels. These areas include the basal ganglia, the thalamus, the pons and the cerebellum. The way that the circulation differs in these areas is that, unlike the normal pattern where the arteries as they get farther away from the heart branch like trees and become progressively smaller, these areas have very small branches that come off main arterial trunks. If one looks at the blood pressure throughout the circulatory system, one can see that initially, for instance, in the aorta the blood pressure is very high and it is pulsatile meaning it is at its highest when the heart contracts and lowest when it relaxes. As you move farther away from the heart, that pulsatility decreases as does the pressure. And so, in effect, the small arteries are protected from the systemic blood pressure by the intervening branches of the intermediate sized arteries. In the areas that we have been speaking about in the brain where you have small branches that come directly off large branches you don’t have the benefit of the pressure decrease over the length of the arterial system so that these arteries are exposed to higher pressures than other arteries of similar size in a more normal configuration. 

The walls of these small arteries are subject to degeneration over time, however, people that have high blood pressure have much more rapid degeneration. I have a slide here that shows a cross-section of several of these small arteries. Some of these arteries are normal in which case you see a round wall at the circumference of the artery. The wall is of uniform thickness and within the walls you can see red blood cells. In others you see that the wall looks irregular. It is thickened and has various degrees of thickening around the outside, and it also is filled with red blood cells. The thickening and irregularity represent degeneration that occurs over time and especially in patients with high blood pressure. It involves deposition of abnormal protein and the result of this thickening is that the artery wall becomes more brittle and more prone to rupture. 

Additionally, small out pouchings of the arterial wall can occur. These are termed Ccharcot-bouchard aneurysms, and these are felt to be a large factor in patients who have intracerebral hemorrhage where the out pouching becomes very narrow and may rupture and bleed. 

If you look at the epidemiology of intracerebral hemorrhage, it causes about 10 to 15% of strokes, so it is a small minority of patients that present with stroke symptoms who have an intracerebral hemorrhage. If you look, roughly 70% of patients that come in with stroke symptoms have what we term an ischemic stroke, which is a situation where a blood clot forms within an artery and cuts off blood flow to part of the brain. In intracerebral hemorrhage, a blood vessel ruptures and blood leaks out. 

Only about 37,000 to 52,000 cases of intracerebral hemorrhage occur each year which is smaller than the number of cases of ischemic stroke. If one looks at the location of these hemorrhages about 50% were are what we call “deep” in location,” meaning they occur not on the surface of the brain but more towards the center. The most common area that is involved is called the basal ganglia. About 16% occur in the brain stem and cerebellum in the lower and more posterior parts of the brain. And based on other demographic characteristics, the incidencets of intracerebral hemorrhage varies from about 10 to 20 cases per 100,000 people per year. 

Although intracerebral hemorrhage is more rare than ischemic hemorrhage, unfortunately it has the highest mortality of all stroke types with only about 38% of victims surviving the first year. The 30 day mortality has been reported anywhere from 35% to 52% and in some ways depends on the location of the hemorrhage so that for patients that have deep hemorrhages about half of the patients will die within the first year. For those that have brain stem hemorrhages, 65% will die in the first year. And if you look at the deaths about half of them occur in the first two days. So this type of stroke really is very serious and has a high mortality. 

Unfortunately, it is the type of stroke that we have the least knowledge of what the proper treatments are, at least in terms of treatment options. As I said earlier, about half of the people die in the first couple of days. This has been a fact has been studied in order to try to find a way to mitigate these deaths. A physician by the name of Dr. Brott performed a study in 2007 which looked at the first three hours after the onset of intracerebral hemorrhage and in patients that came into the hospital after this had occurred. They performed a neurologic evaluation and a CT scan at presentation, at one hour, and at 20 hours after the patient arrived. What they found is that 26% of the subjects showed a substantial growth in the volume of the hemorrhage between the baseline and the one hour scan. So in the first hour after being in the hospital continued bleeding occurred which resulted in an enlargement of the blood collection noted in the brain. 

Additionally, about 12% of subjects had substantial growth between the one and 20 hour CT scans. They also found that patients that did have hematoma enlargement or continued bleeding had worse outcomes over time, and the 30 day mortality was significantly higher in patients with enlargement compared to those without enlargement. It was felt that possibly this could be a point where intervention could be applied to help improve outcomes, since this is a phenomenon that occurs in the hospital after the patients had presented and occursred in a time frame which could be addressed. 

In terms of looking at factors that influence the outcome of patients, the volume of the hematoma or intracranial blood collection has a big impact on outcome and is a powerful predictor of death by 30 days. Also, the extent of disability as measured by the Glasgow Coma Scale at presentation is a good predictor of how people will do. Hydrocephalus is another indicator of increased mortality. Hydrocephalus occurs when blood breaks into fluid filled spaces in the brain and can block outflow of that fluid so that it is trapped and the fluid can build up and increase pressure in the head. 

As we just said, we know that the early risk of neurologic deterioration in intracerebral hemorrhage is high and is usually associated with hematoma enlargement. EIn the expansion of, the hematoma is associated with a nearly five fold increase in clinical deterioration, poor outcome and death. So the prevention of injury from hematoma development enlargement really has been the focus of our therapeutic intervention trials. 

Looking back at the American Heart Association recommendations for treatment of intracerebral hemorrhage, they point out that although there are some clues that a clinician can glean from the patient on presentation, it is impossible to know that whether a person that presents with stroke symptoms has had hemorrhage or has a blocked cerebral artery so that imaging, in particular CT scanning, is important to perform early on. 

Hematoma expansion has been shown to be predictive of clinical deterioration and increased morbidity and mortality. CT angiod geography or contrast CT may identify patients at high risk of hematoma expansion based on the presence of contrast extravasation within the hematoma. Other forms of imaging are reasonable to perform to try to more specifically identify causes of the hemorrhage. Specifically , entities like arteriovenous malformations, tumors, cerebral vein thrombosis or aneurysms as these entities have other treatment considerations that need to be assessed. 

In terms of medical treatments for these patients, as I had said before, in 1999 there were only four small randomized trials looking at patients being treated for intracerebral hemorrhage. One of the trials looked at the use of steroids as a possible way to decrease swelling around the hematoma in the brain. One of them looked at hemodilution, or giving fluids to make the blood thinner, to help improve flow. And one of the trials looked at glycerol which is a medication that may also help decrease the swelling. None of the four studies showed any benefit of the three therapies discussed here. And, in particular, one of the trials showed that patients treated with steroids were more likely to develop infectious complications than those who received placebo. In this particular intervention not only did it not help the patient, it was actually harmful. 

Another treatment strategy that has been discussed or thought of has been to use medications that favor clot formation in order to try to stop bleeding from occurring. Clot formation is the natural way that the body responds to bleeding and the natural way that the body can stop bleeding. Unfortunately, several trials using different mediations have been attempted and have not been shown to benefit patients overall in outcome and, in particular, harm may occur due to unwanted clotting which may result in things like deep venous thrombosis, heart attack and other problematic clotting. 

So the recommendations from the American Heart Association are not to use pro-thrombotic medications or medications that favor clot formation. 

Another strategy that has been discussed is to decrease the arterial pressure which may help decrease the amount of blood that is forced out of the area of rupture. An initial concern about this potential strategy is that if the blood pressure were lowered, the concern was that that would lower the circulation of blood around where the hematoma is because the tissue is compressed around the hematoma. A physician by the name of Dr. Powers performed a study looking at cerebral blood flow during reductions and in arterial pressure in patients with acute hemorrhage u. Using a PET scanner.  I it was a small subject trial including 14 patients with intracerebral hemorrhages who were studied 6 to 22 hours after the onset of hemorrhage. The regional blood flow was measured with a PET scanner and then patients were randomized to receive either a blood pressure lowering medicine or placebo. The goal was to lower the blood pressure by about 15% in those receiving blood pressure reducing medications. After the blood pressure was reduced to the target goal, cerebral blood flow was measured again. They used nicardipine or labetalol as the agents and were able to lower the mean arterial blood pressure from 143 to 119 which was about a 16% change. 

What they found is there was no significant change in blood flow either globally in the brain or around the intracerebral hemorrhage. They concluded that there was a less than 5% chance that cerebral blood flow would fall by more than 2.7 mils per 100 grams of tissue per minute. 

This trial really was one of the first that supported the idea that lowering blood pressure in patients with intracerebral hemorrhages is actually safe. Other trials were published that supported this idea. T– two Japanese trials – one in 1998 and one in 2004- were published that showed a rough dose response relationship between blood pressure and hematoma enlargement. 

So we know that acute high blood pressure is very common in patients presenting with intracerebral hemorrhages. In fact, it is almost unheard of that patients are not hypertensive when they come in. And we now have evidence that there is not a problem with lowering the blood pressure around the clot or in the brain in general. It is felt that elevated blood pressure may contribute to hematoma expansion by forcing more blood out through the hole that has occurred in the arterial system. 

It has been an area of great interest in terms of potential treatment interventions, t. The thought being that if it is safe to lower blood pressure when a patient comes in, doing so may result in less hematoma growth. An NINDS sponsored trial named ATACH for Antihypertensive Treatment of Acute Cerebral Hemorrhage was conducted in the early 2000s. It was a three year multi centered, open labeled, non randomized phase one pilot trial which was aimed at trying to establish the safety of decreasing blood pressure in patients that present with intracerebral hematomas. 

They used a 4 Tier dose escalation design so that initially the target range of blood pressure is 170 to 200. After the requisite number of patients were enrolled, the data was reviewed for evidence of harm. No harm was found and therefore the target range was lowered to 140 over 170 and that process was repeated and the final target goal was 110 to 140 millimeters of mercury. The results of this trial really showed that it is not only safe, but feasible, to rapidly lower blood pressure early in the course of patients presenting with this kind of stroke. 

A more recent trial, which is published in the New England Journal of Medicine in 2013, is the INTERACT II trial that stands for Intensive Blood Pressure Reduction and in Acute Cerebral Hemorrhage Trial II. This was a much larger trial. It included 2,839 patients that were treated within the first six hours after the onset of their hemorrhage. 719 were treated to a low systolic blood pressure goal of less than 140 millimeters of mercury. The remaining 786 were treated to a systolic blood pressure goal of less than 180 millimeters of mercury. The primary outcome was a modified Rankin score of 0 to 2 versus 3 to 6 at 90 days. They also included a prespecified ordinal analysis of the outcomes. Secondary outcomes included safety and quality of life. The results of this trial show that there was no difference in the primary outcome or adverse events. And the P value there was 0.06 which was almost significant but not quite. However, in the ordinal analysis, a benefit of intensive treatment was shown to a level of significance of P = 0.04 and they also found improved quality of life in the intensive group. So this is another major trial that shows that lowering the blood pressure is safe and actually may confer some benefit as demonstrated by the end points that were chosen for the trial. 

The current recommended guidelines for treating elevated blood pressure and spontaneous intracerebral hemorrhage are more liberal than those that we have been speaking of in the trials. Typically, we want to keep the systolic blood pressure less than 200 millimeters of mercury and the target goal really is less than 160. So those were the medical treatment options. The trial looking at trying to form a blood clot to plug the hole, did not show benefit. However the trials showing decreasing the blood pressure showed that it was safe and probably does have some beneficial impact. 

What about surgical trials? In the past, surgery has been a major consideration for patients with intracerebral hemorrhage and that treatment pattern actually was present for some time before clinical trials were undertaken to try to establish whether or not it was the best way to treat these patients. A Seminole seminal trial called the STICH trial which stands for International Surgical Trial and Intracerebral Hemorrhage randomized 1033 patients from 107 centers over an eight- year period beginning in 1995. So this was a large multinational, multicenter trial that gave us some information about surgery in these patients. Patients were randomized within 72 hours and then operated on within 96 hours after the onset of their stroke if they had a clot that was greater to or equal to 2 centimeters in diameter. 

The patients were randomized only if the neurosurgeon was uncertain as to the benefit of the surgery. The patients with Glasgow coma scores less than five were excluded because of the poor outcome that those patients would likely have. The primary outcomes that were looked at were death and, disability as measured by the extent of Glasgow outcome scale at six months. Secondary outcomes were death, Barthel index score and the modified Rankin score at six months. 

506 patients randomized in surgery and 530 were randomized to medical therapy. The groups were well-matched in terms of their characteristics. There was about a 26% crossover rate so that 26% of patients that initially were randomized to the medical arm were operated on, presumably because they had worsening in their exam. Craniotomy was the type of surgical intervention used in 85% of the subjects who crossed over. Whereas if you look at the patients that were operated on as a whole, 75% of the patients underwent craniotomy with the remainder undergoing less invasive surgical techniques. And 93% of the patients were available for analysis at follow-up at six months. 

In an intention to treat analysis, surgery within 96 hours was associated with a non-significant absolute benefit of 2.3% at six months. And o Overall when you review the results of the study there was no clear benefit of surgical intervention in these patients, which was somewhat of a disappointing outcome. However, it is important information to know that the thought currently is that open craniotomy in general does not benefit patients who have had an intracerebral hemorrhage. Some subgroup analysis showed that patients with a Glasgow coma score of 9 to 12, those with low bar clots, and those with clots 1 centimeter from the surface may have been helped by early surgery. However, this wasn’t statistically significant.   

It is interesting though that patients in the Glasgow coma scale score a range of 9 to 12 normally would be only moderately symptomatic from their hemorrhage.  , Wwhereas patients in coma were actually found to do better with medical management. So surgery hurt the worst affected patients. Craniotomy has not been shown to be helpful in this disease process. One of the potential thoughts on why that might be the case is that many of the blood clots that accumulate in intracerebral hemorrhage do so deep in the brain, so that in order to reach them to remove them the surgeon must go through normal brain which causes additional injury. This additional injury may offset any benefit from the surgery itself. 

So consideration to less invasive ways of removing clot has been a more recent area of interest in treating these patients. The potential advantages of minimally inevasive evacuation include possibly reduced operative time, the possibility of avoidance of general anesthesia (because these cases may potentially be performed under local anesthesia), reduction of tissue trauma, especially for the deep lesions, and facilitation of earlier evacuation thaen it is possible or practical with conventional craniotomy, as craniotomy typically takes a fair amount of time to mobilize the team and prepare the operative room to do the procedure. 

The limitations of this approach may include reduced surgical exposure so that targeting the lesion may be more difficult, an inability to treat structural lesions such as arterial venous malformations or aneurysms which can be the cause of intracerebral bleeding, the potential for rebleeding if clot dissolving medications are used to aid in removal of the clot, and the possibility of increased of risk of infection related to prolonged indwelling equipment that may be used to help drain the clot over time. 

Looking back at the STICH trial results it suggested that subjects treated with a non-craniotomy surgical approach had a worse outcome than those treated with conservative management. However, the confidence interval in this estimation included one which brings into question its validity. It was unclear in that particular trial how a given patient was chosen for craniotomy versus less invasive procedures so that the information that comes out of this trial is not very helpful in helping to answer the question about whether less invasive methods may help. 

As I said earlier, clot dissolving medicine, specifically TPA, hasve been considered in treating patients with intracerebral hemorrhage. In general, the method of treatment would be gaining access to the area of the brain where the hematoma is and instilling TPA to help break the clot down and then allowing that to drain out of the head. 

There have been many small trials looking at various protocols and methods for carrying out this type of treatment. In general, these trials have shown that it is relatively safe. Given these results the NINDS funded a multi-center randomized controled trial called MISTIE which stands for minimally invasive stereotactic surgery plus TPA for intracerebral hemorrhage evacuation. This trial was designed to test the hypothesis that early use of minimally invasive surgery plus TPA for three days is safe for the treatment of intracerebral hemorrhage, and it will produce a clot size reduction compared with medically treated patients. 

Again, going back to the American Heart Association recommendations for intracerebral hemorrhage regarding surgery, the current recommendations state that for most patients with intracerebral hemorrhage the usefulness of surgery is uncertain and not recommended. A sSpecial case in point that we won’t get into, but is worth mentioning, is that patients with cerebellar hemorrhage are usually felt to be good candidates for surgery. But hematomas in other locations in general are felt not to be good candidates. The effectiveness of minimally invasive clot evacuation is still being evaluated, but is not currently recommended outside of the clinical trial.

Let’s talk a little bit about the MISTIE trial. We know that there is a strong correlation or relationship between the volume of the hematoma in the brain and the patient’s outcome at 30 days. I have a slide here that shows a table that describes outcome at 30 days related to the volume of the intracerebral hematoma, and in general what one sees is that patients that have very small hematomas tend to do well and as the hematoma increases in size their outcomes become progressively worse.

The inclusion criteria for the MISTIE trial were patients that were older than 18, those that had a Glasgow coma score of less than 13 or an NIH stroke scale of greater than six so that these patients had significant effects from their hemorrhage, but were not comatose and devastated by their hemorrhage. Patients needed to have a spontaneous supratentorial hemorrhage of greater than or equal to 30ccs in volume and over time the clot needed to be stable. So that the patients come in and are evaluated with a CT scan. Another scan is performed at six hours and they are not able to participate in the trial until their two scans six hours apart showed no significant change in the hematoma volume. 

I have a slide here of one of the patients who was enrolled in this trial here at our hospital who had a catheter placed into their hematoma. What the slide shows is that over the course of about one week the hematoma went from a fairly significant size to almost completely gone. In contrast, this other slide shows a patient that was randomized through the trial to the medical arm and over the same amount of time there was not much change in the hematoma over the first week. And actually at day 22 the hematoma had only come down in size very slightly. So this shows a fairly dramatic comparison that with the catheter method the hematoma can be drained fairly rapidly. 

The MISTIE trial has had several iterations. In the MISTIE II trial when the data were looked at of outcomes of patients that were enrolled, what they found was when comparing a similar plot of hematoma volume versus outcome to those that were not treated there were more patients that fell in the good outcome ranges that had actually had larger hematomas, which was support of the fact that patients who had their hematomas drained had better outcomes. And this is also in concert with the observation that has been made in the past that lower volumes tended to have better outcomes and higher volumes tended to have worse outcomes. 

If one looks at the day 365 modified Rankin scale score which is a score of functional abilities, you can see there is roughly 14% reduction in the amount of disability of patients among those who received the catheter drainage compared to those who received only medical therapy. 

Also some interesting observations from the data is that the patients that underwent the catheter drainage part of the study had a shorter length of stay in the hospital and even given the cost of the surgical treatment had a lower cost of care for their hospital stay. 

We did learn some interesting aspects about recovery after hemorrhage in the study as well. The study is unique in the fact that it followed patients for up to a year after their hemorrhage, which is longer than most other study’ies used to have a follow-up time. In those patients that were treated medically what was found was that there was a period of recovery that tended to span the first 180 days where gradual improvement in ability occurred, but after 180 days that improvement plateaued and there was not much significant improvement after that. Whereas those that had the drainage procedure had steady improvement throughout the entire 365 days over which they were followed during the trial. In fact, the rate of recovery was equal or f even greater in the second 180 days compared to the first. 

Again, back to the American Heart Association Guidelines, the recommendations are aggressive full care early after the onset of intracerebral hemorrhage. It recommends against routine open craniotomy for surgical treatments, and it recommends blood pressure control according to the levels in the guidelines. So in summary, what we know about intracerebral hemorrhage treatment thus far is that blood pressure control is a cornerstone of the treatment. It does not cause harm and probably is beneficial. Routine use of open craniotomy for surgical treatment of the disease does not confer benefit, however, less invasive methods particularly drainage of the hematoma cavity with an inserted catheter is showing great promise for helping these patients in the future

Dr. Cheng: Hi, I’m Esteban Cheng-Ching. I’m a neurointerventionalist and stroke neurologist, with the Clinical Neuroscience Institute at Premier Health. I’m going to talk today about acute ischemic stroke treatment and focus on the acute part with emphasis on the endovascular treatment. Treatment of acute ischemic stroke has suffered significant changes over the past six months, which has created a shift in the paradigm of treatment, a change that hasn’t been seen over a decade. And we’re gonna talk about these changes and about the chronological evolution of acute ischemic stroke treatment.

I have nothing to disclose. 

When we talk about acute ischemic stroke, I divide the treatment or the focus on the therapy in three stages. The first one is acute therapy with reperfusion. That’s what I’m gonna focus today. The second stage is etiology workup and secondary prevention, as well as prevention of complications. And the third stage is the phase of rehabilitation. All these three phases tend to overlap. 

We’re gonna talk today again about, about acute therapy. Stroke’s an important disease. It’s the fourth leading cause of death in the US and approximately 795,000 strokes occur per year. As I mentioned, acute stroke therapy has evolved over time beginning in 1995 with intravenous tPA therapy within three hours, subsequently extending the time window to four and a half hours. And then, with intra-arterial therapy; subsequently, we have negative intra-arterial therapy trials that were published, which held that widespread treatment with this therapy. And in 2015, this year, we have publication of subsequent, successful intra-arterial trials. 

In 1995, the NINDS tPA trial was published in the New England Journal. This study was the first study demonstrating, effectiveness of intravenous tPA within three hours from the onset of symptoms. It showed that patients given this treatment were 30% more likely to have minimal or no disability at three months. However, three hours is a short window and many patients were not being treated. It is not until 2008 that we have the ECASS III study demonstrating that intravenous tPA is effective up to four and a half hours. This study showed favorable outcome in patients receiving tPA up to four and a half hours with no significant increased risk in this patient population. 

Even though we have up to four and a half hours for treatment, the sooner we given the treatment the better. This graph demonstrates an increased odds of favorable outcome the earlier the tPA is administered. And as time passes, the favorable outcome decreases. So the sooner we give this treatment, the better.

Even though tPA showed to be effective for the large population of patients with stroke, there are a subset of patients who do not benefit completely from tPA. Patients with large vessel occlusions represent about a third of the anterior circulation strokes. These are patients with occlusions of the intracranial ICA, the M1 segment of the MCA, and the basilar artery. These are large vessels that do not recanalize with tPA. They’re generally resistant to tPA. With reperfusion or recanalization rates of 25% or less, these patients are the ones who have the bigger strokes and the worst outcomes with increased rates of mortality ranging from 27% up to 90% depending on the vessel that is affected. Large vessel occlusions, as I said, are not completely recanalized with tPA so an additional treatment is probably indicated. 

This is an example. This is a 46-year-old woman who presented with right hemiparesis and aphasia. The angiogram on the left demonstrates an occlusion in the M1 segment of the MCA. This patient did not recanalize and after the occlusion evolved, the patient had a big stroke with significant impact on her outcome with serious disability.

So large vessel occlusion strokes are a serious condition. And, as I mentioned, tPA does not recanalize these vessels completely. Intra-arterial therapy may play a role. 

This treatment also have evolved over time. The first study was published in 1999 with the PROACT II trial. In the 2000s, multiple devices were developed for mechanical thrombectomy – the MERCI device, the Penumbra device. And multiple registries were being done at that time. But, randomized trials did not appear until 2013 with negative results in which impacted the field significantly. And as I mentioned before, it’s not until this year when new data appears supporting intra-arterial therapy for stroke.

So I’m gonna talk about the several trials in a chronologic order. PROACT II was published in 1999. This study included patients with acute MCA strokes who presented within six hours from the onset of symptoms. These patients were randomized through intra-arterial urokinase given over two hours, plus heparin, versus a group that received only heparin. And it demonstrated that at 90 days, a modified ranking score of 0 to 2, which means functional independence, was achieved in 40% of patients with Pro-urokinase group, or the intra-arterial group versus 25% in the control group. Unfortunately, a second study was required for this treatment to be approved by the FDA and this second study was nor performed so this treatment did not take off.

In subsequent years, multiple devices were developed for mechanical thrombectomy. In the figure above, we see the MERCI device, which is a corkscrew like device thatgets deployed within the clot and removes the clot. The second figure below demonstrates the Penumbra device, which is a catheter that aspirates the clot. And these two devices are meant to recanalize vessels and they showed to be successful. However, the – however, the rates of recanalization were not optimal. 

The technology continues to evolve. In 2015, we have stent retrievers, which are stents attached to a wire which when deployed within the clot achieve mechanical thrombectomy with recanalization in rates up to 80 and 90%. These devices have been available for the past few years and are currently used most widely for stroke treatment. However, the stent retrievers were not available widely for these studies that were published in 2013 that were negative. 

This is a case example of a patient treated with a stent retriever device. This patient presented with an NIH Stroke Scale of 20, meaning a significant neurological deficit with the other angiogram on the left demonstrating an occlusion in the M1 segment of the left MCA. This angiogram in the picture is before the stent retriever. And after the recanalization with the stent retriever, we see the significant, reperfusion with all the vessels of the MCA appearing in the picture. This patient had improvement of NIH – from an NIH Stroke Scale of 20 to 4, which is minimal neurological deficits.

In 2013, as I mentioned, three studies were published. The first one is the SYNTHESIS Expansion trial, the second is the MR RESCUE, and the third is the IMS III. To understand these trials, we have to know what criteria to take into account when evaluating endovascular treatment for stroke. Here, we’re talking about large disabling strokes in which the index disease is large vessel occlusion. The treatment we are assessing has to be a treatment that has to be effective. Meaning that it has to open the blood vessels within the time period in which it will be beneficial. And the patient population that will benefit are those who will still have some brain to be saved. So these criteria needs to take into account to understand why these three trials were negative.

So the first study, that I mentioned was the SYNTHESIS Expansion. This study included 181 patients and randomized patients to intravenous tPA versus intra-arterial tPA, and concluded that intra-arterial therapy is not beneficial over medical therapy. However, in this study, there was no confirmation of large vessel occlusion, there was no report on the percentage of large vessel occlusion or recanalization rates. We don’t even know if the index disease was present.

The second study is the MR RESCUE. This study evaluated whether Penumbra based imaging is useful for patient selection in intra – for intra-arterial therapy. Penumbra based imaging is the perfusion study to assess how much tissue is damaged and how much tissue is at risk to be infarcted. So this study concluded that Penumbra based imaging is not useful and that intra-arterial therapy is not beneficial compared to medical therapy. However, the enrollment was very slow. Between 2004 and 2011, it included 127 patients. That is about one per month. That is only 64 in the intra-arterial arm and if we take into account that the recanalization rate was 25%, 16 of 64 patients using the MERCI device mainly. 

So can we really conclude that Penumbra based imaging is not useful based on only 16 recanalized patients with a device that did not open the occluded vessels? I don’t think we can conclude that.

The third study is the IMS III, which was a very well designed study. And from this study, we have learned a lot, which has helped the evolution of the treatments in the subsequent successful studies. IMS III included 656 patients randomized to endovascular treatment plus intravenous tPA versus intravenous tPA alone, and concluded that there was no benefit for endovascular therapy added to IV tPA. However, at the time IMS III was started, CTAs were not widely available in the ERs and therefore, only 33% of patients had CTAs. Subsequently, the addition of CTA was amended to the study so CTA was more widely used at the end of the study.

So can we conclude that there was an index disease in the other 66%? I don’t know if we can make this conclusion. Twenty percent of those patients in the intra-arterial arm didn’t have a large vessel occlusion. At the same time, this enrollment was very slow, as well, and expanded from 2006 up to 2012. The devices used were not effective devices with the majority of devices being the MERCI. Only five patients received stent retrievers. And the recanalization rate in this group ranged from 23% up to 44%, so not a good recanalization rate.

Several things we can learn from IMS III. One is that reperfusion was better in large vessel occlusion patients with intra-arterial therapy when compared to intravenous tPA. And with better recanalization, the functional outcome was better. So, for example, a TICI 0 score – TICI is the scale of recanalization, TICI 0 is no recanalization. TICI 0 was associated with 12.7% of good functional outcome. But a TICI 3, which is complete recanalization, was associated with good functional outcome in 71.4%. So the better recanalization, the better the functional outcome.

The second thing we can learn from the IMS studies – IMS I and IMS II – demonstrated a good relationship with time. And with every 30 minute delay, there was a 10% decrease in probability of good outcome. Same thing was seen in IMS III and significant delays were seen in IMS III as compared to the IMS I and II studies. In the subsequent post hoc analysis, the faster reperfusion was associated with better outcomes. So in reality, time is brain and the faster we act, the better the outcome. 

This paper published in the Stroke Journal in 2006 puts this into perspective in patients with large vessel occlusion strokes. For every minute that passes, we lose 1.9 million neurons. 

So for successful acute ischemic stroke endovascular treatment, we have to have certain criteria. We have to have a large vessel occlusion, we have to act fact, we have to use devices that work and open vessels, and the current devices are the stent retrievers, and we have to select the patients correctly. So these are patients with emergency large vessel occlusions, patients with small stroke at the time the procedure is started, (because a big stroke even if we recanalize the vessel, it will not necessarily improve from the recanalization), and patients who are candidates for this therapy should have some reasonable baseline function. And patients who are candidates for this therapy should have some reasonable baseline function. 

In 2014, the MR CLEAN study was present in the World’s Stroke Congress, and this is the first study that was positive for endovascular treatment for acute ischemic stroke demonstrating benefit. This study was subsequently published in the New England Journal, included 500 patients, 233 were in the intra-arterial group, and 267 in the control group. This study was done in, in the Netherlands and the enrollment occurred between December of 2010 and March of 2014. Patients in the study had anterior circulation strokes presenting within six hours and with a large vessel occlusion and the stent retrievers were used in up to 81.5% of the cases. The primary outcome of the study was the modified ranking scale at 90 days, meaning the functional outcome at 90 days. And a modified ranking of 0 to 2, or independence, was achieved in 32.6% in the patients who received intra-arterial therapy versus 19.1% in the control group with a significant difference between groups. The number needed to treat was 7 for independence and this basically represents that for every patient, every seven patients that we treat, we can achieve one patient being completely independent. A graph shown here demonstrates the difference between the Rankin scales in the intervention group and the control group. So a scale of Rankin of 0, 1, and 2, which is independent, was significantly more frequent in the intervention group as compared to the control group.

After MR CLEAN, we have certain conclusions. One is that intra-arterial treatment within six hours after a stroke is effective and safe for patients with large vessel occlusion, and this significantly impacts functional independence at three months. The presentation of this study led to stopping other endovascular acute ischemic stroke trials, which had to undergo interim analysis. This was like a falling domino phenomenon in which all the other studies were stopped or analyzed and demonstrated positive results. 

In the 2015 International Stroke Conference, three other studies were presented and published in the New England Journal of Medicine. The first one is the EXTEND IA, second is the ESCAPE, and the third is the SWIFT PRIME, and these three studies demonstrated positive results for intra-arterial therapy. 

EXTEND IA is the first one. This is a study from Australia and New Zealand. It included 70 patients – 35 in the intra-arterial group and 35 in the control group. It included only 70 patients because it was stopped earlier [stutter] secondary to the publication of the MR CLEAN study. In this group, all patients received intravenous tPA within four and a half hours, and had anterior circulation, large vessel occlusion strokes in the ICA terminus  M1 – or M2 segments. Endovascular treatment had to be initiated within six hours and they were selected based on CT perfusion with the RAPID software. I’m going to explain the RAPID software in the next slide but basically, what they were looking was a mismatch between the size of the perfusion deficit and the actual size of the stroke at the time of the study. And they were eligible if there was a mismatch between between this of 1.2 or by more than 10 cc, and a core infarct of less than 70 cc. 

This slide demonstrates a typical RAPID software sequence. The second line shows the ischemic core, or the infarcted tissue, in pink. And the third line demonstrates the area of perfusion deficit. And the mismatch between these two were the parameters used to select these patients. So a patient with a small infarct and a large perfusion deficit could be a great candidate for reperfusion therapy.

The EXTEND IA also looked at functional outcome at 90 days and the parameter was independent patients with a modified Rankin of 0 to 2. This was achieved in 71% of patients in the intra-arterial group versus 40% in the control group. The number needed to treat was 3.2, which is an impressive number. It means that for every three patients that treat, one patient will become independent. Another important parameter is that in the first 90 days, those patients treated with intra-arterial therapy were able to go home 64 days earlier. That is two months earlier that these patients can go home instead of being in the hospital or in a nursing home or in a rehab facility. And this represents significant impact emotionally, socially, and also, economically.

The graph shown before is the typical modified Rankin scale graph again showing that patients in the endovascular or intra-arterial group had modified Rankin of 0 and 1 significantly, more frequently or in a higher percentage than the tPA only group. 

The second study was ESCAPE study. And, this included 316 patients – 165 in the intra-arterial group and 150 in the control group. These patients had, had anterior circulation, large vessel occlusion strokes and, and the enrollment had to occur within 12 hours from the onset of symptoms. The selection of these patients was based on CT and multiphase CTA. And I’m gonna explain the multiphase CTA in the next slide. So for inclusion, they had to have a small core, an ASPECT score of 6 to 10. ASPECT score is used to assess the amount of tissue that has been damaged at the time the CT is obtained. A higher ASPECT score means a small stroke, a lower ASPECT score is a larger stroke. These patients also had to have moderate to good collaterals on the multiphase CTA with 50% or more of the MCA circulation with collaterals. And there was an emphasis on rapid treatment in this group of patients. 

So this slide, demonstrates the multiphase CTA. In the first slide, we see an MCA occlusion on the left MCA where the arrow is. And on the subsequent phases of the CTA, we see good collaterals in the rest of the MCA distribution. The second line shows an MCA occlusion, the left MCA, with intermediate collaterals in the multiphase CTA. And the third line shows an MCA occlusion with very poor collaterals in the territory of the MCA supplied by that vessel.

So in the ESCAPE study, patients with independence or a modified Rankin of 0 to 2 in 90 days, was achieved in 53% in the intra-arterial group versus 23.9% in the patients in the control group with a number needed to treat of 4. And the other important factor is that the mortality at 90 days was significantly lower in the intra-arterial group – 10.4% versus 19%. So this is the first study demonstrating reduced mortality in stroke patients. 

In the group of patients between six and 12 hours, there was a trend favoring the intra-arterial group. However, with only 49 patients, sample was small and no conclusions could be obtained from this. Again, the modified Rankin graph below shows that patients, in the intervention group achieved modified ranking scores of 0, 1, and 2 in a higher proportion as control compared to the control group.

The third study is the SWIFT PRIME study with 196 patients – again, randomized patients to intravenous tPA plus intra-arterial treatment with the stent retriever versus intravenous tPA in patients with anterior circulation large vessel occlusion treated within six hours. The study used for selection of patients was a CTA or MRI with the RAPID software looking at the target mismatch and number of profile. These patients had to have a small core infarct with a large hypo perfused region to be included in the study. And it showed that, a modified Rankin of 0 to 2 at 90 days was achieved in 60% of patients in the intra-arterial group versus 35% in the control group, which is a significant difference with the number needed to treat of 4 and a good recanalization rate of 88%. Again, the modified Rankin graph shows a higher proportion of patients with independence in the stent retriever group as compared to intravenous.

So all these three studies are different pieces of the puzzle and they led to eventually an  update in the guidelines for the early management of patients with acute ischemic stroke, which was published in June 29 of 2015, and endorsed by all the societies involved in the care of patients with stroke.

According to the current guidelines, patients with acute ischemic stroke should be evaluated for intravenous tPA and treated with this therapy if they’re candidates. All patients should also be evaluated immediately for endovascular treatment and endovascular treatment should be considered with the following criteria. In patients who have a baseline modified Rankin score of 0 to 1, in patients that received intravenous tPA within four and a half hours, patients with large vessel occlusion – meaning occlusion of the ICA intracranially or the M1 segment of the MCA – patients with ages of 18 or above, NIH Stroke Scale of 6 or more, ASPECT score of 6 or more, and in which the treatment can be started within six hours of symptom onset. These guidelines support the treatment of patients with acute ischemic stroke with endovascular treatment and acknowledge the importance to find these patients early and treat them rapidly, which will significantly impact their outcome and improve their functional independence in the long term.

I have a case that is gonna, show a patient with a large vessel occlusion, which was, treated successfully. This is a 70-year-old, man who presented with right hemiparesis and aphasia. On the left, we see an MRA demonstrated, an occlusion in the MCA. And an MRI shows a very small infarct. Even though he had significant deficits, the infarct was small, suggesting that the area of perfusion deficit was probably larger than the infarct that we see in the, iin the diffusion MRI. The patient was taken emergently to the angio suite. On the left, we see an AP view of an angiogram showing an occlusion in the MCA in the M1 segment with reduced, vessels in the MCA distribution. The image on your right is a lateral view demonstrating,  reduced vessels in the MCA distribution. 

These images demonstrate the catheters in the intracranial vessels. On the left, we can see the catheter with the stent retriever in the MCA. And after removal of the stent retriever, the angiogram on the right side shows significant reperfusion with good flow in that previously occluded MCA. 

This is the pre-treatment image is what I have shown you before, to compare to the post treatment image on this slide. And as we can see, the MCA is completely recanalized and the flow in the MCA is improved. This patient had a significantly, good outcome with a rapid recovery and was able to be discharged home.

This other case is a patient with 56-year-old is – who presented comatose, nonverbal, and quadriparetic. The suspicion was a posterior circulation stroke. The MRI only demonstrates a very small right cerebellar infarct despite the patient’s serious deficits. When the patient was taken to the angio suite, we see an occlusion in the basilar artery, which is shown in the image on the right. And on this slide, we can see that on the image on the left, the catheter’s in the basilar artery with a stent retriever across the occlusion with some partial flow. After removal of the stent retriever, removal of the thrombus, there is a complete recanalization of the basilar artery. The patient was initially comatose. After reperfusion, he had a dramatic recovery. On day two, he only had mild ataxia on the right upper extremity and on day three, he was discharged home, completely independent.

In summary, acute ischemic stroke is an emergency. Time is brain and we have to act fast. Intravenous tPA should be considered in all patients with acute ischemic stroke. This treatment can be administered really fast in the ER. And after this, all patients should be evaluated for the possibility of a large vessel occlusion. Endovascular treatment would be recommended if patients have a large vessel occlusion with acute ischemic stroke, which will significantly impact their functional independence and will have a morbidity-mortality benefit. 

Several questions remain for the future. The first one is, is anesthesia or conscious sedation the best way to treat these patients? We still don’t know this, and there are several ongoing studies looking into this question. 

Second question is which patients will benefit the most. So trying to select the patients better to improve their outcome and increase the possibility of administering this therapy to a wider population of patients, should be evaluated. And we still don’t know which is the best imaging technique to select these patients. What about those patients who present beyond the six-hour window from the onset of symptoms? And what about the wakeup strokes? As I said, several research studies are ongoing.

And thanks for listening.