The Brain and Two of the Deadliest Battles - Glioblastoma Multiforme and Stroke

In medicine, nothing is more complicated than the brain. So little is known about this miraculous grey matter comprised of hundreds of billions of cells and how these cells interact with each other as well as the rest of the body. When disease takes hold of the brain, the outcome can be devastating.

But there is hope, particularly with regard to stroke. New imaging technologies and skilled neurointerventional radiologists have changed the paradigm of stroke diagnosis and treatment. And while there hasn’t been much progress in the life expectancy of patients with glioblastoma multiforme, the deadliest and most aggressive type of brain cancer, there has been advancement in the illumination of the tumor during surgery, allowing neurosurgeons greater visibility to excise as much of the tumor as possible.

For this topic of the brain, and in particular, glioblastoma multiforme and stroke, Healthy Living magazine gathered experts for a candid discussion about what is currently known and what might be expected in the future. Participants were Board Certified Neurosurgeons Farhad Limonadi, MD, and Alfred Shen, MD; Board Certified Neurointerventional Radiologist Brian Herman, MD; Board Certified Neurologist Hamid Salari, MD; and Board Certified Medical Oncologist and Hematologist Constantin Dasanu, MD, PhD. Board Certified Cardiologist, Philip Shaver, MD, moderated the discussion.

DR. SHAVER: When I was a medical student, 50 years ago, I was taking my orals in surgery and they asked me to name the three worst cancers a person can have. I said, “Malignant melanoma, pancreatic cancer and glioblastoma multiforme.” I think I’d probably still agree with those choices.

What’s interesting to me is that I’m not sure we’ve done a lot for glioblastoma as far as improving survival in the past 50 years. Out of all the brain cancers, only two percent have such a disproportionate morbidity/mortality. The average life expectancy is only 15 months, often less.

The Central Brain Tumor registry of the United States (CBTrUS) estimated almost 80,000 cases of malignant and non-malignant brain tumors. Two thirds are benign. In the United States, an estimated 16,000 to 17,000 people a year die from malignant brain tumors — worldwide, it’s much more. There are some theories that the incidence is increasing. Perhaps part of that is how much better we are at detecting brain tumors.

DR. SHEN: There are two things going on. People are living longer, and as we live longer, we’re going to see more of these kinds of tumors. I think the other part is the availability of imaging studies. If you become symptomatic, you now have access to imaging studies, CT scans, and MRIs that make it easier to detect these tumors compared to 40 years ago.

DR. DASANU: Not only are we living longer, but we have a number of patients living with immunosuppression because there are more liver transplants, kidney transplants and bone marrow transplants than ever before. In addition, patients with rheumatoid arthritis, systemic lupus and other inflammatory disorders require immunosuppressive treatments. Furthermore, some of the newer anticancer agents have immunosuppressive properties. At age 65, we offer everybody pneumococcal vaccination. Why is that? Immunosenescence, for example, aging of the immune system, is a relatively newer concept. So, not only do we live longer, but we live longer in an immunosenescent state. As a result, we see an increase in the incidence of various cancers including glioblastoma multiforme.

DR. SHAVER: Dr. Limonadi, what’s different about primary brain tumors? Their classification really isn’t like any other tumor because glioblastoma stays in the brain.

DR. LIMONADI: Glioblastoma multiforme, also called GBM, is a fast-growing primary brain tumor that develops from star-shaped glial cell-like astrocytes that support the health of the nerve cells within the brain. It is considered to be stage 4, or the most malignant form of astrocytoma.

It is important to remind ourselves that the human brain is the most complicated entity on earth, as far as we know. Just looking from the perspective that there are a hundred billion neurons in the brain and ten times more glial cells, it is ominous that we are dealing with a very complex entity.

Glioblastoma is the most deadly disease of the brain for the reason that it has this particular subset of cells called glioblastoma stem-like cells. They’re sometimes referred to as stem cells, but the correct terminology is “stem-like” cells. They constantly reinvent themselves, they constantly change, morph and mutate and are radio- and chemo-resistant. Blood-brain barrier is another component, which at the same time as being the most protective barrier of the brain, also inhibits our ability to deliver drugs to these tumor cells.

With regard to comments made earlier, I’m pretty sure that the quality of life for people with glioblastoma multiforme has significantly improved with modern surgical approaches in most cases. The life expectancy of patients with glioblastoma multiforme is less than two years, typically. Fewer than three to five percent of people with the disease have a life expectancy in excess of five years. That really hasn’t changed in the past 20 years. Having said that, at Eisenhower, as in many other institutions, we’ve seen a few patients who have lived beyond the expected life expectancy with glioblastoma multiforme.

DR. SHAVER: Dr. Dasanu, what about the blood brain barrier?

DR. DASANU: It is a great subject of investigation and debate right now, but the bottom line is that it’s a tight junction. It acts like a barrier, not allowing various cells and larger molecules to penetrate into the brain easily.

DR. SHAVER: Here’s what the National Cancer Institute says about the blood brain barrier: “Tightly packed, specialized cells protect the brain from threats like viruses and toxins that may be circulating. This protective blockade doesn’t distinguish between the good guys and the bad guys. It can also prevent cancer drugs from reaching tumors.”

DR. DASANU: There is some data in this regard, but again, blood brain barrier is very complex and not well-explored. More recently, it has been shown that the immune cells circulating in the body do communicate with the white cells in the brain via cytokines [small proteins secreted by immune system cells], the memory T-cells, and some other T-cell subsets known to do immune surveillance in the brain. So, somewhere, somehow, there is communication. Therefore, the brain is not an entirely impermeable structure.

In cancer medicine, we have a multitude of drugs known to penetrate the blood brain barrier. Larger antibodies cannot reach there, but small peptides can. Some chemotherapy agents with smaller molecular weight are also able to penetrate this barrier.

DR. SHAVER: T-cells are white blood cells that are a part of the immune system, helping to build and protect cells, correct? They recognize what’s ours and what’s foreign.

DR. DASANU: Correct.

DR. SHAVER: But there’s almost a reverence I hear when oncologists talk about glioblastoma, which has an ability to exhaust T-cells, among other things.

DR. DASANU: You’re absolutely right, but this issue is very complex. People with glioblastoma are immunosuppressed at baseline. Radiation therapy and chemotherapy used for their treatment cause even more immunosuppression. At the same time, the immune system in the brain can be helped by some drugs that we know penetrate the blood brain barrier. For instance, temozolomide goes through the blood brain barrier due to the smaller size of its molecule. While this drug kills glioblastoma directly, it is also known to modulate the immune system, thereby enhancing its anti-tumor activity.

DR. LIMONADI: There are a number of novel techniques. In my view, they are in infancy for management of glioblastoma multiforme.

The Zika virus is interesting. It has some potential for the simple fact that it has a propensity for the glioblastoma stem-like cells, which is interesting because the West Nile virus also has a propensity for those cells. Research was done trying to kill glioblastoma with the West Nile virus. But it had an equal toxicity for both neural cells as well as the glioblastoma cells and therefore, not useful. What’s special for the Zika virus is that it actually has a predilection to kill glioblastoma multiforme cells, as opposed to neural cells, and that’s what has been shown in studies using rodents. As far as I know it hasn’t really made it to a stage two, stage three critical path.

At this point, the best modality of treatment for glioblastoma multiforme in terms of improving the quality and quantity of life is surgical resection, when feasible. That typically reduces the number of glioblastoma multiforme cells from a hundred billion to one billion. Doesn’t sound like much, but it means that 99 percent of the cells were removed with surgery. And if you add radiation therapy, you remove another hundred-fold cells. And then, of course, chemotherapy.

But progress is not being made as fast for glioblastoma multiforme for the simple reason that the disease involves this most complex multidimensional entity which we don’t even understand.

DR. SHAVER: How about cell phones? Do they cause brain cancer?

DR. SHEN:: There really isn’t any adequate or conclusive data or studies to provide a definitive statement on whether cell phones cause brain cancer. I think we need long term studies, population studies, to really ascertain whether or not cell phone radio waves cause any type of particular brain tumor or tumors in certain locations. There have been some studies, but none of them really panned out. There was a study from France, called CERENAT, in 2014. They suggested high users of cell phones may have an increased incidence of brain tumors. It was a small sample study but it suggested that there may be a small correlation. I think we need really long term studies, 30 to 40 years following people, because we’ve only had cell phones since the mid to late ’90s. Even then there was only a small population of people who could afford them. But now they’re everywhere.

A more recent large study has been underway in Europe since March 2010 (COSMOS) that will follow cell phone users for 20 to 30 years.

The concern about cell phones is that they emit radiofrequency energy in the form of electromagnetic radiation. Although it is considered non-ionizing and low energy (compared to X-rays which are considered ionizing and high energy), its long-term effect suggested that cell phone users reduce their exposure to this low energy radiation by using cell phones for shorter conversations, and to take advantage of hands-free technology.

DR. HERMAN Most kids don’t talk on their cell phones — they text.

DR. SHAVER: What is the most common presentation of brain tumors?

Dr. Salari: Brain tumors can have very different manifestations depending on the location of the tumor and which part of the brain has been affected — cortical or subcortical. One is a presentation of muscle weakness and any sensory deficits, depending on the location in the brain stem and brain stem manifestations. The other one is seizures, which is the common presentation of tumors.

DR. SHAVER: almost 50 percent of people will have a seizure.

Dr. Salari: A large percentage, yes. Another presentation might be very acute if there is a hemorrhage inside the tumor pathway or severe edema of the tumor with compression of mitral structures. So, from a simple headache or a seizure, down to even a catastrophic manifestation like coma, all can be the manifestation of a tumor.

DR. SHAVER: i think it’s important for people to realize the vast majority of headaches aren’t brain tumors. it’s often a new, usually severe, headache in a patient who’s older, who’s not had a history of headaches.

DR. SHEN:: Especially headaches with nausea.

DR. HERMAN: Add to that list, personality changes. People often miss those with frontal tumors.

DR. SALARI: Also, projectile vomiting.

DR. SHAVER: When you suspect the patient has these symptoms, what is the appropriate imaging procedure? Dr. Herman: MRI is the gold standard.

DR. SHAVER:Why is it better than a CT scan?

DR. HERMAN: CT is a good, quick, first go. And CT has advantages of seeing things like blood and calcium. But for the real tissue differentiation, MRI is far superior.

DR. SHAVER: How about the skull. is mri better?

DR. HERMAN: If you’re looking for a tumor involving the skull, MRI is still better. If you were looking at bony processes like infection or trauma that would affect the skull particularly, then CT is the way to go.

DR. SHAVER: What about the survival rate for brain tumors? Five years survival for a primary malignant brain tumor including lymphoma and leukemia is 6.2 percent in 75 years of age or older. if you’re 20 to 44, it’s 61 percent. i think this may get back to what we’ve said about the immune system being one of the factors.

DR. DASANU: Yes. The immune system is definitely important. Primary brain tumors, such as glioblastoma multiforme and anaplastic glioma, are unique because of their fast growth rate. But some of the affected patients have a damaged immune system due to various acquired or inborn immune disturbances, prior radiation therapy, or systemic chemotherapy agents.

DR. SALARI: In our older population, besides the non-malignant tumors, we see more high grade gliomas and glioblastoma multiforme.

DR. SHAVER: Dr Shen, define for us what stereotactic surgery is and what you’re able to do to remove the tumor. how does Dr. herman assist with that?

DR. SHEN:: Stereotactic surgery is a form of surgery that merges imaging and a three-dimensional coordinate system to precisely localize a target inside the brain. This can be used for biopsies, ablations, implants and radiation. It is also a useful modality to help the surgeon navigate within the brain during surgery. I often call it the GPS system for brain surgery. It is an extremely useful tool to help determine the location of a tumor or mass, but it can also be used to define the borders of a mass and to localize an adjacent critical anatomy or structures.

With regard to Dr. Herman’s field, we’ve come a long way in terms of neuroimaging and how it helps us define the details of brain anatomy and the location and extent of tumors and vascular lesions. During the CT era, we often couldn’t see really small tumors or lesions that we now see on MR imaging. MR spectroscopy allows us to analyze the chemical composition of a mass to assist in diagnosis. MR fiber tractography allows us to actually visualize the white fiber tracks of certain functional areas in the brain and to see its relationship to an adjacent tumor. These neuroimaging modalities in combination with stereotactic technology help the neurosurgeon immensely in the planning and intraoperative care of our patients.

DR. SHAVER: how do you do real time with MRI?

DR. SHEN:: The idea of intraoperative MRI is before you do the surgery, you already have a static imaging study that tells you the extent of the tumor, the size and location. As the surgery progresses, when you think you’re done, you can temporarily close the wound and bring the MRI machine into the operating room and scan the patient. You can visualize on the new image if there’s any remaining tumor. If it’s safe, you go back in and resect that area. Another useful advance for visualizing a tumor during surgery is the use of fluorescence-guided surgery (FGS).

DR. LIMONADI: Talking about glioblastoma multiforme, many people agree that the most potential objective advance in recent years has been using FGS using 5- aminolevulinic acid (5-ALA). FGS permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain — in the resection of glioblastoma multiforme. Most agree that the more you resect, the greater the life expectancy. The patient’s quality of life is also significantly improved. Essentially, with FGS, you tag the cancerous cells with flourescein, and then during the operation you can see them better, allowing you to resect them more objectively. FGS has not been completely standardized, but I think it is one of the most significant discoveries in the past five years.

DR. SHAVERr: Dr. herman, are there several different varieties of MrI and neuro imaging, like perfusion MrI?

DR. HERMAN: Functional imaging has been a major advancement in MRI, to which you’re referring, which is diffusion and perfusion imaging. And that allows us to evaluate viability or risk — brain at risk. That’s a key element of stroke imaging. It is also important to diagnostic imaging for tumor evaluations.

DR. SHAVER: Dr. Dasanu, do immunotherapies succeed in glioblastoma? It seems to be a hot bed of research at this point.

DR. DASANU: In glioblastoma, immunotherapy is still experimental. Overcoming the blood brain barrier remains a major challenge, so, ways of penetrating it are currently being explored. Yet, there have been advances made over the last decades. Temozolomide has been around for more than a decade and a half, and became standard therapy after maximal surgical resection of the tumor. It has a decent penetrability through the blood brain barrier, and is used in conjunction with radiation. This combined treatment improved survival in persons diagnosed with glioblastoma in the 21st century.

Bevacizumab, also known as Avastin®, is used as a second line of therapy of glioblastoma. I have several patients with glioblastoma multiforme in my practice who surpassed the two-year mark since the diagnosis was made. Bevacizumab binds and neutralizes a protein called vascular endothelial growth factor (VEGF). VEGF represents “fuel” for the blood vessels of the tumor. By decreasing the VEGF, there is no further blood vessel generation to support tumor growth. In addition, there’s less small blood vessel permeability, leading to decreased brain swelling in the area surrounding the tumor.

DR. SHAVER: It supplies blood to the tumor, so you’re trying to cut off that blood supply. It’s more vascular, right?

DR. DASANU: That is correct. But there are vessels being formed in the body every day. VEGF is nourishment not only for the vessels of the tumor, but also for the vessels in the body. As a result, bevacizumab can cause some side effects such as a tendency for bleeding, impaired wound healing, high blood pressure, and kidney dysfunction. But yes, that is the main mechanism of action of this drug. Dr. Shaver: Let’s move on to the subject of stroke. There have been some changes in the timeliness of treating stroke. We used to have a three-hour window and that has changed.

Dr. Herman,you offer a therapy based on perfusion and diffusion imaging which has a larger window than the previous criteria. explain what exactly you do with an MrI when you’re talking about the perfusion versus diffusion. Is one just blood flow and the other viability?

DR. HERMAN: Yes. The imaging is looking at the speed of enhancement of the tissue. In perfusion imaging, we’re looking at the rapidity of blood flow through the tissue. You can quantify the rate of blood flow and you know at which point the brain tissue will die. So, we have a very good actual number that you can achieve in terms of viability of the brain. The other side of it is the diffusion imaging which looks at the early changes of cell death. The water now moves differently within the cells and through the interstitium and this lights up like a light bulb on the diffusion imaging. It allows you to see what part of the brain has died and what part is at risk of dying. You simply compare the two. Hopefully the part at risk is much larger — the penumbra. The umbra is the part that has died. If there’s a large salvageable portion, then that person has the ability to revascularize that part of the brain and regain function.

The clinical side of that is that you’ll see the clinical deficit for the part of the brain that’s not functioning, so even though it’s a perfusion [blood flow] deficit, it hasn’t died. Clinically, you’ll see loss of function correlating to that territory — weakness, vision, speech, etc.

DR. SHAVER: Dr. Salari, what are the causes of stroke — ischemic and hemorrhagic?

DR. SALARI: Eighty to 85 percent of strokes are ischemic. Despite all of the advances that we have had in terms of being able to take care of ischemic infarcts much more efficiently, in terms of hemorrhage, there still hasn’t been much change. [Ischemic strokes occur when an artery to the brain is blocked. A hemorrhagic stroke is either a brain aneurysm burst or a weakened blood vessel leak.]

DR. SHAVER: In cardiology, we understand that time is heart muscle. Is it equally important to mention that time is brain?

DR. HERMAN: That depends.

This “time is brain,” slogan has become so perpetuated. I often explain to people the brain doesn’t have a watch, doesn’t know the time, and that’s the response to your earlier suggestion that the timing is essentially a made-up number. The way the brain survives is by collaterals. So, why is it that someone could survive six or 12 or 24 hours following a stroke? Because they have a variable degree of collateral flow that keeps that brain alive.

DR. SHAVER: But you would encourage people to get to the emergency department just as soon as they have one of the stroke indicators such as facial asymmetry, upper extremity drift, difficulty speaking, or weakness on one side?

DR. HERMAN: Yes. What I wouldn’t agree with is denying care for those patients who are beyond some arbitrary time. That’s where I take issue. Yes, you should come in as quickly as you can. But people should not be denied treatment because of the time factor.

DR. SHAVER: You think they should have an MRI scan?

DR. HERMAN: Or a perfusion CT, yes.

DR. SHAVER: Isn’t it standard to do a CT to be sure that they’re not bleeding?

DR. SALARI: One is doing a basic CT and CT perfusion. That’s one paradigm. The other one is MRI, as Dr. Herman said — MRI, MRA [magnetic resonance angiography], diffusion, perfusion. Personally, I think we get much more information with MRI with perfusion, diffusion. We can eliminate a lot of things that mimic a stroke.

DR. SHAVER: Is CT the standard practice in most hospitals?

DR. SALARI: Yes, most hospitals [use it] because it’s fast and they may not have the added ability of MRI like we have.

DR. HERMAN: It also depends on what you’re going to do with the data. If your algorithm is trying to decide between using tPA [tissue plasminogen activator] or not, then a CT may provide enough information for you.

DR. SHAVER: And then you would just use time as your factor, as long as there was no hemorrhage?

DR. HERMAN: You would use the CT to look for signs of edema, delayed findings of parenchymal [essential tissue] death already occurring.

DR. SHAVER: Dr. Herman, do we have MRI and MRI interpretation available 24/7?


DR. SHAVER:We have the same thing for cardiac. Do we have a re-perfusion vascular specialist available 24/7?


DR. SHAVER:What are the stroke time frames now?

DR. SALARI: We typically administer IV tPA within three hours, then extend it in certain cases to four-and-a-half hours. In the last couple of years, multiple studies have shown that beyond even six hours or 24 hours, some of the patients might be a candidate for embolectomy. Which is great news. This is something that Dr. Herman mentioned, that all patients, [depending on the timing] might be eligible for embolectomy.

The only problem with that is we need to have good assessment of how much damage has already been done — stroke volume and the patient’s outcome in terms of disability. The recent studies designed it in a way that with an imaging study they measure the volume of the stroke. If the volume of the stroke is not more than a certain amount, and there is a resistant parenchymal, then those people are candidates for embolectomies.

DR. SHAVER: So, embolectomy, not tPA. Is tPA still used within the four-and-a-half-hour time frame?

DR. SALARI: Yes, tPA is four-and-a-half hours. In the new studies, this has been extended to 24 hours. If a patient comes in six hours after a stroke, that patient is obviously not going to be a candidate for IV tPA, but may be a candidate for an embolectomy.

DR. SHAVER: Dr. Herman, explain an embolectomy.

DR. HERMAN: Very simply, it means passing a device up into the vessels of the brain to hopefully capture a clot. You withdraw, either with aspiration and mechanical assistance, or the stent retriever, which is the one we use. Essentially, we grab the clot and pull it out and use the reverse flow to help us.

DR. SHAVER: You’ve seen some pretty remarkable recoveries over the years?

DR. HERMAN: Yes. Last week, as an interesting anecdote, I saw something that I’d never seen before. We had a fairly young woman, age 62, with an M1 occlusion [blocked middle cerebral artery]. I removed her clot. It took about two minutes to re-perfuse her [to restore blood flow]. After I pulled the clot out, I looked at her and I said, “How are you doing?” And I actually watched her facial droop go away, her face having been so asymmetric. She just looked up, her eyes opened and her face straightened up right in front of me. I had never actually seen that before. I’d seen patients become normal on the table, but I’d never seen the face reconstruct itself symmetrically.

In terms of strokes, if you have a TIA [transient ischemic attack, or “mini stroke”] or any focal neurologic symptom of any kind, your workup should include an evaluation of all the vessels of the neurovascular [system]. It doesn’t have to be done right away, but you need to see that all the vessels are open and there isn’t an anatomic cause for a TIA. And then a cardiac workup should follow it.

DR. LIMONADI: One of the treatment modalities that is advancing quickly is interventional neuroradiology. One of my favorite professors in neurosurgery once told me, “If you really want to be an honorable and good neurosurgeon, you will eliminate yourself from the equation.” Which means that you completely eliminate yourself, because our job is to save human lives, not our profession. I think interventional neuroradiology has been one of the major advancements in neurosurgery as a whole because it has minimized the necessity of opening a patient’s skull and putting a clip on an aneurysm.

DR. SHAVER: Dr. Herman, how do you approach these aneurysms?

DR. HERMAN: The real problem is when aneurysms grow large, they incorporate branches. If you occlude the aneurysm, you also occlude the branches, which will result in stroke. So, that’s where the trouble lies. However, even wide-necked aneurysms can be tackled, which we couldn’t do before with stent-assisted or balloon-assisted coiling. Once we tackle the incorporation of the branches then there’s almost nothing that can’t be done. We can even deploy a flow-directed stent that takes about a year to work, but eventually the aneurysm will disappear and those branches will stay open as well.

DR. SHAVER: Can coils cause a clot?

DR. HERMAN: It’s actually a mechanical occlusion, but yes, it eventually clots. But in the short run it doesn’t — it’s a mechanical thrombosis.

DR. SHAVER: And you’re able to isolate that so that it stays just in the aneurysm?


DR. SHAVER: We know the risk factors for stroke: high cholesterol, smoking, hypertension and family history. By reversing all of those we could prevent a large percentage of strokes. How about risk factors for brain tumors?

DR. LIMONADI: Aside from exposure to vinyl chloride or ionizing radiation, there’s no objective evidence linking any environmental factor to brain tumors. We know that brain tumors are more common in elderly than young people. Cancerous brain tumors are more common in men than women. And benign brain tumors are more common in women than men.

We know that metastatic brain tumors are different. Fifty percent of the most common cancerous brain tumors are metastatic brain tumors. DR. SHAVER: Of course, it never hurts to maintain a healthy lifestyle.

DR. LIMONADI: Absolutely. Don’t smoke, don’t drink too much alcohol, maintain a healthy lifestyle, exercise routinely, be happy, don’t be too stressed and minimize exposure to radiation and toxins as best as you can. Perhaps most importantly, note that it is the quality and not just quantity of years we live, and what we accomplish in those years that matters most.

For more information about the signs and symptoms of stroke, visit To contact Eisenhower Neuroscience Institute, call 760.837.8020.