Stroke: Inside Stories
words by Maryann Brinley / illustration by Eric Miller
Some things about stroke are familiar, especially for anyone working in a healthcare environment. But below the surface, what you don’t know about stroke may be surprising.
rom the first moment the Brain Attack Team (BAT) at UMDNJ-University Hospital is notified by pager that a stroke victim is on the way into the hospital for treatment, everyone — the attending physicians in neurology and endovascular neurosurgery, the residents, the nurses and EMS personnel — scrambles in very familiar ways as the ambulance races toward them and especially right after its arrival. Their battle to save brain cells is swift and their actions, including blood tests, imaging scans and possible interventions are spelled out. There are protocols to follow.
“Is the stroke real? Where is it? Does it have a clear clot? Hopefully, within minutes, decisions are made about what needs to happen,” explains Charles J. Prestigiacomo, MD, FACS, New Jersey Medical School, associate professor, Department of Neurological Surgery, Radiology, Neurology and Neuroscience. “Any stop or pause in that chain results in a waste of time and precious brain cells,” insists Prestigiacomo, who is also the director of cerebrovascular and endovascular surgery. Night or day, every single day, there are certain emergency steps taken at a comprehensive stroke center like UH, which is one of only 10 in the state. “Our statistics show that we are one of the most active,” he says.
Like the steps taken at a skilled stroke center, warning signs are also often clear or at least they should be:
- Sudden numbness or weakness of the face, arm or leg, especially
on one side of the body
- Sudden confusion, trouble speaking or understanding
- Sudden trouble seeing in one or both eyes
- Sudden trouble walking, dizziness, loss of balance or coordination
- Sudden, severe headache with no known cause
Yet, not everything about a stroke is apparent at all. In fact, every stroke, especially one in its acute phase, holds dramatic inside stories, metabolically and clinically, with twists and turns that are just now beginning to emerge. Experts like Kenneth Maiese, MD, NJMS, professor and chair of the Department of Neuroscience, are only starting to see the cellular metabolism inherent in a stroke. What exactly is happening at the cell level during this cascade of meta-biological events? Why do some patients survive the initial period only to die within days? What new tools are being used by interventionists like Prestigiacomo inside the vascular system to save patients from poor outcomes? And why is that narrow window of time (one to three hours) for using chemical thrombolytics (drugs to melt or break up a clot) opening wider now for some stroke victims?
Stroke in a Test Tube
Maiese and his research team are involved not only with stroke but the aging process as well because they are all linked, he believes, including disorders like Alzheimer’s, cancer, heart disease and vascular problems. “We want to keep our work cutting edge and novel. We are always looking at what goes on inside the cell, what causes the injury, what we can do to increase survival. The really key issue now is longevity,” he explains. “You want to protect the cell, of course, and scientists have focused basically on survival until now but what if that cell survives but lives for only two days before dying? You never know what to expect and we want to understand stroke at every level,” he says. Survival and longevity don’t always go hand in hand.
A calm, consummate teacher, Maiese starts this scientific discussion at the very beginning in a series of what he calls “stories” about stroke. “A stroke in the brain is caused by loss of oxygen and it only takes four minutes for damage to occur.” Soon, an easel with oversized white paper comes out along with a red marker. His illustrations make the metabolic chemistry lessons go down easier. This is a tale of research discovery that has many parts including Wnt, FoxO, EPO, nicotinamide (Vitamin B3) and D-NAAM, all roads this expert has been traveling to understand and manipulate cell life and death.
The Wnt protein and its big family of genes are involved in the development of the nervous system, according to Maiese, playing different roles, following various pathways in which they sometimes increase life but can also be responsible for cell overgrowth or death from cancer. “In some of our models, we actually create a stroke in a test tube by decreasing oxygen and reducing glucose which is what the brain uses for survival.” By doing this, Maiese discovered that brain cells —and there are several kinds including neurons, EC endothelial, astrocytes and the microglia or immune cells — express Wnt. “Something is going on and we know that Wnt increases longevity and is protective there in the cell.” Even as a cell’s DNA becomes degraded after an incident and is nearing the end in a process known as apoptosis or programmed cell death, this Wnt can reverse the course and still be protective.
When a brain cell gets injured, in a stroke for instance, in early apoptosis, membranes that ordinarily stay inside, flip out and attract microglia whose job it is to engulf dying cells. “We actually have real time video footage of this process where we follow the action and watch the microglia travel from one neuron to the next, simply talking to healthy cells before moving on to sick ones,” Maiese says. When these membranes stick out of their cell —picture a little bug with outstretched appendages — they act like GPS systems, alerting microglia to come on over. “The microglia will eat up the damaged cell. But they’ll pass right by a happy neuron.” Early in a stroke, before apparent symptoms show up, this metabolic repair system can become activated. Maiese believes that it’s this process occurring over time during which microglia take away injured, but still functioning, neurons. Wnt saves cells by keeping those GPS-like appendages inside. “We took this research to the next level and gave Wnt to animals,” he explains. “Patients would be the next step” but that is “many years off.”
To really comprehend stroke, however, “there is a whole set of cascades that need to be addressed,” Maiese explains, and his group focuses on FoxO, a transcription factor linked to Wnt which is activated during oxidative stress. EPO, erythropoietin, found in the vascular system, the gastrointestinal tract, the muscles and also in the brain, is also in Maiese’s research pipeline. He has shown that if you stress a neuron, EPO expression increases at the start of a chemical cascade. EPO is a “big deal,” according to Maiese, because it’s a multi-million dollar business for the pharmaceutical industry and already approved by the Food and Drug Administration for treatment of anemia. “EPO actually untangles the amyloid deposits in the Alzheimer brain. We’ve given it to animals, used it in cells and it’s now being considered for clinical trials.”
The story of nicotinamide or Vitamin B3 and stroke is also one that Maiese tells. This over-the-counter supplement shields cells during a stroke but there is a fine line in the concentration of nicotinamide when it goes from protective to destructive. Studying nicotinamide pathways led Maiese to the Drosophilia, a fruit fly with an ordinarily very short life. “A team of our investigators cloned a gene called D-NAAM in these flies that can increase cell life span by 30 percent. We were the first.” And by the way, D-NAAM,” he adds, “can also protect agains stroke.”
Stroke in a Patient
But, away from the laboratory, what’s new for patients right now? First, the length of time between a stroke and treatment is still critical to survival but that window is opening wider than just three hours, according to clinician Prestigiacomo. Maiese examines the cellular basis of stroke in the lab, but both he and Prestigiacomo also treat patients. Prestigiacomo notes, “It used to be that we could only give intravenous tPA (tissue plasminogen activator), a drug that dissolves clots, between one to three hours from the time of the clot formation.” There are studies now that suggest this time frame be expanded to four and one half hours. For intra-arterial medication, that cut-off rule for tPA to be delivered directly inside the arteries at the site of the clot is six hours. And the options and tools now available to mechanically dislodge a clot have not only increased but the window for using them has been lengthened to eight hours after the onset of a stroke.
“What’s important here is to look not just at the treatment but at each patient. Your brain circulation is different from my brain circulation,” he points out. “A clot in the same spot might have different outcomes for each of us. Our blood flow comes in from different avenues. That’s called the penumbra, the area at risk but not necessarily dead yet. And that’s what we want to rescue.” For some individuals, this part of the brain can survive for not three or four and a half hours but up to five, six or eight hours. Thanks to special sequences of MRIs called diffusion and perfusion studies, Prestigiacomo and his team can establish whether or not a person qualifies for intra-arterial tPA (administering the tissue plasminogen activator directly into the artery as opposed to the vein) not just by the tick of the clock but by their own physiology. “Treatment becomes very patient-specific,” he says.
Meanwhile, two new mechanical devices are available to interventionists who go inside the arteries to open a blocked blood vessel. “These tools are rapidly evolving,” he explains. One looks like a little corkscrew while another serves as a suction catheter that breaks the clot. “The nice thing about this is that you don’t need medication, which can increase the risk of bleeding.” Where once permanent stents were used, now there are retrievable stents connected to a wire that can be deployed to squash the clot and pull it out.
Take the 45-year-old woman he treated just a few weeks ago. With a family history of high blood pressure and diabetes, she was at risk for a stroke but not taking good care of herself. Severe tightness in her carotid artery should have but didn’t alert her to the impending problem. What sent her to the UH emergency room were hand and leg weakness and numbness on one side of her body. “We saw that she had a clot in the middle cerebral artery but because of the timing, she didn’t qualify for the intravenous option. It was too late. Quickly, I took her to the angiography suite, used the Penumbra system, which sucked out the clot, and opened the blood vessel.” That very afternoon she was able to lift her arm and leg up off the bed. Two days later, she was discharged with just a slight drift, which is a subtle weakness in the arm. When he saw her for an office visit seven days later, Prestigiacomo reports, “She was normal.” Because the source of her clot was probably her heart, she’ll be taking blood thinners to keep her healthy. But on the National Institutes of Health (NIH) stroke score scale, she was back to normal.
“It’s a very exciting time,” he says. Healing after a stroke never ceases to amaze this doctor, who works closely with Chirag D. Gandhi, MD, and Andrea Hildalgo, MD, and her neurology colleagues as well as his neurosurgical residents. “There are some patients who, by all criteria and textbooks, aren’t going to pull through but six months later, they are in my office, shaking my hand, saying thank-you.”.
On The Neurosurgical Team
The NJMS Neurosurgical residency program consistently ranks at the top of all national charts and has earned five-year board approval twice with no citations, a rare achievement in
medicine. “I’ve got a strong team,” reports Prestigiacomo.
Current residents include: Lana Christiano, MD, Gaurav Gupta, MD, Alexandros Zouzias, MD, Reza Karim, MD, Krystal Tomei, MD, Antonios Mammis, MD, Pinakin Jethwa, MD, James Barrese, MD, Rachid Assina, MD, George Sinclair, MD, John Quinn, MD, Brian Fernholz, MD, Soon Jung, MD, and Patrick Reid, MD. Fellows are: Jacqueline Kraus, MD, and Ennis Jesus Duffis, MD.