A new view on brain surgery

Li, MD, associate professor of neurosurgery, was in the midst of an open-brain surgery and the “her” was Lisa Inouye, who lay awake on the operating table. Li was removing a tumor in a region of Inouye’s brain that controls movement, and her lucid state allowed Li to ask Inouye to perform certain tasks, ensuring that he was not cutting out parts of her brain critical for those actions.

As instructed, the neurologist began rattling off a list of physical to-dos — touch your nose, tap your fingers, kick your leg out. Inouye touched, tapped and kicked as Li cut out bits of tumor.

“It was textbook,” Li recalled.

That is, until he saw what appeared to be more tumor tissue — this part of the mass hadn’t shown up on a pre-operative brain scan. After a bit of visual inspection and prodding — brain tumors feel mushier than healthy brain tissue — Li surmised the tissue was very likely part of the tumor and needed to be taken out. But before making the cut, he conducted one more review, this time using a new, experimental tool. Li had been collaborating with Eben Rosenthal, MD, a surgeon-scientist who is developing a targeted fluorescent dye that clings to and illuminates cancer. The idea behind this new dye — Inouye was the seventh Stanford patient to consent to its use during brain surgery — is to help surgeons spot cancer in real time, as they operate.

He aimed a special camera at the possibly cancerous tissue, and from the screen emanated a glow of confirmation.

By the end of the surgery, Li had removed 98% of Inouye’s tumor — a good bump from the 90% he had anticipated. Although it’s still early in the dye’s development, Li sees potential for its use in future operations. “It’s clear how this dye could act as a guide for surgeons in murky territory,” he said. “Determining where and what to cut is not always so obvious.”

In fact, more often than not brain surgery requires a bit of guesswork. In search of more reliable guides than inexact visual and tactile cues, brain surgeons have turned to technology. Some, like Rosenthal, are developing newer imaging methods that they hope will let surgeons augment what they see with the naked eye. And some are turning to MRI — normally a diagnostic tool — to steer the course of their procedures.

MRI in the operating room

Beyond simple magnification, MRI used during surgery, known as intraoperative MRI — or iMRI — enhances the surgeons’ view as they work. It enables them to see below the brain’s surface. Operating suites outfitted with MRI machines are available in about 100 U.S. hospitals, including Lucile Packard Children’s Hospital Stanford and the new Stanford Hospital, opened in November. It’s one of the features of the new hospital that Li said he’s most excited about.

MRI produces images using a combination of radio waves and powerful magnets, which is why earrings are not allowed in an MRI — the metal would skew the image, or the magnetic field could even strip the jewelry from the patient’s ear. For this same reason, it’s unwise to use an MRI in an operating room full of metal surgical tools. So hospitals and surgeons have taken precautions: The MRI, though still in the room, is located in a separate chamber away from metal, behind sliding doors that block radiofrequency.

In a typical iMRI surgery, a patient lies still in the central opening within the large, tube-shaped machine. Instead of using a scalpel to cut diseased tissue, surgeons use a laser.

Laser surgery with the iMRI happens in a series of small steps: With the patient’s body inside the MRI and head poking out, the surgeon zaps parts of the brain tumor with the laser. To check on progress, the surgeon stops and moves the patient into the center of the MRI machine, turns it on, and takes images of the brain tissue and ablated tumor. (In an iMRI image, ablated tissue appears as a different shade than normal tissue.)

“Sometimes a tumor is so deep you don’t want to resect it and risk injury to the brain,” said Li. “But the iMRI setup lets you use the laser and monitor its whereabouts to precisely kill the cancer, which helps shrink the tumor and, most importantly, stops it from growing.”

Shooting a scalding hot laser into the brain might sound a little brazen, but the laser is less like a lightsaber and more like a dynamic beam of heat that can be tuned in exquisite detail. Part of the iMRI imaging technique is something called magnetic resonance thermography, which produces a heat map revealing the temperature of the laser beam, allowing surgeons to closely monitor which parts of the laser are heated, and to what degree.

Cancer surgery is not the only use for iMRI at Stanford: Two other Stanford surgeon-scientists, Jaimie Henderson, MD, and Casey Halpern, MD, professor and assistant professor of neurosurgery, respectively, use iMRI to treat epilepsy on a routine basis. Before moving operations into the new hospital, they, like Li, made do with the diagnostic MRI outside the operating room.

“It was a little cumbersome,” said Halpern. “We had to cart our surgical tools down to radiology and finagle a sterile setup, but we wanted to offer this revolutionary service to the patients who would benefit from it.”

Precision heat

Halpern and Henderson use a laser paired with MRI to treat one of the most common types of epilepsy, known as mesial temporal sclerosis, which can be traced to a region of the brain called the hippocampus. Laser zapping aside, the go-to surgical therapy has traditionally been to remove the part of the brain that’s causing seizures. And while it’s effective and generally regarded as safe, not everyone is willing to part with a piece of their mental engine.

“MRI-guided laser ablation is a much less invasive way to kill the problematic tissue,” said Halpern. “It’s highly effective, and only requires a 3-millimeter incision, cutting down on complications and recovery time dramatically.”

So instead of slicing out a chunk of brain tissue, Halpern and Henderson scorch the problematic tissue with a tiny laser and remove it to silence the seizures.

Henderson and Halpern have conducted nearly 100 MRI-guided epilepsy treatments. “We do the whole thing in the MRI scanner, and we use MRI imaging to guide every step,” Henderson said.

“It lets us oversee and precisely control the effect of the laser as it heats up and progressively burns the area from which the seizures originate,” said Henderson.

When the laser is initially turned on, at low power to avoid damaging any tissue unnecessarily, the patient is moved a few inches back into the bore of the scanner, where the surgeons can take MRI images and use them to guide the position of the laser if need be.

“We can see and move the laser in near real time,” said Henderson. “We know exactly what the laser is doing, at the precise location that it’s doing it, which lets us ablate the parts of the brain that are responsible for the seizures while ensuring that the normal brain structures in the vicinity are preserved.”

While iMRI is a promising alternative for some epilepsy patients, it’s not necessarily the right alternative, or possible, for everyone. And that’s OK. The goal of much of the work by Henderson and Halpern, including the adoption of iMRI, is treatment personalization.

“Several years ago, before this surgery was an option, I had a patient with really debilitating seizures. She was a prime candidate for a more traditional, resection-based treatment,” said Halpern. But she refused the treatment, not wanting her brain handled in such an invasive way. So when Halpern began pursuing iMRI, he presented the new option to her, which she embraced, and the procedure was successful.

“iMRI won’t be the answer for everyone, but it will be for some people. That’s a big part of why we investigate new therapies, even if we have a few that work well already,” said Halpern. “We want to have an arsenal of therapeutic tools. That’s really a big focus of our epilepsy program here — selecting the right procedure for the right patient so we can treat them in an effective, personalized way.”

The quest for precision during brain surgery goes back decades. In Rosenthal’s near 20-year career as a surgeon, the problem that motivated his creation of the cancer-targeted fluorescent dye remains. “Surgeons most often can’t see cancer and, on average, they end up leaving anywhere from 10% to 40% of the tumor behind,” he said. His solution has a simple premise: Mark the cancer with something you can’t miss. “It’s sort of like you’ve added phosphorous to illuminate parts of the ocean.”

Rosenthal’s efforts put him at the forefront of the development of fluorescence-guided surgery for cancer patients.

The luminescence agent developed by Rosenthal and colleagues combines two ingredients: an antibody that latches onto tumor cells and the bright green fluorescent label. When injected into a patient intravenously, the tandem molecules flow throughout the bloodstream, binding to cancer cells. Then, during a procedure, the surgeon shines infrared light onto the tissue. The light hits the fluorescent marker and sends a bright signal to a special camera that detects the light’s refraction, forming an image that the surgeon observes on a nearby screen. The image reveals where those glowing markers have docked in the body and, by extension, where to cut.

The antibody-fluorescent dye hybrid Rosenthal works with first made it to the operating room on an experimental basis in 2015, in head and neck cancer. Once a surgeon has removed the glowing mass of tissue, it can be examined in greater detail. The hope is that the mass has “clean margins,” with no sign of fluorescence bleeding through the edge of the sample.

“For decades surgeons have had to largely depend on pre-operative scans and the look and feel of tissue to determine what to remove during surgery. With this fluorescent-guided surgery, our goal is to enhance precision, clarity and the confidence that we’re resecting to the best of our ability,” said Rosenthal, a professor of otolaryngology-head and neck surgery. “Ultimately, I see this as a tool that could help surgeons confirm the absence of disease, detect any additional disease, or help determine where disease begins and ends.”

For now, Rosenthal’s dye is in the clinical trial stage: He and fellow surgeons administering the dye are collecting data for a study of the technique’s safety in several cancer types, including brain, pancreatic, liver, and head and neck. If the results are positive, they’ll expand the trials.

“Distinguishing tumor from normal or swollen surrounding brain can be really tricky under standard microscopes — sometimes indistinguishable,” said Melanie Hayden-Gephart, MD, associate professor of neurosurgery who has used Rosenthal’s fluorescent aid in surgery. “So this type of fluorescent-based excision could both enhance the efficiency of the operation — meaning that you would be able to more readily identify tumor versus normal — and it could improve the resection and overall outcome for the patient.”

As a patient, Inouye fully supports the integration of science and clinical care. “After the success of my surgery, I’ve signed up for more studies because I believe that research can make a difference in patient care. When I came to Stanford, I told my doctors I needed them to buy me time,” said Inouye. “I told them, ‘Whatever time you can give me will make a difference.’ I know I’m not the only patient who has felt or will feel that way.”