Hypoparathyroidism is a common complication of thyroid surgeries, affecting as many as 30% of these patients (J Clin Med. 2020;9:830), and it can occur during central compartment lymph node surgery as well. Patients may develop either temporary or permanent hypocalcemia. Recent advances in intraoperative, near-infrared imaging technology, such as devices that harness the glands’ natural autofluorescence to illuminate them during surgery, may offer effective tools for surgeons to help avoid these negative outcomes.
Explore This IssueFebruary 2021
“The ability to better identify and preserve normal parathyroid glands during this surgery could reduce patient morbidity, length of hospitalization, and overall cost of care,” said Mark Zafereo, MD, associate professor, department of head and neck surgery, and section chief, head and neck endocrine surgery at The University of Texas MD Anderson Cancer Center in Houston. “In recent years, intraoperative techniques for better identification of parathyroid glands have centered around the natural autofluorescence of parathyroid tissue, as well as the use of fluorophores, such as indocyanine green [ICG]. Unfortunately, neither of these techniques is without challenges.”
Head and neck surgeons say they’re excited about the possibilities of both ICG, which involves intravenous injection of a contrast green dye, and even newer near-infrared autofluorescence imaging systems to reduce the incidence of these outcomes. Some have begun to provide feedback to manufacturers, so the devices may be modified to make them easier to use. Potential concerns include up-front costs for a new technology (see “Cost: When to Invest?” on page 16) and the optimal scenarios for using it, they say.
Protect the Parathyroids
It’s important to clearly image and identify the parathyroid glands, which are about the size of a grain of rice and often blend in with other tissues nearby. Surgeons found that older technologies like ultrasound and sestamibi scans were inadequate: They were used mostly preoperatively and only identified abnormal parathyroids, not healthy glands, according to researchers exploring more effective imaging modalities (J Biomed Opt. 2011;16:067012). In 2018, the American Thyroid Association (ATA) published a statement emphasizing the need for better strategies to manage or minimize hypoparathyroidism and included advanced imaging modalities as one way to achieve that goal (Thyroid. 2018;28:830-841).
“Hypoparathyroidism may cause long-term symptoms such as muscle spasms, weakness, brain fog, anxiety, skeletal disease, or renal dysfunction, and it dramatically impacts a patient’s quality of life,” said Brendan C. Stack Jr., MD, professor and chairman, otolaryngology–head and neck surgery at Southern Illinois University School of Medicine in Springfield, Ill., and a co-author of the ATA’s statement. “Look at the condition from another perspective. About 70,000 people in the U.S. are estimated to have hypothyroidism—overall, a very low prevalence. Out of those 70,000 people, about three-quarters are postoperative surgery patients. The condition can exist for other reasons, but it’s largely caused by central neck surgery.”
The ability to better identify and preserve normal parathyroid glands during this surgery could reduce patient morbidity, length of hospitalization, and overall cost of care. —Mark Zafereo, MD
During surgery, the practitioner may accidentally remove the parathyroid glands or cut off the very tiny vessels that provide their blood supply, causing the organs to die. These outcomes are often temporary, but a small percentage of patients experience permanent loss of their parathyroid glands, said Dr. Stack. Newer near-infrared imaging devices could help surgeons mitigate these risks, which is crucial even if the total number of patients affected is small, he added.
“You may have only a 2% to 3% chance of developing hypoparathyroidism overall, but in any given patient we could have a 0% or 100% risk. At this time, there’s limited treatment for this condition. The surgeon is advised to keep a working parathyroid gland in the neck.”
How Technologies Compare
In the past 10 to 15 years, technology emerged to help surgeons identify various structures near the thyroid, including robust nerve monitoring capability using a specialized endotracheal tube that provides a signal when nerves are stimulated, said David Terris, MD, professor and surgical director at Augusta University Thyroid and Parathyroid Center in Georgia. While nerve monitoring improved the procedure’s safety and quality immensely, it did not address the challenge of identifying the parathyroid glands, he said.
ICG-enhanced fluorescence imaging was approved by the FDA for clinical use in 1959 and was first used to assess macular degeneration in patients, but in recent years, various ICG devices have been used in thyroid and parathyroid surgery. Although adverse reactions to ICG dye are very rare (fatal allergic reactions are estimated to occur in as few as one out of 333,000 cases) and the technology is an effective way to assess parathyroid gland function (Br J Surg. 2016;103:537-543), surgeons point out its drawbacks.
“After you inject the patient, the dye works only for a short time, and it’s clunky and cumbersome to use,” said Dr. Terris. Once injected, the contrast dye has a half-life of three to five minutes and may be eliminated after 20 minutes (Gland Surg. 2017;6:579-586).
Phillip K. Pellitteri, DO, an otolaryngologist–head and neck surgeon in private practice in Danville, Penn., also finds ICG imaging systems “cumbersome” to use, requiring a camera and tripod. Although relatively safe, ICG dye still carries a potential toxicity risk, and “the stimulating light may not penetrate the fat or tissue over the parathyroid glands,” he said.
In 2011, a group of biomedical engineers at Vanderbilt University published a paper on near-infrared imaging technology using autofluorescence as a “nonintrusive, real-time, automated, in vivo method for the detection of the parathyroid gland” during surgery (J Biomed Opt. 2011;16:067012). When parathyroid tissue is excited by light at a near-infrared wavelength of 785 nanometers, it exhibits intense fluorescence (J Clin Med. 2020;9:830). After reading this paper, Dr. Pellitteri said he was intrigued by the capability of the technology when he first heard about it around 2016.
“It’s thought that there’s a calcium-sensing entity in these glands that’s molecularly active when stimulated by specific wavelengths of light,” he said. “This could create real-time autofluorescence that can be projected on a video screen and can be digitally recorded. With real-time autofluorescence, you have the advantage of looking and working at the same time, and this expedites the procedure. It’s a smoother, more efficient evaluation.”
With real-time autofluorescence, you have the advantage of looking and working at the same time, and this expedites the procedure. It’s a smoother, more efficient evaluation. —Phillip K. Pellitteri, DO
The goal of faster surgery is a lower rate of complications, said Dr. Pellitteri. “We want to preoperatively or intraoperatively identify abnormal parathyroid tissue so it can be targeted in the operating room and removed. One scenario [for its use] is when parathyroid surgery has to be repeated, and there is re-emergence of hypocalcemia. You’re at the best advantage when you target those glands and remove them with as little disturbance as possible.”
Near-Infrared Systems: Pros and Cons
Currently, there are two devices based on autofluorescence in the near-infrared spectrum approved by the FDA to identify parathyroid tissue during surgery: the Parathyroid Detection PTEye System, manufactured by AIBiomed Inc. in Santa Barbara, and Fluobeam, manufactured by Fluoptics in France. Dr. Terris believes that this is “a disruptive, meaningful new technology that will improve outcomes,” is more practical to use than ICG, and eliminates the need to inject any dyes.
PTEye is “almost like a Geiger counter. You hold it up to the tissues, and if the tissue is parathyroid, the number will be very high. It works very well and is best used for tissue verification,” he said. “You want to preserve the glands. You don’t want to overlook them or mistake them for fat. Sometimes, we’ll send a frozen section to the lab during the operation, but that’s time consuming.” PTEye eliminates the need for this step, he noted. Fluobeam consists of a device aimed into the wound that quickly causes the parathyroids to appear white when compared to nearby tissues, said Dr. Terris. “Anything that isn’t parathyroid, such as muscle or fat, looks sort of dark gray. We want to accurately identify the parathyroids if we can, so we can dissect them away from the thyroid and preserve them.” These devices could also be useful as a way to scan a removed thyroid to identify if any parathyroid tissue was accidentally taken out with it, allowing surgeons to re-implant it during the procedure, he noted.
Before the COVID-19 pandemic, Dr. Stack traveled to Geneva, Switzerland, to train on both PTEye and Fluobeam systems. He believes that as these devices are used by more surgeons in the coming years, the technology will be modified and improved by manufacturers.
“Fluobeam provides a more panoramic visual identification, while PTEye uses an auditory signal and a numerical display,” said Dr. Stack. Both he and Dr. Terris said that Fluobeam would be easier to use during surgery if the light source and camera were smaller in diameter and gave this feedback to manufacturers. “If the parathyroid gland is more than 1-2 millimeters within the tissue, you may not get enough exposure of light from the Fluobeam, and it won’t stimulate parathyroid autofluorescence.”
Best Clinical Scenarios for Use
While these surgeons agree that the new imaging technologies are a positive disruption, questions remain as to the best situations for their use. This has yet to be defined, said Dr. Pelliterri.
“Right now, I think this technology’s greatest utility is for identifying the parathyroid glands during thyroidectomy,” he said, adding that ICG, which is tracer-dependent, may have a place in parathyroid re-exploration surgery, while autofluorescence may be of use during abnormal parathyroid gland surgery. “As experience is gained in using these for parathyroid exploration, the technology will improve. The initial efforts were quite clunky and difficult to use in the operating room. Now, they’re more streamlined and efficient to use to identify the glands, to secure the identification with autofluorescence, and to protect the parathyroid glands during the removal of the thyroid.”
Dr. Zafereo has used autofluorescence devices in about 75 surgical cases so far, and while it does fluoresce most normal parathyroid glands, challenges remain for its use in standard clinical practice, “including a lot of false-positive fluorescence associated with cancerous lymph nodes, brown fat, or other artifacts, as well as the need to turn off the surgical lights in order to use the device, which slows down the surgery.” For the most challenging cases, patients with significant nodal metastases, autofluorescence imaging isn’t as useful due to the significant levels of false positive fluorescence, he said.
Dr. Terris suggested combining both imaging techniques, using an autofluorescence device to identify the parathyroid glands and ICG to sense blood flow to them through tiny vessels that may look intact to the naked eye, but can be easily damaged during surgery. He added that that these imaging devices may be most useful for surgeons who perform a low volume of procedures because they’re less comfortable distinguishing these tissues due to limited experience.
Dr. Pellitteri agreed. “Autofluorescence systems may give less-experienced surgeons more confidence to achieve successful parathyroid surgery, and it may also play a useful role in surgical training,” he said. “ICG also has some potential toxicity risk, which is eliminated entirely in autofluorescence technologies. While ICG has a role, as autofluorescence improves, I think it will probably become the pre-eminent modality.”
Susan Bernstein is a freelance medical writer based in Georgia.