You’ve probably heard that childhood chicken pox can reemerge as shingles as an adult – in about one third of all adults, in fact, and as many as half of those who live to be 85. You’ve probably not heard that this same varicella-zoster virus (VZV) can directly cause stroke and heart attack, cognitive impairment, burning mouth syndrome, vision loss, bowel and bladder dysfunction, irregular heartbeat and a growing list of other problems – often with no hint of the excruciating zoster rash. Hope Hartman was among the unaware until March 2013, when she learned about VZV the hard way.
Hartman was 37, with daughters ages two and four. Like most of us, she had chicken pox as a kid. She had heard of the shingles connection, but, as she put it, “I believed shingles to be something that only affected the elderly – why would I have shingles?”
A strange, painful rash took root inside her ear. Her doctor thought it was an infection and prescribed topical antibiotics. They didn’t help. Excruciating pain in the middle of the night sent her to the emergency room at a Denver community hospital. Doctors there were at a loss. She was admitted; she was discharged. She was taken off blood thinners she had been taking for a blood clot in her leg a few months prior. Bell’s palsy paralyzed the right side of her face. Hartman’s husband, Mike, took an iPhone photo of the rash in her ear and sent it to his mom, a former nurse. “It looks like zoster,” she replied. Mike looked around the web and settled upon something called Ramsay Hunt syndrome. It’s cause: VZV. He was right, it turned out. But Hartman was far from out of the woods.
Right place, right time
University of Colorado School of Medicine researchers, who have quietly been exposing VZVs secrets since the late 1980s, remain at the vanguard of the still-developing science of understanding and treating VZV. Maria Nagel, MD, a CU associate professor of neurology and immunology, applies findings from the research lab to the care of a wide range of UCHealth patients.
Nagel has studied VZV since VZV research pioneer and then-CU Neurology chair Donald Gilden, MD, asked her to be a CU neurovirology fellow in 2006 (he had, in 2002, already recruited her to be a CU Neurology resident). Her smarts and affinity for medical research didn’t hurt – she had been working labs since her undergraduate days at the University of Chicago and through her medical training at the University of Illinois.
But Gilden surely also recognized in this first-generation Filipino immigrant the sort of person who, years later, in a morning stacked with meetings, invites you in, swivels her office chair in your direction, and focuses her deep well of enthusiasm on explaining the topic of VZV neurovirology in layman’s terms, occasionally reaching over to gently touch the top edge of your laptop screen in empathy. When Gilden died in 2016, Nagel ascended to his role leading CU’s VZV research. She is now recognized as one of the planet’s top clinical VZV experts.
Fortunately for Hartman, one of her doctors was familiar with Nagel’s work and referred her. More than two months had passed since that night in the emergency room by the time Hartman called the Nagel’s office on a Friday. When Nagel got wind of the symptoms – by that point, Hartman’s eyes were becoming damaged – she asked that Hartman be at the UCH Neurology Clinic at 8 a.m. on Monday morning.
Nagel collaborates with a range of physicians and scientists on the function of a virus that lurks quietly in nerves before emerging in various systems around the body. But her work is primarily done in concert with two PhD research colleagues: Randall Cohrs, PhD, a herpes virus expert (VZV also goes by herpes type 3); and Ravi Mahalingam, PhD, who specializes in animal models for the study of VZV. Both worked with Gilden for decades. Building on that foundation, their collaboration with Nagel, Cohrs said, has “elevated our research from that of a very, very good group to a world-wide recognized group that can treat people and heal them.”
Add the research fellows, postdoctoral researchers, graduate and even undergraduate students working in Nagel’s and colleagues’ labs and CU has amassed what she describes as “the largest group of researchers in the world exploring the clinical manifestations and mechanisms of VZV-induced diseases.”
Among their current studies include a continuation of a National Institute on Aging project Gilden launched back in 1988 to study a possible VZV link to giant cell arteritis, also known as temporal arteritis for its tendency to cause inflammation and wincing pain in and around the temples of one’s head. Nagel and colleagues have found that fully 70 percent of patients with the painful condition have VZV viral antigens – a sign that the body is fighting the virus – in their inflamed arteries. The implications translate directly to patient care: traditional giant cell arteritis treatment involves suppressing the very immune system that’s fighting the virus.
“This can really alter treatment,” Nagel said. “Instead of just immunosuppressive drugs, which can worsen the virus’s impact, they should be treated in addition with an antiviral agent.”
Once diagnosed with Ramsay Hunt syndrome, Hartman was placed on steroids as well as antivirals. But to Nagel’s eyes on that Monday morning, it was too low of an antiviral dose. Nagel had Hartman admitted to UCH and prescribed intravenous antivirals. She also put her back on blood thinners. The rash went away, the eye recovered, and physical therapy at UCH restored almost all the movement on the right side of her face. VZV seemed to have retreated. But it wasn’t finished yet.
Viruses in space
Nagel’s diagnostic skill rests on years of experience both in clinic and doing diverse VZV research. A sampling of hers’ and colleagues current slate: There’s a National Institute of Neurological Disease and Stroke study looking at how the anti-clotting drug clopidogrel (trade name Plavix) may or may not also have antiviral properties with respect to VZV. They’re working with CU Skaggs School of Pharmaceutical Sciences professor Tom Anchordoquy to develop nanoparticles capable of delivering molecules that block VZV – and potentially other – viral replication while the virus is still in white blood cells early in its life cycle. They’re working with CU Department of Ophthalmology research professor Niklaus Mueller, PhD, on VZV’s persistence in the cornea. They’re even working with NASA.
As the certificates of appreciation and photos of space shuttle crews on his office wall attest, Cohrs is taking the lead with the space agency. NASA wanted to better understand how the stresses of spaceflight affect dormant viruses such as VZV: you don’t want astronauts battling shingles or other zoster-triggered maladies during an 18-month Mars mission. Cohrs analyzed astronaut saliva samples taken before and after shuttle missions and showed that VZV and other herpes viruses indeed reactivated during spaceflight – one of the astronauts even developed shingles. Next up is to work with the U.S. Antarctic Expedition at McMurdo Station, a sort of space-station analog where prior research has shown increased viral shedding.
While there’s much research to be done, the bottom line with many of the non-skin-related problems associated with VZV appears to be inflammation, Nagel said. She suspects, and the evidence points to, the connection between shingles and strokes/heart attacks having to do with the virus inflaming arterial walls and causing damage that leads to blockage of the artery or hemorrhage. The same thing is probably happening in the brain, where VZV is implicated in major strokes, as well in as cases of what appear to be dementia that are in fact the result of many mini-strokes slowly starving parts of the brain.
In Hartman’s case, VZV returned a few months later, announcing its arrival in the form of a splitting sinus headache on the left side. An MRI found a large blood clot – one that had formed despite Hartman being back on blood thinners. Nagel put her back on intravenous antivirals and upped the blood-thinner dose. Six months later, the same blockage happened on the right side. Nagel discussed the possibilities of surgery with Hartman, but decided that, given the risks, they would keep her on blood thinners and antiviral pills while monitoring her closely. That monitoring, with help from UCHealth hematologist Kathryn Hassell, MD, continues today.
Hartman marvels that she was lucky enough to have found Nagel, who treats patients from around the world, in her own backyard.
“She has saved my life multiple times,” Hartman said. “She’s a brilliant woman and she spends a lot of time with her patients. She cares a lot. I can’t say enough good things about her.”
Awareness is key
As Hartman’s case showed, the availability of good antiviral drugs means the biggest medical hurdle for many VZV patients is diagnosing it in the first place, Nagel said. The challenge is for doctors and patients to recognize the many manifestations of conditions VZV can cause.
VZVs life cycle drives that malicious diversity. Once the immune system clears the virus from the bloodstream after the initial chicken pox infection, it hides out in neural ganglia – bundles of nerves at the intersections of major nervous-system highways. When age-, disease- or stress-weakened immune systems allow, VZV can take those roads to many places, Nagel said: the skin, the brain, the arteries, the heart, the eye, the bladder, even the gut, where VZV in enteric ganglia may be complicit in mysterious abdominal pain, chronic constipation, and ulcers. It’s not clear that either the varicella (chicken pox) vaccinations the U.S. Food and Drug Administration approved in 1995 or the zoster (shingles) vaccination it approved in 2006 can stop all these viral manifestations, either, she said.
From the perspective of improving medical care, Nagel said, “the first and most important thing is increasing awareness of physicians that VZV can produce multi-system disease.”
The time = now
To that end, Nagel’s clinical time is spent largely consulting with UCHealth and specialists from as far away as Eastern Europe and Australia about particularly tough cases. Often, she said, patients have seen 20 or so doctors of various specialties before she gets the call. Richard Davidson, MD, a CU Ophthalmology professor and practice director for UCHealth Eye Centers, described Nagel as “a world expert on VZV.”
“It’s a tremendous resource to have her on campus to help care for our patients,” Davidson said in an email. “VZV can be a devastating disease, especially when it affects the eyes. Dr. Nagel’s collaboration has made a significant improvement on our ability to care for these patients.”
In the long-term, Nagel hopes she and her team can get to the root of what causes the VZV-induced inflammation that then damages tissues and harms patients, she said, ideally through a CU Neurology center focusing on neurovirology. With the U.S. over-65 population – of whom 95 percent will harbor VZV – expected to nearly double to 84 million by midcentury, there’s no time to waste, she said.
“This is going to be a significant disease with our aging population,” Nagel said.