Jeff Marquis and Kelly Thomas, fellow research participants and spinal cord injury patients, in a rehab session.
Seven years ago, mountain biking near his home in Whitefish, Montana, Jeff Marquis felt confident enough to try for a jump he usually avoided. But he hesitated just a bit as he was going over. Instead of catching air, Marquis crashed.
Researchers' major new insight is that recovery is still possible, even years after an injury.
After 18 days on a ventilator in intensive care and two-and-a-half months in a rehabilitation hospital, Marquis was able to move his arms and wrists, but not his fingers or anything below his chest. Still, he was determined to remain as independent as possible. "I wasn't real interested in having people take care of me," says Marquis, now 35. So, he dedicated the energy he formerly spent biking, kayaking, and snowboarding toward recovering his own mobility.
For generations, those like Marquis with severe spinal cord injuries dreamt of standing and walking again – with no realistic hope of achieving these dreams. But now, a handful of people with such injuries, including Marquis, have stood on their own and begun to learn to take steps again. "I'm always trying to improve the situation but I'm happy with where I'm at," Marquis says.
The recovery Marquis and a few of his fellow patients have achieved proves that our decades-old understanding of the spinal cord was wrong. Researchers' major new insight is that recovery is still possible, even years after an injury. Only a few thousand nerve cells actually die when the spinal cord is injured. The other neurons still have the ability to generate signals and movement on their own, says Susan Harkema, co-principal investigator at the Kentucky Spinal Cord Injury Research Center, where Marquis is being treated.
"The spinal cord has much more responsibility for executing movement than we thought before," Harkema says. "Successful movement can happen without those connections from the brain." Nerve cell circuits remaining after the injury can control movement, she says, but leaving people sitting in a wheelchair doesn't activate those sensory circuits. "When you sit down, you lose all the sensory information. The whole circuitry starts discombobulating."
Harkema and others use a two-pronged approach – both physical rehabilitation and electrical stimulation – to get those spinal cord circuits back into a functioning state. Several research groups are still honing this approach, but a few patients have already taken steps under their own power, and others, like Marquis, can now stand unassisted – both of which were merely fantasies for spinal cord injury patients just five years ago.
"This really does represent a leap forward in terms of how we think about the capacity of the spinal cord to be repaired after injury," says Susan Howley, executive vice president for research for the Christopher & Dana Reeve Foundation, which supports research for spinal cord injuries.
Jeff Marquis biking on a rock before his accident.
This new biological understanding suggests the need for a wholesale change in how people are treated after a spinal cord injury, Howley says. But today, most insurance companies cover just 30-40 outpatient rehabilitation sessions per year, whether you've sprained your ankle or severed your spinal cord. To deliver the kind of therapy that really makes a difference for spinal cord injury patients requires "60-80-90 or 150 sessions," she says, adding that she thinks insurance companies will more than make up for the cost of those therapy sessions if spinal cord injury patients are healthier. Early evidence suggests that getting people back on their feet helps prevent medical problems common among paralyzed people, including urinary tract infections, which can require costly hospital stays.
"Exercise and the ability to fully bear one's own weight are as crucial for people who live with paralysis as they are for able-bodied people," Howley notes, adding that the Reeve Foundation is now trying to expand the network of facilities available in local communities to offer this essential rehabilitation.
"Providing the right kind of training every day to people could really improve their opportunity to recover," Harkema says.
It's not entirely clear yet how far someone could progress with rehabilitation alone, Harkema says, but probably the best results for someone with a severe injury will also require so-called epidural electrical stimulation. This device, implanted in the lower back for a cost of about $30,000, sends an electrical current at varying frequencies and intensities to the spinal cord. Several separate teams of researchers have now shown that epidural stimulation can help restore sensation and movement to people who have been paralyzed for years.
Epidural stimulation boosts the electrical signal that is generated below the point of injury, says Daniel Lu, an associate professor and vice chair of neurosurgery at the UCLA School of Medicine. Before a spinal cord injury, he says, a neuron might send a message at a volume of 10 but after injury, that volume might drop to a two or three. The epidural stimulation potentially trains the neuron to respond to the lower volume, Lu says.
Lu has used such stimulators to improve hand function – "essentially what defines us" – in two patients with spinal cord injuries. Both increased their grip strength so they now can lift a cup to drink by themselves, which they couldn't do before. He's also used non-invasive stimulation to help restore bladder function, which he says many spinal cord injury patients care about as much as walking again.
Not everyone will benefit from these treatments. People whose injury was caused by a cut to the spinal cord, as with a knife or bullet, probably can't be helped, Lu says, adding that they account for less than 5 percent of spinal cord injuries.
The current challenge Lu says is not how to stimulate the spinal cord, but where to stimulate it and the frequency of stimulation that will be most effective for each patient. Right now, doctors use an off-the-shelf stimulator that is used to treat pain and is not optimized for spinal cord patients, Harkema says.
Swiss researchers have shown impressive results from intermittent rather than continuous epidural stimulation. These pulses better reflect the way the brain sends its messages, according to Gregoire Courtine, the senior author on a pair of papers published Nov. 1 in Nature and Nature Neuroscience. He showed that he could get people up and moving within just a few days of turning on the stimulation. Three of his patients are walking again with only a walker or minimal assistance, and they also gained voluntary leg movements even when the stimulator was off. Continuous stimulation, this research shows, actually interferes with the patients' perception of limb position, and thus makes it harder for them to relearn to walk.
Even short of walking, proper physical rehabilitation and electrical stimulation can transform the quality of life of people with spinal cord injury, Howley and Harkema say. Patients don't need to be able to reach the top shelf or run a marathon to feel like they've been "cured" from their paralysis. Instead, recovering bowel, bladder and sexual functions, the ability to regulate their temperature and blood pressure, and reducing the breakdown of skin that can lead to a life-threatening infection can all be transformative – and all appear to improve with the combination of rehabilitation and electrical stimulation.
Howley cites a video of one of Harkema's patients, Stefanie Putnam, who was passing out five to six times a day because her blood pressure was so low. She couldn't be left alone, which meant she had no independence. After several months of rehabilitation and stimulation, she can now sit up for long periods, be left alone, and even, she says gleefully, cook her own dinner. "Every time I watch it, it brings me to tears," Howley says of the video. "She's able to resume her normal life activity. It's mind-boggling."
The work also suggests a transformation in the care of people immediately after injury. They should be allowed to stand and start taking steps as soon as possible, even if they cannot do it under their own power, Harkema says. Research is also likely to show that quickly implanting a stimulator after an injury will make a difference, she says.
There may be medications that can help immediately after an injury, too. One drug currently being studied, called riluzole, has already been approved for ALS and might help limit the damage of a spinal cord injury, Howley says. But testing its effectiveness has been a slow process, she says, because it needs to be given within 12 hours of the initial injury and not enough people get to the testing sites in time.
Stem cell therapy also offers promise for spinal cord injury patients, Howley says – but not the treatments currently provided by commercial stem cell clinics both in the U.S. and overseas, which she says are a sham. Instead, she is carefully following research by a California-based company called Asterias Biotherapeutics, which announced plans Nov. 8 to merge with a company called BioTime.
Asterias and a predecessor company have been treating people since 2010 in an effort to regrow nerves in the spinal cord. All those treated have safely tolerated the cells, but not everyone has seen a huge improvement, says Edward Wirth, who has led the trial work and is Asterias' chief medical director. He says he thinks he knows what's held back those who didn't improve much, and hopes to address those issues in the next 3- to 4-year-long trial, which he's now discussing with the U.S. Food and Drug Administration.
So far, he says, some patients have had an almost complete return of movement in their hands and arms, but little improvement in their legs. The stem cells seem to stimulate tissue repair and regeneration, he says, but only around the level of the injury in the spinal cord and a bit below. The legs, he says, are too far away to benefit.
Wirth says he thinks a combination of treatments – stem cells, electrical stimulation, rehabilitation, and improved care immediately after an injury – will likely produce the best results.
While there's still a long way to go to scale these advances to help the majority of the 300,000 spinal cord injury patients in the U.S., they now have something that's long been elusive: hope.
"Two or three decades ago there was no hope at all," Howley says. "We've come a long way."
She figured the pain would go away. But instead, it intensified that night. Kamil's husband drove her to the Cedars-Sinai hospital, where she was admitted to the coronary care unit. It turned out she wasn't having a heart attack after all. Instead, she was diagnosed with a much less common but nonetheless dangerous heart condition called takotsubo syndrome, or broken heart syndrome.
A heart attack happens when blood flow to the heart is obstructed—such as when an artery is blocked—causing heart muscle tissue to die. In takotsubo syndrome, the blood flow isn't blocked, but the heart doesn't pump it properly. The heart changes its shape and starts to resemble a Japanese fishing device called tako-tsubo, a clay pot with a wider body and narrower mouth, used to catch octopus.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks," explains Noel Bairey Merz, the cardiologist at Cedar Sinai who Kamil went to see after she was discharged.
"The heart muscle is stunned and doesn't function properly anywhere from three days to three weeks."
But even though the heart isn't permanently damaged, mortality rates due to takotsubo syndrome are comparable to those of a heart attack, Merz notes—about 4-5 percent of patients die from the attack, and 20 percent within the next five years. "It's as bad as a heart attack," Merz says—only it's much less known, even to doctors. The condition affects only about 1 percent of people, and there are around 15,000 new cases annually. It's diagnosed using a cardiac ventriculogram, an imaging test that allows doctors to see how the heart pumps blood.
Scientists don't fully understand what causes Takotsubo syndrome, but it usually occurs after extreme emotional or physical stress. Doctors think it's triggered by a so-called catecholamine storm, a phenomenon in which the body releases too much catecholamines—hormones involved in the fight-or-flight response. Evolutionarily, when early humans lived in savannas or forests and had to either fight off predators or flee from them, these hormones gave our ancestors the needed strength and stamina to take either action. Released by nerve endings and by the adrenal glands that sit on top of the kidneys, these hormones still flood our bodies in moments of stress, but an overabundance of them could sometimes be damaging.
Elaine Kamil
A study by scientists at Harvard Medical School linked increased risk of takotsubo to higher activity in the amygdala, a brain region responsible for emotions that's involved in responses to stress. The scientists believe that chronic stress makes people more susceptible to the syndrome. Notably, one small study suggested that the number of Takotsubo cases increased during the COVID-19 pandemic.
There are no specific drugs to treat takotsubo, so doctors rely on supportive therapies, which include medications typically used for high blood pressure and heart failure. In most cases, the heart returns to its normal shape within a few weeks. "It's a spontaneous recovery—the catecholamine storm is resolved, the injury trigger is removed and the heart heals itself because our bodies have an amazing healing capacity," Merz says. It also helps that tissues remain intact. 'The heart cells don't die, they just aren't functioning properly for some time."
That's the good news. The bad news is that takotsubo is likely to strike again—in 5-20 percent of patients the condition comes back, sometimes more severe than before.
That's exactly what happened to Kamil. After getting her diagnosis in 2013, she realized that she actually had a previous takotsubo episode. In 2010, she experienced similar symptoms after her son died. "The night after he died, I was having severe chest pain at night, but I was too overwhelmed with grief to do anything about it," she recalls. After a while, the pain subsided and didn't return until three years later.
For weeks after her second attack, she felt exhausted, listless and anxious. "You lose confidence in your body," she says. "You have these little twinges on your chest, or if you start having arrhythmia, and you wonder if this is another episode coming up. It's really unnerving because you don't know how to read these cues." And that's very typical, Merz says. Even when the heart muscle appears to recover, patients don't return to normal right away. They have shortens of breath, they can't exercise, and they stay anxious and worried for a while.
Women over the age of 50 are diagnosed with takotsubo more often than other demographics. However, it happens in men too, although it typically strikes after physical stress, such as a triathlon or an exhausting day of cycling. Young people can also get takotsubo. Older patients are hospitalized more often, but younger people tend to have more severe complications. It could be because an older person may go for a jog while younger one may run a marathon, which would take a stronger toll on the body of a person who's predisposed to the condition.
Notably, the emotional stressors don't always have to be negative—the heart muscle can get out of shape from good emotions, too. "There have been case reports of takotsubo at weddings," Merz says. Moreover, one out of three or four takotsubo patients experience no apparent stress, she adds. "So it could be that it's not so much the catecholamine storm itself, but the body's reaction to it—the physiological reaction deeply embedded into out physiology," she explains.
Merz and her team are working to understand what makes people predisposed to takotsubo. They think a person's genetics play a role, but they haven't yet pinpointed genes that seem to be responsible. Genes code for proteins, which affect how the body metabolizes various compounds, which, in turn, affect the body's response to stress. Pinning down the protein involved in takotsubo susceptibility would allow doctors to develop screening tests and identify those prone to severe repeating attacks. It will also help develop medications that can either prevent it or treat it better than just waiting for the body to heal itself.
Researchers at the Imperial College London found that elevated levels of certain types of microRNAs—molecules involved in protein production—increase the chances of developing takotsubo.
In one study, researchers tried treating takotsubo in mice with a drug called suberanilohydroxamic acid, or SAHA, typically used for cancer treatment. The drug improved cardiac health and reversed the broken heart in rodents. It remains to be seen if the drug would have a similar effect on humans. But identifying a drug that shows promise is progress, Merz says. "I'm glad that there's research in this area."
This article was originally published by Leaps.org on July 28, 2021.
