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The Fire Within
Nerve damage in neuropathy progresses sooner than previously thought, lending urgency to earlier detection and treatment.
Photos by Chris Hartlove
With his pain gradually improving, William Loughran is headed back to the gym.
“If we wait until these patients have large-fiber neuropathy, we’ve needlessly lost time and nerve function. This is one more reason to be aggressive about controlling patients’ glucose levels.”
William Loughran retired from his job as a bank director in northeast Maryland in 2014, when he was 68. Like many new retirees, he vowed to ramp up his exercise routine.
“I started going to the gym three or four times a week and walking every day,” he says. “I felt better than I had in years.”
But then, after a long day of walking with his son during a visit to California, it began: “I went to bed, and the soles of my feet felt like they were on fire,” Loughran recalls. “It was jabbing pain, pins-and-needles pain, and it was pretty severe.”
Within weeks, Loughran’s feet had become so painful that driving his car was a struggle. “Just the slight pressure from the pedals was too much to tolerate,” he says. For months, he spent almost all of his time at home, in bare feet.
Loughran had developed peripheral neuropathy, a condition shared by hundreds of thousands of Americans. Peripheral neuropathy often begins with damage to the unmyelinated small-fiber nerves, resulting in numbness, tingling and lightninglike shooting pains, most commonly in the feet and hands. The best-known causes of peripheral neuropathy are type 2 diabetes and chemotherapy, but there are several other potential culprits. Vitamin B12 deficiency, high cholesterol, smoking and HIV/AIDS have all been implicated. Roughly one-fifth of peripheral neuropathy cases have no clear cause at all.
After several false starts with physical therapists, podiatrists and other specialists, Loughran realized that he needed to see a neurologist. He searched online and learned that Johns Hopkins has a prominent research program in peripheral neuropathy.
In early 2016, Loughran found himself in the Johns Hopkins office of Mohammad Khoshnoodi, an assistant professor of neurology. Here at last he received a thorough workup. “Dr. Khoshnoodi did much more extensive blood work than anyone else had done,” Loughran says. “He did nerve conduction studies to see if I had damage to the large-fiber nerves, which I didn’t. And he took three skin biopsies from my leg.” The idea of having skin samples extracted sounded odd at first, Loughran says. But if that was what was required, he was game.
The technique of using skin biopsies to assess peripheral neuropathy was pioneered at Johns Hopkins in the early 1990s by Justin McArthur, who now chairs the Department of Neurology, and the late John Griffin, one of the best-known neurologists in Johns Hopkins history. A major advantage of these biopsies is that they permit objective, quantifiable measurement of nerve damage. They can be taken sequentially from the same sites over a period of months or years, allowing researchers to see exactly how a patient’s nerves and their supporting structures change over time, and how that neurological damage is affected by changes in the patient’s underlying condition (whether that be diabetes, chemotherapy exposure or something else).
Sequential skin biopsies have become an increasingly powerful tool for uncovering the mysteries of neuropathy. Last spring, Khoshnoodi and five Johns Hopkins colleagues published a much-discussed study in JAMA Neurology that offered some provocative findings. The study considered skin biopsies that were taken sequentially from 52 patients with neuropathy at Johns Hopkins between 2002 and 2010, along with biopsies from 10 healthy volunteers for purposes of comparison.
The study’s first striking finding was that patients with impaired glucose regulation—a condition often known as prediabetes—saw their neuropathies progress just as aggressively as patients with full-blown diabetes. The second finding was that nerve damage increased just as fast at sites on the patients’ upper thighs as it did on patients’ toes and feet, where they actually perceived their symptoms.
“This study reinforces the idea that early neuropathy tends to progress,” says Michael Polydefkis ’93, a professor of neurology and the paper’s senior author. “Primary care doctors should always take it seriously, even if the patient is just talking about slight numbness.”
The fact that prediabetes can cause neuropathies just as severe as full-blown diabetes is relatively well-known among neurologists and endocrinologists, Khoshnoodi says, but it isn’t sufficiently appreciated by generalist primary care doctors. The sequential skin biopsy study should be a wake-up call, he says. “If we wait until these patients have large-fiber neuropathy, we’ve needlessly lost time and nerve function,” he says. “This is one more reason to be aggressive about controlling patients’ glucose levels.”
Left unattended, Polydefkis says, peripheral neuropathy can advance to more severe kinds of neurological dysfunction, including problems with balance, blood pressure regulation and difficulties in walking. In this study, 14 of 52 patients with small-fiber neuropathy progressed to mild large-fiber neuropathy, meaning that their ankle reflexes were reduced and they were less sensitive to the vibrations of a tuning fork. Such problems are often a prelude to more severe deficits in motion and sensation.
Though Loughran arrived at Johns Hopkins too late to take part in that particular sequential skin biopsy study, the three specimens taken from his ankle confirmed that his skin had a significantly reduced density of small-fiber nerves—the classic sign of small-fiber peripheral neuropathy.
Loughran says he was grateful to have a definitive diagnosis after months of confusion and anxiety. While there are currently no treatments that readily reverse neuropathy in Loughran’s situation, peripheral neuropathy pain can be relieved with various combinations of anti-seizure medications, antidepressants and opioid pain relievers.
None of those drugs can cure the condition or even slow its progression. What can slow neuropathy’s progression—at least for many patients—is correction of the underlying cause. If the patient’s neuropathy is caused primarily by diabetes or prediabetes, strict control of blood glucose levels through diet, exercise and medication can do the trick. If the neuropathy is caused by vitamin B12 deficiency, that is usually simple to correct. If chemotherapy is the villain, the patient and his or her oncologist may want to consider a change in treatment.
“Skin biopsies can tell us exactly how much neuropathy you have, but they don’t tell us anything about the cause,” says Ahmet Hoke, a professor of neurology and another of the study’s authors. “The blood work becomes key. The blood work helps us establish the etiology.”
In Loughran’s case, the blood work strongly suggested prediabetes. He is acting accordingly. “I’ve cut out sodas,” he says, “and I’m trying to get back to exercising.”
For many patients, that last step is easier said than done. “We tell them to exercise,” Polydefkis says, “but exercise can be intolerable because of the burning pain and electric shocks in their feet. That’s why it’s so important to find the right combination of medications to get the neuropathy symptoms under control. Those medicines won’t cure the neuropathy, but they’ll allow patients to be more active, which in turn helps with glucose control when diabetes is a factor.” Swimming and other nonweight-bearing exercises are often the best options, Polydefkis adds.
Hoke notes that the sequential skin biopsy study also shed light on the still-unsettled question of why exactly diabetes and prediabetes tend to damage the nerves. Some theories have emphasized the fact that the longest sensory neurons, which extend all the way from the spine to the toes, have huge metabolic needs because of their extreme surface-to-volume ratios. The metabolic dysfunctions associated with diabetes, according to this theory, make it difficult for the long neurons to balance their energy requirements, and they eventually stop working properly. Other scientists have emphasized a simpler, more mechanical model. Diabetes, they say, slowly damages the blood vessels that supply nerves with oxygen and nutrients. Diabetic neuropathy, in this view, is mostly a problem of the vasculature.
The Johns Hopkins studies tend to support the metabolic theory, Hoke and Polydefkis say (though both add that vascular problems probably contribute). “What’s so interesting,” Hoke says, “is that we see damage that is just as bad in prediabetes as in diabetes. That suggests that it isn’t the overall amount of glucose that is causing the neuropathy, but instead that it’s rapid fluctuations in glucose levels. There’s something about those fluctuations that the nerve cells can’t tolerate.”
What about patients who have been diagnosed with diabetes or prediabetes but don’t have any symptoms of neuropathy? “If I were in that situation, I would be vigilant,” Polydefkis says. “There’s reason to believe that nerve damage is already occurring in such patients. I would be very careful about trying to keep my glucose levels stable.”
Howell Todd’s story began much like Loughran’s. He retired as a university president in 2001, moving to a 55-acre farm in rural Tennessee. He looked forward to spending his days reading and raising crops. Not long after retirement, however, he began to notice odd tingling in his feet when he exercised on his elliptical trainer.
“At first, it was just uncomfortable,” he says. “Then, it began to progress. It got to the point where I would wake up at 2:30 in the morning with my feet flaming.”
In 2012, he flew to Johns Hopkins for a workup. Like Loughran, Todd had skin biopsies that clearly indicated peripheral neuropathy. Unlike Loughran, however, Todd turned out to have no identifiable underlying cause—no diabetes or prediabetes, no hyperlipidemia, no B12 deficiency. His is one of the roughly 20 percent of peripheral neuropathy cases that are classified as idiopathic.
These are the cases that Polydefkis finds most frustrating. All he can do as a neurologist is suggest medications to keep the symptoms in check. (He recommended that Todd start a daily regimen of pregabalin and tramadol, a combination that Todd says has served him well for four years.)
Todd says that he is glad he made the trek to Johns Hopkins, even if there is no miracle cure at hand. “Dr. Polydefkis had an excellent bedside manner,” he says. “He and everyone there took the time to talk with me. I’ll be 73 this fall, and I’m still able to do maintenance work on the farm, as long as I watch my limits. I don’t think I could have done that without the medications he suggested.”
While there are currently no treatments that readily reverse peripheral neuropathy, Johns Hopkins researchers are looking at a number of potential molecular targets for medications and are also actively involved in planning clinical trials.
Hoke has been studying medications that might offer protection to cancer patients’ nerve cells before they begin chemotherapy. In 2014, he and his colleagues screened thousands of compounds from a Johns Hopkins drug library. They discovered that ethoxyquin—an antioxidant that is sometimes used as a pet food additive—seems to protect nerves exposed to paclitaxel and cisplatin, two of the most notoriously neurotoxic chemotherapeutic drugs. In recent months, Hoke and Polydefkis have also tested ethoxyquin in animal models of diabetic neuropathy, with promising results. To bring these studies closer to human clinical trials, the team recently received one of the inaugural grants from the Louis B. Thalheimer Fund for Translational Research, a new Johns Hopkins effort to accelerate the development of university discoveries.
Polydefkis is also involved in an international clinical trial of a new medication that may be effective against a rare and devastating inherited neuropathic disorder. The condition, known as transthyretin familial amyloid polyneuropathy, affects roughly 10,000 people worldwide, usually striking in middle age.
“The transthyretin protein normally has a four-leaf clover structure,” Polydefkis says. “But in people who inherit this condition, it has a malformed structure and clumps within the nerves. When those deposits build up, peripheral nerves start to malfunction, and the patient experiences peripheral neuropathy. The disease eventually involves sensory, motor and autonomic nerves, and it is fatal.”
The ongoing clinical trial is assessing a medication known as patisiran, which inhibits the liver’s production of the malformed proteins. Polydefkis and his colleagues have a specific role: to examine skin biopsies sent every few months from trial participants around the world. “We’ve been getting biopsies from Brazil, from Norway, from all sorts of places,” Polydefkis says. “We’ve seen some dramatic improvements over time in these patients’ nerves. It’s an example of a severe form of peripheral neuropathy, a fatal form, that appears to be changing before our eyes.”
Loughran, meanwhile, has signed up for a study that will closely monitor patients’ neuropathic status, glucose control, blood pressure and a wide variety of other variables, with an eye toward developing a deeper understanding of how these factors affect each other.
“My symptoms are gradually improving,” he says. “I’ve finally gotten to the point where I can at least do some exercise. It was initially both feet—front, back, everywhere. Now it’s regressed to just the bottom of the feet. And now that I’ve heard about this possible prediabetes, I’m going to get back to the gym.”
“We’ve seen some dramatic improvements over time in these patients’ nerves. It’s an example of a severe form of peripheral neuropathy, a fatal form, that appears to be changing before our eyes.”
For Mark E. Rubenstein, It’s Personal
Much of the recent Johns Hopkins research on peripheral neuropathy, including this year’s high-profile study of sequential skin biopsies, has been financially supported by Mark E. Rubenstein, a trustee emeritus of The Johns Hopkins University and Johns Hopkins Medicine.
This sort of gift is nothing new for Rubenstein. For decades, he has supported several lines of medical research at Johns Hopkins. This one, however, is more personal for him than others, as he himself has contended with one of the most severe types of diabetic neuropathy.
Rubenstein, who retired in 2004 as chief executive of the Rubenstein Company, a major commercial real estate firm, was diagnosed with type 2 diabetes more than 40 years ago. He has long experience with the common symptoms of diabetic neuropathy, including numbness, tingling and shooting pains in the feet. In 2011, those symptoms suddenly blossomed into something much more severe. “Over a period of two weeks, I lost 15 pounds,” he says, “and the muscles in my left leg started to waste away.”
Those were the hallmarks of diabetic amyotrophy, which is sometimes known as Bruns-Garland syndrome. The condition often recedes on its own but sometimes leads to full-blown paralysis in the affected limb. Rubenstein went to see Michael Polydefkis at Johns Hopkins, who prescribed new medications to manage the pain and, more importantly, referred Rubenstein to expert physical therapists for an exercise program that allowed him to rebuild the lost muscle in his leg.
“He’s a fantastic doctor,” Rubenstein says. “He has great empathy for patients. He really got me through this.”
Polydefkis, for his part, is grateful for the research support Rubenstein has provided in the last few years. “For an ambitious program like ours,” he says, “it makes an enormous difference to have this kind of open-ended support.”
“Skin biopsies can tell us exactly how much neuropathy you have, but they don’t tell us anything about the cause. The blood work becomes key.”