Her Chronic Pain Was a Medical Mystery. Was It an Unexplained Condition?

Leslie Levine’s searing pains started the day after Thanksgiving in 2006. They began in her toes, which turned strangely dark. Then the agony crept upward. “It felt like my legs were being dipped in boiling oil 24/7,” she said.

The emergency room and a series of doctors could do little but scratch their heads and offer her painkillers.

“I was living on oxycodone and very grateful for it,” Levine said, then Harvard University’s chief patent attorney. But it wasn’t enough. “By January, I was on disability, because I was in such pain and could hardly walk.”

Her internet search for answers led her to Dr. Anne Louise Oaklander, a neurologist at Massachusetts General Hospital, who was then developing a hypothesis about inexplicable pain disorders like Levine’s: What if they were caused by an overactive immune system?

Oaklander treated Levine as if that were the case and the pain—thankfully—disappeared within five days. “I didn’t know how I was going to live with that level of pain,” Levine said, adding that it returns every time she stops treatment.

Now, Oaklander has published a series of 55 case reports including Levine’s, suggesting that a number of people who suffer pain or other neurologic symptoms—which may have been diagnosed as fibromyalgia, chronic fatigue syndrome, mental illness, or a host of other problems.

Oaklander thinks that some percentage of people who have small fiber neuropathy—which can be caused by diabetes, chemotherapy, or other toxins—actually have a previously undiagnosed autoimmune problem.

Although it’s too soon to say how many people might be affected by this autoimmune-related small-fiber polyneuropathy, nearly 50 million Americans complain of regular or chronic pain. If even a fraction of them could be effectively treated with autoimmune therapies rather than high-dose painkillers, they may get better relief without risking an opioid addiction, said Oaklander, who is also an associate professor of neurology, at Harvard Medical School.

“This is not just some rare, esoteric disease that Harvard eggheads are investigating,” she said. “It is common. People—including kids and teens—are sick, but they don’t know what they have and their doctors don’t know, either.”

Small-fiber polyneuropathy, in which nerves misfire, is common among people with diabetes or who have been treated with chemotherapy. But in roughly half the patients who suffer the same pain, numbness, or itching, there isn’t any obvious cause.

The same tiny nerves also line the gut, Oaklander said, so people with this condition can have gastrointestinal symptoms, such as nausea or vomiting when they try to eat—which often gets misdiagnosed as an eating disorder. Even fainting when standing up or difficulty getting out of bed can be caused by damage to these small nerve cells, she said.

In Oaklander’s study, 55 mostly female patients all had objective measures of damage to small-fiber peripheral nerve cells and no diabetes or other known cause of neuropathy.

All were treated with intravenous immunoglobulin or IVIg, a therapy effectively used against other autoimmune-related nerve conditions. The case review showed that 77 percent of the patients responded to IVIg, with their pain dropping on average from 6.3 to 5.2 on a 10-point scale. Their internal organ function also improved.

It’s still too soon to declare that Oaklander’s discovered a new condition, and certainly no one recommends starting autoimmune treatment for anyone with unexplained pains.

But Marinos Dalakas, director of the Neuromuscular Division at Thomas Jefferson University in Philadelphia, says her results are convincing enough to encourage him to test some of his pain patients for markers of autoimmune disease. If he found such signs, Dalakas said he would try them for three months on a treatment like IVIg to see if their symptoms improve.

To definitively prove that IVIg is effective for appropriately selected patients, someone would have to conduct two, large, expensive clinical trials, likely to take 5-10 years. Oaklander has already applied to the National Institutes of Health for a research grant to prepare for one such trial.

Still, to have advanced the science this far was “courageous,” one colleague said.

“It takes great courage to persist, to believe in your data, and to press on in the face of skeptics,” Stephen Hauser, chairman of the neurology department at the University of California, San Francisco School of Medicine, told The Daily Beast. “I think the world is beginning to catch up to Anne Louise.”

Before changing his own medical practice, Hauser said he would want to see the results of a large, blinded trial, and confirmation that IVIg or another autoimmune treatment offers pain patients a significant improvement in their quality of life.

“I do think these patients represent a huge problem for the medical community for which better treatments are sorely needed,” Hauser added.

IVIg, which has side effects like nausea, headaches, and flu-like symptoms, must be delivered via infusion. And it’s pricey—costing $10,000 per monthly dose—because each dose contains purified proteins from 5,000-8,000 blood donors who have been screened for infectious diseases, Hauser said.

The therapy works, Oaklander said, because “it bamboozles the immune system,” overwhelming it with harmless proteins to distract it from attacking the nerves.

If an autoimmune condition lingers untreated, continued attacks can leave permanent nerve damage, Oaklander said. “It’s really important that doctors recognize when neuropathy is autoimmune and dampen down the attack as soon as possible.” But that hadn’t previously been recommended.

She periodically dials back her patients’ IVIg to see if their nerves have healed enough to stop treatment. About 16 percent of the patients in the case review were able to wean off their IVIg without their symptoms returning. “If you can protect the nerves for a period and let them regrow, the autoimmune attack may die down,” she said.

Oaklander said she hopes her new paper, published in the journal Therapeutic Advances in Neurological Disorders, will give patients some ammunition when they ask their insurance company to pay for autoimmune therapy.

Levine’s insurance company refused to pay for IVIg treatments for four years, insisting she take much cheaper steroids, instead. But the steroids didn’t help nearly as much and their side effects would land her in the hospital every few months, Levine said. Finally, realizing that IVIg would be cheaper, her insurer let her back on the treatments two years ago—and she’s been side-effect free since.

“I just had my monthly treatment this morning,” Levine, who now runs a support group for people with neuropathy, said. “It’s changed my life.”