Pain study points to a mirror image

For more than a century, doctors have reported cases of a mysterious phenomenon: When a patient's arm or leg was injured, the opposite limb would sometimes feel chronic pain, as well.

Now, Massachusets General Hospital research on rats suggests that such opposite-limb symptoms may stem from a previously unrecognized connection of pinpoint accuracy between the nerves on one side of the body and the mirror-image spot on the other side.

The research provides the "first conclusive proof" that trauma on one side of the body can cause opposite-side nerve damage, said Dr. Gary J. Bennett of McGill University in Montreal, a leading pain specialist who was not involved in the research. "There's no precedent for this; it's a completely out-of-the-blue discovery."

After all, he added, "if you break your left foot, you don't expect any change in the bones of your right foot."

The study in rats is to be published in the Annals of Neurology as researchers have been making great progress in understanding pain and finding biological evidence that it is not just in patients' heads.

But the mechanism of the mirror-image injury remains a riddle, said Dr. Anne Louise Oaklander, the study's lead author and head of Mass. General's nerve injury unit. But she said her findings could already help patients get their opposite-side pain taken seriously.

"So many patients notice that they have symptoms in the area immediately opposite a one-sided injury, and typically these are dismissed by the physician or the patient is told that because one limb is injured, it puts extra stress or strain on the opposite side," she said.

"But in fact," she said, "some patients -- and we do not yet know how many -- may be experiencing consequences of this type of crossover injury."

Oaklander used a relatively new method to make her discovery, performing a biopsy on a tiny patch of skin and then counting the nerves related to pain. Loss of such nerve endings has been linked to chronic pain after an injury.

She began applying some of the new biopsy methods to diagnose patients and do research several years ago. She wanted to figure out why some patients recover easily from shingles, an excruciating skin-and-nerve disease that tends to attack older people, while others suffer for years with post-shingles pain.

In the course of that work, she found, to her own surprise, that people with post-shingles pain not only lost most of their nerve endings at the spot where the shingles erupted, but also lost about half their nerve endings at the same spot on the opposite side of the body.

Shingles comes from a virus, so the obvious assumption was that the virus had somehow spread to the opposite side.

But Oaklander had seen and written animal research articles suggesting that opposite-side effects could occur after injuries, as well, so she decided to try to pin down that crossover phenomenon.

She and coauthor Jennifer Brown experimented on more than 50 rats, watching them for up to five months after a major nerve had been cut in one hind paw. They found that at the point on the opposite paw that exactly mirrored the site of the injury, the rats lost half of their skin nerve endings within a week; by five months later, the nerves had not been restored.

The crossover syndrome may remind some of so-called phantom limb pain, in which the brain creates the hallucination of sensation in a body part that is no longer there. Both are seemingly impossible phenomena that scientists can only explain by citing the great complexity of the pain pathways that pass through the brain, the spinal cord, and the rest of the body.

Oaklander speculates that crossover injury could be a side-effect of mechanisms that evolved in the body to help coordinate the right side with the left. But her lab is just beginning to look into it, and other labs are likely to join in the exploration.

"First you have to know something happens before you can find the reason," Bennett said. Oaklander's paper, he added, "will produce a tremendous amount of new research in both animals and patients, looking to see how widespread it is and to try to figure out its causes."

Crossover nerve injury also may be involved somehow in triggering or maintaining the pain on the injured side of the body, she said. For example, the severity of post-shingles pain is correlated with the severity of crossover damage, she has shown.

The new research also holds a lesson about the need for caution in scientific experiments, Oaklander said. In many experiments, possibly hundreds, researchers have damaged one paw of an animal and compared the effect with what happens in the uninjured paw, assuming that the uninjured paw was completely unaffected, she said.

The crossover injury paper indicates that in such experiments, researchers must be sure to use completely uninjured animals for comparison, as well. In Oaklander's experiments, the injured rats were compared with a group that underwent a sham operation and another group that was left alone.

Bennett said he did not believe the discovery of crossover injury would overturn any experiments that were an important foundation of neurology. Rather, he said, "we'll have to go fix a couple of corners, probably."

The mystery of crossover pain began at least as far back as the Civil War, when a few soldiers who had nerve damage from bullets or shrapnel on one side of the body suddenly developed pain on the opposite side for no obvious reason. Past experiments in animals had produced hints of the crossover effect, but nothing as dramatic and definitive.

"This is in your face," Oaklander said. "It's not subtle."

Carey Goldberg is reachable at goldberg@globe.com.