Myoclonus

Parents learn that it doesn't take much to start a biological storm in a toddler's brain

CHRISTY'S PARENTS WERE AT their wits' end. About two months before, she had been fine, walking and talking like any 2-year-old. Then she got a cold. First her eyes started jiggling; then her body began jerking. The twitches were so strong she couldn't talk or walk. She fell often, was covered with bruises, and had trouble sleeping. Her parents had taken her to a pediatrician, who referred them to a neurologist. He said Christy was still fighting a virus and would get better. When she didn't, her parents brought her to me for another opinion.

My physical examination included tests of balance and coordination. From Christy's responses I could see she had suffered an injury to her cerebellum, a fist-sized structure at the base of the brain that helps execute movements. But I also knew that her jerks and eye movements had to originate in the brain stem, a slender stalk of tissue that connects the brain to the spinal cord. Her problems with language and behavior probably meant other brain structures were involved too. I told the parents that Christy had OMS--opsoclonus-myoclonus syndrome. The name is simply a description of the symptoms. Opsoclonus refers to the jiggling eye movements, and myoclonus is a term for the muscle jerks.

OMS is caused by a brain injury, but the problem can't be easily detected on brain scans. The brain contains a staggering thousand trillion junctions between neurons. It would take a malfunction in only a small percentage of neurons to produce Christy's symptoms.

"Can this be cured?" her mother asked. I shook my head. "I'm talking about treatment, not cures."

The parents seemed incredulous.

I explained that in about half the known cases, the cause is thought to be a viral infection. The other half are caused by a tumor called a neuroblastoma in the chest or abdomen. This type of pediatric tumor accounts for about 8 percent of cancers in children, and it occurs most often in toddlers. Only about 4 percent of those children--roughly 30 U.S. cases each year--develop opsoclonus-myoclonus. We needed to do more tests on Christy to know if her OMS was caused by a tumor.

Her blood tests, X rays, electroencephalogram, and urine sample showed nothing unusual, but I ordered a CAT scan just to make sure. A tumor of only millimeters in diameter can be extremely difficult to detect.

When the CAT scan was completed, the radiologist pointed out a small blotch in the chest--a tumor. Within a week Christy was in the operating room and a surgeon cut out the mass. Lab results confirmed it had not spread to other parts of her body.

Strangely enough, the tumor itself is not directly responsible for OMS symptoms. Christy's immune system was getting a message to strike the tumor, and the message was prompting an attack on a protein in her brain.

Why does the immune system assail the very constituents it is designed to protect? The explanation begins with the maturing immune system. During fetal development, it tries to eliminate the immune cells that can recognize proteins the body manufactures itself--the so-called self proteins. The problem is that the system of elimination is not foolproof. Some sequestered tissues--like brain cells--remain vulnerable to immune cell activity. So if a tumor or virus makes a protein that also appears on brain cells, the immune system will hunt down and attack those cells as well. It's a biological version of friendly fire. In Christy's case, the tumor had primed her immune system to attack a protein on the cerebellum's Purkinje cells, which connect with neurons in other parts of the brain to coordinate movement and aid learning.

A few weeks after Christy's surgery, her neurological condition worsened. I explained to her stunned parents that we could try to weaken the immune response by treating her with adrenocorticotropic hormone (ACTH), the same hormone secreted by the pituitary gland. ACTH would prompt her adrenal glands to produce steroids, and steroids help rein in immune cell activity.

Physicians have more questions than answers when treating OMS. Should we give Christy chemotherapy to kill her immune cells, even though her tumor was benign? Should we try filtering the attacking antibodies from her blood, even though we don't know if it will work in kids her age?

Christy's parents were taught how to give her daily ACTH injections and how to monitor side effects, which can include fluid retention, behavioral problems, and sleeplessness. A week later, she was much better, and she could walk if she kept her legs apart for better balance. She still couldn't talk, but she suffered fewer jerks and eye abnormalities. Her parents' sense of hope made me feel like a hero.

Three months later, Christy's mother called. She was frantic. "Christy's worse. We were down to the lowest dose of ACTH, and she was due to come off the medication at the end of the week. Then she got a cold and deteriorated."

The panic in her voice frightened me. "Bring her in," I said, wondering what to do next. I wanted to avoid conventional treatments, such as immunosuppressants or chemotherapy, because they inflict widespread destruction on the immune system.

By the time the family arrived, I had a plan. I said we would give Christy an intravenous dose of immunoglobulins (IVIG), or antibodies. By flooding her blood with so many normal antibodies, we might be able to throw off the signaling that was directing the attack. If it worked, I explained, we'd give it to Christy once a month for several months.

The procedure costs as much as $20,000, so I had to convince Christy's insurance company of its worth. The representative had never heard of opsoclonus-myoclonus. Was the treatment standard care or research, he asked. I said I would fax reports on the few published cases of IVIG treatment that I knew of. We waited. Two weeks passed. Approval came--for one dose.

Christy returned to the clinic, and the nurse infused her with IVIG. The procedure took three hours. While everyone else worried, Christy fell asleep in her mother's arms.

Later the father took me aside. If Christy's OMS had been treated earlier, he asked, could she have recovered? I said that although the syndrome has been known for at least 40 years, few physicians are aware of it. Too often the telltale eye movements and muscle jerks are mistaken for symptoms of a simple viral infection. So no one gets treated for OMS right away If you're hit on the head with a brick, we are quick to follow certain protocols. But we are only beginning to realize that when the immune system attacks brain cells, the consequences can be just as serious.

The antibodies seemed to work, and Christy soon regained lost ground. I decided to reduce the ACTH dosage but not stop it altogether.

That was months ago. I recently received a birthday announcement from the family Christy had turned 3. Her cheeks were puffy from steroids, but she was running. Smiling faces in the family photo told me everything I wanted to know.

Still, Christy's future is uncertain. I don't know if she will ever be able to live independently or hold a job. I don't know if she'll have learning disabilities or mental retardation. I do know that relapses will be likely ACTH withdrawal and childhood infections--particularly those that produce a fever--could provoke her immune system into another rampage. I worried that using drugs to subdue her immune system might weaken her resistance to serious infections or even another kind of tumor. Although we take precautions, the hormone, too, could stunt her growth and harm her health. And nobody knows how long children who suffer from OMS need to be treated.

Above all else, do no harm--the tenet of my medical education--echoed in my thoughts. But there were no better options for treating OMS. At least Christy's brain had an opportunity to resume its critical development. The rest was up to the plasticity and resilience of youth.

The case described in Vital Signs is based On a true story. Some details have been Changed to protect the patient's privacy.

Michael Pranzatelli is a professor of neurology and pediatrics at Southern Illinois University School of Medicine and director of the National Pediatric Myoclonus Center. He saw his first case of opsoclonus-myoclonus during his neurology residency in 1980. "Very little was known," he says, "and very little could be done." Today we know a bit more, he adds, such as the role of immune-cell signaling. "But very few pediatricians are aware enough of this syndrome. If it goes untreated for a year, there's no way to prevent brain injury."

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