Volume 16, Number 3
A Hand Up for Dystonia
New studies are shedding light on the causes, on therapy.
My career was flourishing in 1964. I was happy," says Leon Fleischer of a time before his life as a concert pianist suddenly became oddly focused -- literally and figuratively.
After years of electrifying his audiences, Fleischer, at 36, one day noticed a slight curling of the fourth and fifth fingers on his right hand. "Within 10 months," he says, "my fingers had curved inward until the tips pressed my palms-an oddly defensive posture, I thought." Fleischer tried to play through the problem. "Even when my hand was exhausted, I kept going." But it got worse. Piano concertos for the left hand became staples of his scaled-back performance.
Fleischer's story --and it has Hopkins ties -- holds no surprises for neurologist "Buz" Jinnah, M.D., Ph.D., who specializes in dystonia. Dozens of Jinnah's patients -- especially those with primary dystonia, the sort that's independent of other disease or trauma-have come to him after years thinking they have something else. It's a type of Parkinson's. It's a form of seizure. It's all in your head, they're told.
Because dystonia brings near-simultaneous contraction of opposing muscles
that control the trunk, neck, limbs -- or fingers -- those parts twist toward
the stronger "winning" muscle. Winner muscles differ from patient to patient,
says Jinnah, as can the intensity or duration of contractions. "All this
infuses the disease with variety. It can be subtle." Add the fact that dystonia
is the endpoint of varied insults-mutant genes, a dearth of dopamine, stroke,
cerebral palsy or other injury of the brain's basal ganglia -- "and you get,"
he says, "the most poorly diagnosed of all movement disorders." Yet Jinnah and his colleague Ellen Hess, Ph.D., hope to change all that -- and improve therapy -- by understanding the disease. Their studies with realistic animal models are making headway. They've already resulted in a clinical drug trial.
Hess's work began with a type of mutant mouse nicknamed tottering. She was told it had epilepsy. But Jinnah's clinical eyes saw postural twisting that's a hallmark of dystonia. Further, Hess adds, the mouse's EEG revealed no activity typical of epilepsy: "Even the mouse was misdiagnosed."
At the time, no one knew what ailed the animal. "Now," says Jinnah, "we know it carries a mutation for an abnormal calcium channel." Since then, Jinnah and Hess have found four other channel mutations in mice, each giving characteristic dystonia-like symptoms. One mouse, for example, models torticollis, a dystonia affecting the head and neck. Tottering mimics paroxysmal dystonia. Jinnah says it's looking like dystonia may be one of the "channelopathies," a newer disease category that includes, for example, common migraine.
When Hess and Jinnah shut off key calcium channels in tottering mice with a standard blocker, the rodents' dystonia lifted. That discovery's led to an NIH-sponsored trial at Hopkins of the channel-blocker nifedipine for generalized dystonia patients (see page 7). It would be the first oral dystonia medication in years.
At the brain level -- dystonia surely stems from a glitch in brain control -- Hess has shown the cerebellum plays a stronger role than suspected. "The dogma says basal ganglia cause the problem," says Jinnah. "That's because people with strokes there may develop dystonia." But coordinating muscle contraction is also cerebellar. Recently, Hess and Jinnah saw the cerebellum of tottering mice light up in studies of nerve activity. And when they injected a mild stimulant to that area in normal mice, the animals got dystonia.
Will this help maestro Fleischer? "Not immediately," says Jinnah. "But even now, we can do something for everyone." When Fleischer visited Hopkins neurologist Dan Drachman, M.D., several years ago, Drachman led him to a new program at the NIH using botox for focal dystonia. Last November, the joy at Fleischer's two-handed comeback concert -- after 30 years -- was palpable.
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