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.
Hopkins helped steer concert painist Leon Fleischer to botox.
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. It would be the first oral
dystonia medication in years.
Buz Jinnah and Ellen Hess are married in real life, as are their scientific efforts to ease dystonia.
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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