When David Diehl, a third-generation family farmer, became a paraplegic five days after an autoimmune condition attacked his spinal cord in 1991, he began driving his tractor and combine using rails and his hands. When his doctor diagnosed multiple sclerosis in 1998, he made adjustments. When the MS left him blind in his left eye in 2000, he relied on faith and family to move beyond it.
But what really threw him was breaking into uncontrollable laughter at a friend's funeral three years ago, when he bit his tongue so hard to stifle it that "I could almost taste blood."
That involuntary laughter, and sudden, uncontrollable crying jags, are part of a neurological disorder that left Diehl, of East Helena, Mont., confused and apologetic. The inappropriate emotional outbursts during serious heart-to-heart talks with his wife Arlene stressed their otherwise rock-solid 35-year marriage. She missed her formerly good-natured husband. It wasn't easy to have him interrupt a serious talk by laughing at her.
"It would really inflame things," she said. "I would try to communicate to him that his reaction wasn't normal, but he really couldn't see it."
Diehl, now 55, felt frustrated and embarrassed because "the outward expression did not match what was going on inside."
Ultimately, a neurologist 90 miles away in Great Falls, Mont., explained that the MS wasn't causing this disconnect between Diehl's emotions and outbursts. Instead, the doctor diagnosed pseudobulbar affect, which can accompany such neurological conditions as MS, amyotrophic lateral sclerosis (Lou Gehrig's disease), Parkinson's disease, brain tumors, and traumatic brain injury.
PBA interferes with relationships and employment in patients already grappling with loss of control over their brains and bodies. The effects can range from occasional to constant, from mild to crippling.
It's not a new condition; it was noted as early as 1872, when naturalist Charles Darwin wrote, "Certain brain diseases, such as hemiplegia, brain-wasting, and senile decay, have a special tendency to induce weeping."
Arlene Diehl, 54, says she recognized the PBA before her husband did, because she'd seen the same patterns in her own father, who struggled 20 years with MS. She also observed it in David's brother Dan, before his death from ALS, but she said, "I didn't know it had a name."
For many years, there was little to offer PBA patients like Arlene's father, husband and brother-in-law. But that's about to change.
Last Friday, after more than four years of review, the U.S. Food and Drug Administration approved the first and only therapy designed to improve symptoms of PBA. The new medication, Nuedexta from Avanir Pharmaceuticals in Aliso Viejo, Calif., combines the over-the-counter cough suppressant dextromethorphan with quinidine, a generic drug to restore normal rhythms to erratically beating hearts.
In clinical trials, Nuedexta was safe, reduced the frequency and severity of PBA episodes, and showed a significant advantage over a placebo. But in 2006, the FDA expressed concerns that higher doses of the drug combination raise the risks of dangerous cardiac rhythms. By reducing the doses of quinidine from 30 milligrams to 10 milligrams, Avanir satisfied the FDA's concerns about cardiac risks. In a Phase III clinical trial of the drug with MS patients, half the study participants who got the drug reported no PBA episodes in their last two weeks of the study.
"This is wonderful news for all the patients who suffer from PBA," said Dr. Erik Pioro, a Cleveland Clinic neurologist who specializes in ALS and related disorders, moments after hearing of the FDA nod. "They will now have an effective, safe, and well-tolerated treatment for this distressing and extremely isolating condition."
In the absence of something better, doctors have treated PBA with off-label prescriptions for antidepressants or levodopa, which boosts levels of the neurotransmitter dopamine. But these have a range of side effects and haven't been subjected to large studies in PBA patients.
Diehl has been among those taking antidepressants to help with the laughing and crying, even though he's not clinically depressed. But he's excited at the prospect of being able to take one pill, Nuedexta, instead of three for PBA. In fact, during a family dinner on Sunday night, his older daughter heard her father becoming overly animated during a discussion and asked aloud, "When is that drug going to be available?" Arlene Diehl recalled. "She was in a kind way saying to her father, 'you're overreacting and we're anxious for you to get on that drug.'"
David Diehl already knows something about Nuedexta, because at the suggestion of his neurologist, he participated in one of the studies that ultimately led to FDA approval. During that trial, in which some patients got the medication and others got a placebo, all patients subsequently had the option of taking the drug. Diehl believes it helped him, and said, "With this drug, there was no downside. This was the only drug I've ever taken where there were no side effects for me."
The most common side effects reported in clinical trials were falling, dizziness, headache, nausea and diarrhea.
Avanir plans to make the drug available in the first quarter of 2011, said CEO Keith Katkin, and will start by providing 30-day samples to select doctors who treat PBA. In an interview Monday, Katkin said the drug is taken once daily for the first seven days; and then twice daily. Avanir estimates the drug will run $3,000 to $5,000 a year, or about $250 a month. To assure that all patients who want the drug can get it, Avanir is establishing a co-payment assistance program capping the maximum amount that qualifying patients pay out-of-pocket.
Other patients with limited incomes will get the drug free through a patient assistance program, Katkin said. "These patients have stood by us through our clinical studies. We could not have made it to where we are at without them... if they qualify on the criteria, then they have access to free product for as long as they want to have and receive a prescription for it."
Avanir has other plans for Nuedexta, he said. "We think that PBA is just the first approval for Nuedexta." Clinical trials found that the drug reduced the pain of nerve damage from diabetes, called peripheral neuropathy. Katkin said it may prove useful in involuntary movements called dyskinesias, and could help with cognition in dementia. It also has potential in regulating other emotional disturbances, such as anger, irritability and frustration associated with many disorders, he said.
Katkin said he believes many physicians who recognized PBA may not have bothered to make a separate PBA diagnosis because they didn't have any targeted therapy to offer their patients. "It's our hope and expectation that with the first approved therapy, now doctors will be more comfortable making that diagnosis because they can offer a treatment option," he said.