We’ve only recently established the connection between brain injuries such as concussions and degenerative brain diseases like Alzheimer’s. We don’t fully understand yet why or how this is happening, and there’s not much we can do to prevent it now.
But help may well be on the way. There are three pharmaceuticals being tested that may reduce the amount of secondary brain damage that occurs right after the initial injury.
Potentially first out of the box is progesterone, with the results of its planned interim clinical study analysis expected sometime in 2013. Progesterone is best known as a reproductive hormone produced naturally in the body, but it’s also a powerful neurosteroid produced by the central nervous system. One study showed the glial cells naturally produced progesterone in the neurons of both men and women in the hours immediately after they had suffered severe traumatic brain injuries.
In two Phase II studies, the mortality rate among patients receiving pharmaceutical progesterone was approximately half of another group receiving only a placebo. Its manufacturer, BHR Pharma LLC is currently conducting a double-blind, placebo-controlled Phase III clinical trial on 1,180 severe TBI patients at about 150 sites in 20 countries to demonstrate that this pharmaceutical is effective in reducing injuries to the brain.
If the tests are successful, progesterone may “within a year or so, provide the basis for the first approved neuroprotective agent to treat severe TBI,” according to its manufacturer.
Not far behind is cyclosporine, which operates on the theory of the mitochondria, the tiny energy centers in the brain cells, are being destroyed by excess calcium. Cyclosporine has been used to prevent tissue rejection in organ-transplant recipients since the early 1980s, but a
Swedish firm, NeuroVive Pharma, has been working for nearly two decades to prove that its medicine, called NeuroSTAT, can also protect mitochondria in brain injuries.
After an injury to the brain, a protein called cyclophilin D enables pores in the mitochondria’s membrane to open, through which water seeps. The mitochondria fill up, pop and die, ending cellular energy production and killing the brain cell. However, cyclosporine inhibits the cyclophilin D from helping open the pores, thus preserving the mitochondria, according to NeuroVive Pharma. “As mitochondria survive to produce energy for the brain cell, fewer brain cells die during the secondary (injury) stage,” it said. “Protecting brain cell mitochondria and energy production is the critical front line in the war against TBIs.”
Earlier mouse-model studies showed an 80 percent reduction in neural damage through the use of cyclosporine, the company said. Another mouse-model study by researchers at the University of Rochester, published this year in Nature magazine, showed that too much cyclophilin led to Alzheimer’s-like symptoms, but that “the administration of cyclosporine inhibited cyclophilin’s actions and the Alzheimer’s symptoms were reversed,” according to the company. While NeuroVive is not targeting Alzheimer’s, the study shows the potential future importance of so-called cyclophilin inhibitors in treating many neurodegenerative diseases.
NeuroVive is conducting a Phase II/III trial in conjunction with the European Brain Injury Consortium and hopes to win regulatory approval in the United States and Europe within the next three to five years.
Finally, Neuren Pharmaceuticals and the Department of Defense are developing their own drug to prevent brain injuries from progressing into degenerative brain diseases. Called NNZ-2566, it’s basically an anti-inflammatory. “The drug is based on a very similar chemical that occurs naturally in the brain, but it has been altered in such a way that it stays in the body longer,” Neuren said. “NNZ-2566 was discovered by scientists at the University of Auckland in New Zealand who found that it had an ability to protect nerve cells from damage. Since 2004, scientists from the U.S. Army Walter Reed Army Institute of Research have been involved in research to show how NNZ-2566 reduces brain damage and seizures after TBI.”
It’s currently being tested in a 260-patient Phase II clinical trial at 13 hospitals in the United States, so it’s still several years out from approval.
If approved at all…. While drugs from all three companies show promise, more than 30 once-promising TBI pharmaceuticals have reportedly failed to show benefit in human Phase III studies and not won FDA approval. No TBI pharmaceutical has ever received approval for use in humans, but these three are closest to being the first.
With three recent studies linking concussions to future degenerative brain diseases, there’s one big question that combat vets, athletes and other brain-injury victims have to be asking themselves: “What may happen to our brains?”
It’s a critical question because we have to know how this disorder develops in order to know how to prevent it from progressing.
Unfortunately, all we have are theories at this time. But they are at least a starting point.
John Medina, author of the best-selling book, “Brain Rules,” has written extensively about some of the theories of chronic traumatic encephalopathy (CTE), and much of this column will be devoted to summarizing his findings in a 13-part series of posts on his blog site “Brainstorm”: http://blog.spu.edu/brainstorm/
Originally, we believed that the original brain injury was the cause of CTE. When our brains are shaken by roadside bombs in Iraq or head-on collisions with an oncoming linebacker, there is damage because the inside of our skull is just as hard as the outside. Nerve tissue is sheared by the blow or scraped against the inside of the skull, causing permanent damage.
But even permanent damage doesn’t explain the progressive nature of CTE, starting with headaches and leading to cognitive impairment and ultimately to dementia and death. What’s causing that?
One of the hallmarks of CTE is that the brain contains tangled knots of a protein called tau. This protein is a normal component of neurons. In fact, it has been compared to a food supply line that provides nutrients to the brain cells. When the supply line is interrupted, according to one theory, the brain cells begin to die from lack of nutrition.
But tau has another function, which is holding together the cell walls of neurons. When the tau begins to lump up, the cells walls lose their form and begin to collapse, then to leak. That allows a salty brine outside the neuron to invade the cells, damaging and ultimately killing them, according to a second theory.
A third theory involves a specialized group of cells called microglial cells. These are damage control officers that can migrate around your entire brain searching out problems like foreign organisms, damaged cells or localized injuries. Then they provide damage control by unleashing a whole host of chemical molecules, some of which destroy the invaders and some of which promote healing. However, the problem comes with the repeated injuries, according to this theory. The microglial cells, which had been partially activated from a previous injury, spring into action again and again. Finally, they adapt to repeated injuries by remaining partially activated all the time, a status known as “priming.” This may be a part of degenerative brain diseases.
Finally, a fourth theory involves mitochondria, the tiny energy centers within each brain cell. There’s some speculation that when the cells begin to leak after an injury, calcium comes seeping in. Mitochondria, which are tiny beanlike structures surrounding the cell’s nucleus and dotting its cell walls, begin trying to eat the calcium until they eventually fill up and pop. Without those tiny energy centers (you could think of them as batteries), the cell begins to die.
Obviously, researchers have much more work to be done. CTE could be a result of any of these processes, it could be a combination of any or all of them, or it could be a new mechanical function that we haven’t recognized yet.
So that complicates the next – and most critical – question: What, if anything, can we do to prevent CTE from progressing?
Words can’t convey the horror of the shootings at Sandy Hook Elementary School in Newtown, Conn. Every parent grieves for the lost lives, particularly those of the children, and is overwhelmingly sorry for their parents.
But it’s not only the deaths. Everyone in that school – teachers, aides and particularly the children – has been traumatized to some degree by this tragedy.
Early reports indicate that some of the children were told to close their eyes as they were led out of the school. That was an excellent idea. The less they saw and heard, the less damage there is likely to be.
The extent of that damage will vary from child to child. Some children are unusually sensitive, while others are more resilient to stress. Some children may have experienced previous trauma and be more susceptible to stress. Obviously, those who lost friends will be among the more devastated.
So these kids are going to need counseling for post-traumatic stress disorder because they have now seen the kinds of things that a combat vet sees. They may have only seen them once, but they’ve seen them at an unusually impressive age.
Parents will need to watch their children very carefully in the days and weeks to come, looking for changes in behavior.
One likely manifestation will be nightmares, or as some soldiers call them, “night terrors.” Keep your children close, keep them safe, and comfort them. Talk about their dreams and their fears and their feelings.
Watch for avoidance, not wanting to go near the school or even not wanting to go outside. Watch for unusual reactions to loud noises or sirens or uniforms.
Many victims of PTSD can’t handle the emotions, and they become numb or desensitized. It’s important … gently … to talk about those emotions because it’s dangerous to let them become bottled up. Bottling up bad emotions may result in bottling up good emotions, as well.
Another common symptom of PTSD is hyperarousal. For these kids, that would mean that they’re constantly alert to the possibility that something similar will happen again. They may be checking the hallways regularly to make sure that another guy with another gun isn’t coming back to finish the job.
Depression is common, as is anger. That’s a product of fear that comes from being in danger, espeially in a frightening situation over which they have no control.
This would be a good time to check the household for toys that might bring back bad memories. Guns and ambulances come to mind.
And it’s critical not to re-traumatize a child by allowing him or her to watch violence television shows, movies or video games. Children shouldn’t see those things anyway, but it’s important now to make sure children aren’t exposed to them.
Finally, understand that this is likely to be a problem that unfolds. It will take a while for kids to process what they’ve been through, so symptoms of PTSD may not show up for days or perhaps even weeks.
Veterans now face two daunting questions arising from a third study linking concussions with degenerative brain diseases, which can cause cognitive, behavioral and mood impairment – and ultimately death.
The newest study, another collaboration between Boston University and the Boston VA Healthcare System, found evidence of chronic traumatic encephalopathy (CTE) in 68 brains that had been donated to them posthumously. They included 64 athletes, including 18 who were also military vets, plus three additional vets without a sports background and one individual who was neither – he had a history of injurious head-banging behavior.
Among the athletes, 34 were professional football players. However, nine of the athletes had played only college football. And six had played only high school football.
But all showed the classic signs of CTE: tangled knots of a protein known as tau in the brain cells. These tau lesions can damage brain cells and ultimately lead to their death, according to Dr. Ann McKee, lead author of the study.
The study also added another new element. It concluded the CTE is a progressive disorder, and it divided CTE into four stages, each with its own distinctive symptoms. Headaches and deteriorating attention and concentration were common in stage one. In stage two, symptoms expanded to include depression, explosive outbursts, and short-term memory impairment. By stage three, victims were having trouble thinking and were having difficulty with executive functions like planning, organization, multitasking and judgment. Dementia , including memory loss and cognitive impairments severe enough to impact daily living, were characteristic of stage four.
It’s alarming to think that high school and college football players could be doing such damage to their brains that they would die early of degenerative brain diseases, but the study provided several examples: Eric Pelly, a former high school football and rugby player who died at the age of 18 from complications resulting from concussions and who was diagnosed with stage 1`CTE, and Ron Perryman, a former Boston College linebacker who died from respiratory failure associated with Amyotrophic Lateral Sclerosis (ALS) at the age of 42 and was diagnosed with both CTE and motor neuron disease (MND).
So there are two daunting questions that vets, athletes and anyone suffering from brain injuries need to ask.
First, how and why does an earlier injury lead to a possible degenerative brain disorder years later?
And second, what can we do to prevent it?
We’ll consider those questions in the next two parts of this series of columns.
Veterans are largely protected from being thrown off the “fiscal cliff” if the Republicans in Congress can’t reach a nonpartisan compromise with the Obama Administration.
Largely protected … but still not nearly enough.
Vets won’t get their benefits cut, says Rep. Jeff Miller, Fla., who chairs the House Committee on Veterans Affairs. “The good thing is that the law states and the president has agreed that veterans dollars and their benefits are off the table as it relates to the sequestration,” Miller explains. “The only area that the VA is vulnerable in is in some of the administrative areas or some of the areas that (the Department of Defense) actually handles, like Arlington Cemetery.”
That spares the VA from $1.2 trillion in sequestration cuts, but the problem is that the Veterans Administration is completely overwhelmed at the moment with the influx of Vietnam and current-era vets seeking help. Even with a budget that has doubled to $125.3 billion over the past decade, it can’t begin to handle more than 1 million new Iraqi-Afghan vets, about a third of whom are seeking mental health care.
“With as many as 1 million troops due to become veterans in the next five years, on top of the 22.3 million already in the system, the agency is staggering under backlogs in disability compensation claims, bottlenecks in mental health care, and criticism over a general lack of accountability,” Bloomberg News reported last month.
“The system is completely overwhelmed,” Craig Bryan, a clinical psychologist and associate director for the National Center for Veterans Studies at the University of Utah, told Bloomberg News. “We did not prepare the VA system for what many of us would argue is the natural consequence of combat and protracted warfare, and we’re trying to play catch-up.”
In mid-November, the VA had about 896,000 disability compensation and pension claims pending, almost double the number of cases pending at the end of October 2009. Two thirds of those claims had been in the system for more than 125 days, which is the agency’s target time to have such claims resolved.
Four months may not seem like a long time, but those delays are living hell to vets in physical and emotional pain. Dr. Bruce Swarny has patients who wait at least two months and drive 400 miles round trip to visit him in the Glendive (Mont.) Medical Center. He estimates that about half of them have contemplated suicide.
Montana leads the nation in the rate of suicide, but it’s also a huge problem nationally. The VA estimates that 18 vets a day take their own lives, and 1,600 to 1,800 veterans receiving VA care commit suicide each year, according to a 2011 report by the inspector general.
To understand why, just take a look at Fox Company, 2nd Battalion, 23rd Marine Regiment – a group of Marine Reservists from Salt Lake City. Tony Dokoupil tells their harrowing story in the Daily Beast.
They arrived in Baghdad a day before the statue of Saddam Hussein fell. As they walked into the city, they accepted flowers from women and patted children on the head. Then their radio operator was shot through the head, and they were in the midst of a withering crossfire. To protect themselves, they shot at everything that moved – and they killed a bunch of civilians, including women and children.
The Daily Beast reported that: “Although all the men in the unit came home alive, many came home changed. Within five years, one in four had been diagnosed with post-traumatic stress disorder. Today one in two of them carries debilitating psychic wounds, according to an estimate by the men. They are jobless, homeless, disposed to drugs and alcohol, divorced from their spouses, and cut off from their former selves. One made love to his girlfriend, the mother of his twin daughters, then immediately drowned her in a warm bath. If you ask the military and mental-health establishment what happened to the men of Fox Company, the answer is simple: they lived through ‘events that involved actual or threatened death,’ felt ‘intense fear,’ and like the 300,000 other service members who share this narrow official path to PTSD, they were badly shaken by it.”
Their full story is at http://www.thedailybeast.com/newsweek/2012/12/02/a-new-theory-of-ptsd-and-veterans-moral-injury.html?utm_medium=email&utm_source=newsletter&utm_campaign=cheatsheet_afternoon&cid=newsletter%3Bemail%3Bcheatsheet_afternoon&utm_term=Cheat%20Sheet. It’s a heart-breaking tale, but a must-read nonetheless.
That’s why it’s not enough just to have the VA protected from sequestration cuts. It must be strengthened and streamlined to provide care to the men and women that this country has put into harm’s way.
I also have to say that I’m personally outraged by the political posturing and the partisanship that I see each day in Washington. This isn’t about winning a jousting match with the Obama Administration. It’s about human lives.
A quarter century ago, when there still was some civility in Washington, D.C., former President Lyndon Baines Johnson made a remarkable point to his would-be biographer, Doris Kearns Goodwin. Johnson said: “A political party at a national convention draws up a program to present to the voters. The voters can either accept it by giving the party full power, reject it by taking the party completely out of power, or give it qualified approval by giving one party the Congress and the other party the presidency. And when we in the Congress have been given a qualified mandate, as we were in 1956, it means that we have a solemn responsibility to cooperate with the president and produce a program that is neither his blueprint nor our blueprint but a combination of the two. It is the politician’s task to pass legislation, not to sit around saying principled things.”
Well, that’s exactly what we have today: a Democratic president, a Democratic Senate, but a stanchly Republican House of Representatives. The only thing we lack today is Johnson’s “solemn responsibility to cooperate.”