Sunday, April 29, 2012

Little Evidence for a Direct Link between PTSD and Chronic Traumatic Encephalopathy

Fig. 2 (Omalu et al., 2011). Photomicrographs of tau-immunostained section of the frontal cortex.


Nicholas Kristof wrote an op-ed piece in the New York Times the other day about an Iraq War veteran with post-traumatic stress disorder (PTSD) and alcohol use problems who ultimately took his own life.
Veterans and Brain Disease

By NICHOLAS D. KRISTOF
Published: April 25, 2012

He was a 27-year-old former Marine, struggling to adjust to civilian life after two tours in Iraq. Once an A student, he now found himself unable to remember conversations, dates and routine bits of daily life. He became irritable, snapped at his children and withdrew from his family. He and his wife began divorce proceedings.

This young man took to alcohol, and a drunken car crash cost him his driver’s license. The Department of Veterans Affairs diagnosed him with post-traumatic stress disorder, or P.T.S.D. When his parents hadn’t heard from him in two days, they asked the police to check on him. The officers found his body; he had hanged himself with a belt.

This tragic but all-too-common story had an unusual ending. An autopsy of the veteran's brain revealed signs of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease seen most often in athletes with repeated concussions from contact sports such as professional football and boxing. CTE results in cognitive and behavioral changes including memory impairments, poor impulse control, alterations in mood, suicidal behavior, disorientation, and ultimately dementia (Lakhan & Kirchgessner, 2012).

Diagnosis of CTE is usually post-mortem, because the brain tissue has to be stained for characteristic protein abnormalities which cannot be visualized in a living human. A defining pathological feature is tauopathy - abnormal accumulations of the tau protein seen in other dementias (e.g., Alzheimer's disease). In particular, aggregations of hyperphosphorylated tau into neurofibrillary tangles and accumulations of neuronal TAR DNA-binding protein-43 (TDP-43) are seen, as in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (Lakhan & Kirchgessner, 2012).

There have been a string of high profile media reports about CTE pathology found at the autopsy of several American football players: Mike Webster, Terry Long, Chris Henry, Tom McHale, Owen Thomas, and others. Dr. Bennett Omalu and his colleagues at the Brain Injury Research Institute have conducted some of these autopsies (e.g., Omalu, Bailes et al., 2011).1

Now, Omalu and colleagues have put forth the speculative idea that PTSD is on a continuum with CTE (Omalu, Hammers et al., 2011). Why? PTSD needn't be associated with concussions or traumatic brain injury (TBI) at all. The traumatic event exposure for PTSD (from DSM-IV-TR) "...must have involved both (a) loss of 'physical integrity', or risk of serious injury or death, to self or others, and (b) a response to the event that involved intense fear, horror, or helplessness (or in children, the response must involve disorganized or agitated behavior)." Head injury isn't part of the definition.

Omalu's target population is soldiers and veterans with TBI from the war (not, for instance, survivors of the 2011 earthquake and tsunami in Japan):
Following our elucidation of CTE in athletes, we hypothesized that PTSD in war veterans may belong to the CTE spectrum given that active military personnel are high-risk cohorts for repeated subconcussive and concussive traumatic brain injuries; for example, bomb blasts can cause traumatic brain injuries from primary pressure wave and acceleration-deceleration injury mechanisms. We expanded our CTE surveillance and brain tissue analyses to include deceased military veterans who were diagnosed with PTSD.

OK, that sounds reasonable -- if there's well-documented evidence of subconcussive and concussive brain injuries. Which brings us back to Kristof's article:
That Marine was the first Iraq veteran found to have C.T.E., but experts have since autopsied a dozen or more other veterans’ brains and have repeatedly found C.T.E. [NOTE: none of these cases has been published.] The findings raise a critical question: Could blasts from bombs or grenades have a catastrophic impact similar to those of repeated concussions in sports, and could the rash of suicides among young veterans be a result?

“P.T.S.D. in a high-risk cohort like war veterans could actually be a physical disease from permanent brain damage, not a psychological disease,” said Bennet Omalu, the neuropathologist who examined the veteran.

Oh no! Here we have an unfortunate example of mind-body dualism. PTSD is a physical brain disease, and this is independent of exposure to bomb blasts. There is ample evidence that exposure to traumatic events can physically change the brain (Sapolsky, 1996, 2001). Stress increases the levels of glucocorticoids, which in turn damage the hippocampus. This is visible on MRI scans (Bremner, 2006). The amygdala, a subcortical area involved in processing fear and other emotions, is overactive in those with PTSD while frontal lobe regions controlling the amygdala are underactive (Koenigs & Grafman, 2009).

However, it needn't result in permanent brain damage! In his 2006 review, Bremner notes that effective PTSD treatments can improve memory and restore hippocampal volume.

With this background in mind, let's return to the case report of the 27 yr old Marine. I believe there could be causes of CTE pathology that are unrelated to his military service in Iraq. I'll introduce these items as bullet points and then go into detail about each.
  • Committed suicide by hanging.
  • After deployment, played football in a league on base.
  • One hit from the side caused him to fall to the ground; after this, he was confused and showed signs of a concussion [in my view].
  • He continued to play football and hockey but was not diagnosed with a concussion (although he suffered his “bell rung”).
  • Motor vehicle accident under the influence of alcohol, flipped his car, woke up later hanging upside down in the car.

Any or all of these incidents might have injured his brain in a way that could result in (or at least exacerbate) CTE, yet the authors either dismissed them as insignificant or minimized their impact. I am not a neuropathologist so I won't address the actual autopsy findings at this point. However, I do believe there are legitimate questions about the cause(s) of CTE in this Marine, as outlined below.
  • Suicide by hanging - this causes anoxia, or a lack of oxygen to the brain. Anoxia causes permanent damage and shrinkage of certain brain regions. It also produces astrogliosis, which was reported in the present case study. But can it cause any of the other microscopic neuropathological findings? Perhaps not, but a few relevant papers are listed in the Appendix.
  • Football - this is a classic cause of CTE. The Marine suffered at least one concussion after his service in Iraq (described below) and had his "bell rung" a number of times (possible subconcussive events):

After his deployments he was stationed at a base and played football in a base league. During a football game in 2009, approximately 9 months after his second deployment, he reported being hit from the side causing him to fall to the ground. He stood up, stumbled, fell again, and then continued the game. Other players noticed that he was confused and kept asking the count and details of the next play and he had to be removed from the game. The events of the following week were unclear and he reported residual headaches and memory problems.

There were no significant findings on a conventional CT scan, but this is standard (as the authors themselves have noted).
  • The Marine also had a remote injury that resulted in a nasal bone fracture and other possible blows to the head before and after deployment. Yet the authors speculate:

It is our belief that his eventual CTE risk outcome occurred as a result of his lifetime and cumulative exposure to repeated subconcussive and concussive traumatic brain injuries, with his military exposures being the primary injuries that precipitated CTE.

Very little information is provided about his history of blast exposures in Iraq so it seems highly speculative to attribute CTE to those events primarily.
  • Motor vehicle accident
He woke up later hanging upside down in the car. It was not clear whether he lost consciousness from a head injury or from stuporous alcohol intoxication. He noted the following morning that he suffered from headaches and vomited; however, it was not also clear whether these symptoms were alcohol-related or head injury–related. He lost his driver's license after this crash for driving under the influence and refusing a blood-alcohol test.
But the loss of consciousness, headaches, and vomiting could very well be due to a TBI or concussion he suffered in the car accident!


Military Service:
  • Reported exposures to mortar blasts and IED blasts less than 50 m away (but was never diagnosed with TBI)
  • During the second deployment he was court marshaled twice for acting out, insubordination, fighting, hazing, and assault, and was dropped 1 rank.
  • "Described only a few incidents during his deployment that he found bothersome":

There was an incident during the 3rd week of his first deployment when he witnessed a vehicle in his patrol blown up, and marines killed and wounded. In another incident, approximately 2 weeks later, while hooking up their disabled vehicle to tow, 2 marines in his section were shot and he helped to patch them up. In yet another incident, he witnessed a school bus full of Iraqi citizens, many of whom were children, blown up by an IED.

  • Diagnoses: PTSD with hyperarousal (irritability and insomnia) and numbing. Also alcohol abuse... In a clinic visit 2 months prior to his suicide, he reported persistent PTSD symptoms.

He visited a Veteran Affairs Medical Center the day before he committed suicide and reported having a new job as a football coach with his old high school, and was currently attending a community college. His driving under the influence charges had been dismissed.

This is certainly a very tragic case study, and I'm in favor of autopsies to consider possible causes of suicides in military veterans. But to speculate that PTSD is a permanent degenerative brain disease on the basis of one published case,2 without adequate explanation and appropriate caveats, is irresponsible and damaging.


Let's return to Kristof's opinion piece:

The discovery of C.T.E. in veterans could be stunningly important. Sadly, it could also suggest that the worst is yet to come, for C.T.E. typically develops in midlife, decades after exposure. If we are seeing C.T.E. now in war veterans, we may see much more in the coming years.

So far, just this one case of a veteran with C.T.E. has been published in a peer-reviewed medical journal. But at least three groups of scientists are now conducting brain autopsies on veterans, and they have found C.T.E. again and again, experts tell me. Publication of this research is in the works.

The finding of C.T.E. may help answer a puzzle. Returning Vietnam veterans did not have sharply elevated suicide rates as Iraq and Afghan veterans do today. One obvious difference is that Afghan and Iraq veterans are much more likely to have been exposed to blasts, whose shock waves send the brain crashing into the skull.


Kristof must not have read Omalu et al. very closely, because in that paper they described an earlier autopsy conducted on a Vietnam veteran who died of natural causes.

In 2010 we encountered CTE changes in the brain of a 61-year-old deceased Vietnam war veteran, who died suddenly as a result of coronary atherosclerotic disease. This case was reported in the Stars and Stripes news magazine of the Department of Defense. The case was not published because we did not have comprehensive access to the medical records and family and social histories.

Yes, that study was presented in Stars and Stripes, a military newspaper:

“This is a sentinel case,” Omalu said. “The brain findings in this deceased Army veteran are similar to the brain findings in the retired contact-sport athletes. Now, we need to look at more brains.”

The case suggests that some veterans diagnosed with post-traumatic stress disorder, a psychological disorder, may actually have brain disease caused by concussions, he said.

...and why don't we go ahead and speculate about TBI even though there are no records of such:

Though he cannot prove the veteran suffered head trauma from blasts in combat, Omalu said it’s possible, because the former soldier had never shown any signs of psychotic behavior or drug use prior to going to Vietnam, according to family members and medical records.

It's also possible that the veteran was traumatized by events in Vietnam and started using stimulant drugs, which can cause psychotic behavior. Returning to case published in Neurosurgical Focus:
The authors report this case as a sentinel case of CTE in an Iraqi war veteran diagnosed with PTSD to possibly stimulate new lines of thought and research in the possible pathoetiology and pathogenesis of PTSD in military veterans as part of the CTE spectrum of diseases, and as chronic sequelae and outcomes of repetitive traumatic brain injuries.
Now that's a study for Medical Hypotheses, isn't it?

But seriously, I'm not denying CTE "as chronic sequelae and outcomes of repetitive traumatic brain injuries." And I mean absolutely no disrespect to the veterans and families who are affected by PTSD, concussions, and perhaps CTE in some cases.

Kristof again:

Frankly, I was hesitant to write this column. Some veterans and their families are at wit’s end. If the problem in some cases is a degenerative physical ailment, currently incurable and fated to get worse, do they want to know?

I called Cheryl DeBow, a mother I wrote about recently. She sent two strong, healthy sons to Iraq. One committed suicide, and the other is struggling. DeBow said that it would actually be comforting to know that there might be an underlying physical ailment, even if it is progressive.

“You’re dealing with a ghost when it’s P.T.S.D.,” she told me a couple of days ago. “Everything changes when it’s something physical. People are more understanding. It’s a relief to the veterans and to the family. And, anyway, we want to know.”


What would I tell Ms. DeBow? That PTSD is indeed a physical brain disease. It's not a ghost. And it isn't necessarily permanent.

Yes, it's easier to understand a brain injury that is caused by a physical force outside the head, instead of by a state of turmoil, sadness, and grief inside the head. But PTSD is a physically real injury nonetheless.


Footnotes

1 The other major CTE research group is the Center for the Study of Traumatic Encephalopathy at Boston University (e.g., McKee et al., 2009).

2 Yes, Kristof keeps mentioning other unpublished cases. Perhaps I'll amend this post or do a follow-up once they're published. Or even if I find them online in abstract form.

UPDATE (May 17, 2012): A new paper by Goldstein et al., 2012 reports on 4 new cases of CTE in military veterans, linking the pathology to blast exposure. However, 3 of the 4 also had concussions from other events. See Blast Wave Injury and Chronic Traumatic Encephalopathy: What's the Connection?


References

Bremner JD. (2006). Traumatic stress: effects on the brain. Dialogues Clin Neurosci. 8:445-61.

Koenigs M, Grafman J. (2009). Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala. Neuroscientist 15:540-8.

Lakhan SE, Kirchgessner A (2012). Chronic traumatic encephalopathy: the dangers of getting "dinged". SpringerPlus 1:2 doi:10.1186/2193-1801-1-2.

McKee AC, Cantu RC, Nowinski CJ, Hedley-Whyte ET, Gavett BE, Budson AE, Santini VE, Lee HS, Kubilus CA, Stern RA. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 68:709-35.

Omalu B, Bailes J, Hamilton RL, Kamboh MI, Hammers J, Case M, Fitzsimmons R. (2011). Emerging histomorphologic phenotypes of chronic traumatic encephalopathy in American athletes. Neurosurgery 69:173-83; discussion 183.

Omalu B, Hammers JL, Bailes J, Hamilton RL, Kamboh MI, Webster G, & Fitzsimmons RP (2011). Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurgical focus, 31 (5) PMID: 22044102

Sapolsky RM. (1996). Why stress is bad for your brain. Science 273:749-50.

Sapolsky RM. (2001). Atrophy of the hippocampus in posttraumatic stress disorder: how and when? Hippocampus 11:90-1.


Appendix

Anoxia/hypoxia:

Acute hypoxia promote[s] the phosphorylation of tau via ERK pathway - hyperphosphorylated tau is a hallmark of CTE, but it did not appear to result in neurofibrillary tangles in this case.

Morphological analysis of astrocytes in the hippocampus in mechanical asphyxiation

Pathological role of hypoxia in Alzheimer's disease - mostly about amyloid beta, not tau.

TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system - did not exhibit TDP-43 inclusions, however.

[NOTE: It could have been that the cause of death was entirely irrelevant, but a statement to that effect would be reassuring.]

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4 Comments:

At May 02, 2012 10:47 AM, Anonymous Anonymous said...

Very good, I like this post because it is done as a scientific report explaining the various theories and leaves room for opposing theories. Thus far I've enjoyed your blog very much, thank you!

 
At May 17, 2012 11:08 AM, Blogger David Dobbs said...

So glad you took this up. My BS filter went off loud when I saw that Kristof piece, but I had no time to run this down. Nice job doing so.

 
At May 17, 2012 11:22 AM, Anonymous JM said...

Good post, but with a strong reductionist bias, e.g.: "PTSD is a physical brain disease".
Actually, it is better understood as a psychological pathology, and treated as such.
This does not make it 'less real' at all.

 
At May 17, 2012 2:00 PM, Blogger The Neurocritic said...

Thanks, David. In light of the new findings on CTE reported yesterday in the NYT and elsewhere, I'm writing a new post and will have a short addendum to this one.

JM - Saying that a disease ultimately has a physical basis isn't necessarily reductionist, unless you're a mind/brain dualist. Psychological and physical insults both cause changes to the brain, and the brain is just as responsible for behavior in both cases. Saying that trauma changes the brain doesn't mean that psychotherapies aren't helpful for treating PTSD, either.

My point was that some military veterans and their families are more willing to accept that an explosion or concussion caused the behavioral changes, rather than witnessing (or perpetrating) death and destruction.

 

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