Depression, PTSD in Women Tied to Subsequent Dementia

Women with depression or posttraumatic stress disorder (PTSD) or who have experienced a traumatic brain injury (TBI) are at increased risk for subsequent dementia, new research suggests.

A cohort study of more than 100,000 female veterans showed that those who had one of these “military-related risk factors” at baseline were 50% to 80% more likely to develop dementia 4 years later than women without PTSD, TBI, or depression.

The findings were even more dire for those who had two or more of these risk factors, such as TBI with depression. For those women, the risk for developing dementia was doubled.

“These ‘military-related risk factors’ aren’t unique to the military, but military veterans have a probably 3 to 5 [times] greater chance of these exposures,” lead author Kristine Yaffe, MD, San Francisco Veterans Affairs (VA) Medical Center and Departments of Psychiatry, Neurology, and Epidemiology & Biostatistics at the University of California, San Francisco, told Medscape Medical News.

“This is the first study that I’m aware of looking at older women veterans and trying to understand what the risks are for getting dementia. And we think the findings are quite robust and important,” she added.

Dr Kristine Yaffe

Yaffe noted that the results may also be generalizable to nonveteran women.

“I think the biology is not different whether you’re a veteran or not. The difference here is just in the exposure. If you’re a military veteran, your chances are much higher you’ll be exposed” to these risk factors, she said.

The findings were published online November 12 in Neurology.

Disparity in the Field

Although past research has shown a significant link between dementia and TBI, PTSD, or depression, these studies “have been conducted almost exclusively among men,” the investigators write.

“This is a considerable disparity in the field, especially because more women are joining the military and female veterans may be at greater risk for certain psychiatric conditions compared to male veterans,” they add.

“It turns out that there is very little known about women veterans, particularly the older women. They just haven’t been asked to be part of research in any topic really,” said Yaffe.

For the current study, “we actually identified every female veteran who was 55 or older and who was getting their care at the VA,” she reported.

The investigators then assessed records from the National Patient Care Databases and the Vital Status File database for 109,140 female veterans who sought care from a US VA medical center between October 2004 and September 2015.

All of the included study participants (mean age, 68.5 years) completed at least one follow-up visit and were assessed at baseline for TBI, PTSD, depression, and comorbid conditions on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.

At baseline, 488 of the women had TBI only, 1363 had PTSD only, 20,410 had depression only, 5044 had more than one military-related risk factor, and 81,835 had none of these risk factors.

ICD-9-CM codes from the 2016 version of the VA Dementia Steering Committee were used to determine dementia prevalence at baseline and dementia incidence at follow-up.

Increased Dementia Risk

During a mean follow-up of 4.0 years, 4% of the study participants developed dementia.

After adjusting for demographics and comorbid conditions such as diabetes mellitus, hypertension, and alcohol and tobacco use, there was a significantly greater risk for developing dementia in the women with vs without the following conditions:

  • PTSD: adjusted hazard ratio (HR), 1.78; 95% confidence interval [CI], 1.34 – 2.36;
  • Depression: HR, 1.67; 95% CI, 1.55 – 1.80; or
  • TBI: HR, 1.49; 95% CI, 1.01 – 2.20.

The investigators note that the finding that having a TBI increased dementia risk by 50% parallels “estimates from our prior study of male veterans in which TBI was similarly associated with a 60% increase in the risk of dementia.”

As for the almost 80% increased risk for dementia in the women with PTSD, “this is consistent with other investigations in male veterans that report an increase in risk of 80% to 100%,” the researchers write.

“There is [also] a robust body of evidence to support depression as a risk factor for developing dementia with studies in both community-based populations of women and (mostly male) veterans,” they add.

Yaffe noted that although their findings showed the highest risk for PTSD, followed by depression, and then TBI, “a ratio of 1.5 vs 1.8 may not be statistically different from one another. All three of the risk factors are important — and they often go together.”

The rates of incident dementia in those with TBI, depression, or PTSD only were 5.7%, 5.2%, and 3.9%, respectively, compared with 3.4% of the women who had no military-related risk factors (all comparisons, P < .001).

The incident dementia rate was 3.9% in the women who had more than one military-related risk factor; and their adjusted HR for dementia was 2.15 compared with those with none of the risk factors (95% CI, 1.84 – 2.51).

“These findings highlight the need for increased screening of TBI, PTSD, and depression in older women, especially female veterans,” the investigators write.

“If women have a history of PTSD or depression, they probably should be followed more closely and given periodic screening for their memory and other cognitive aspects as they get older,” Yaffe added.

In addition, these risk factors “are something we can maybe do something about. Certainly you can try to prevent traumatic brain injury with helmets and seat belts, and hopefully you can try to better treat PTSD and depression. And maybe all of this could actually decrease risk of dementia,” she said.

She noted that the study isn’t saying that an individual with one of these risk factors will definitively develop dementia. “It means that it increases your risk but it’s not a 1-to-1 correlation,” said Yaffe.

“Clear Need for More Studies”

In an accompanying editorial, Andrea L.C. Schneider, MD, PhD, and Geoffrey Ling, MD, PhD, from the Department of Neurology at Johns Hopkins University School of Medicine, Baltimore, Maryland and the Uniformed Services University of the Health Sciences, Bethesda, Maryland, note that although the study provides new evidence, it “also highlights that there is a clear need for more studies.”

They also point out that the “important findings” need to be confirmed and that causality needs to be determined.

“Future studies will need to include both men and women to assess directly for possible interaction by sex in associations between TBI, PTSD, and depression and dementia risk. Indeed, animal studies suggest sex differences in response to TBI and sex differences in the neurobiology of PTSD and depression,” they write.

“Given this, it is possible that neuropsychiatric conditions may be differentially associated with dementia risk in men vs in women,” they add.

The editorialists note that the study also relied only on ICD-9-CM codes to define the military-related risk factors and dementia — and that these codes are less sensitive than diagnostic interviews.

“It follows that a higher number of encounters with the health care system would make an individual have more opportunities to receive a diagnosis,” they write.

Overall, “a great deal more remains to be learned about the associations, underlying mechanisms, and possible sex differences in associations relating neuropsychiatric conditions…with dementia, both in military veteran populations and in general populations,” write Schneider and Ling.

“But importantly, the study by Yaffe et al. suggests that associations of TBI, PTSD, and depression with increased risk of dementia also occur in female military veterans and are not unique to male military veterans,” they conclude.

Blood Test for Concussion OK’d

Helps inform management, including decision on whether CT scan is indicated

 A blood test aimed at guiding management of patients suspected of having concussion won FDA approval on Wednesday, the agency said.

The test, which measures levels of two proteins in blood, does not by itself provide a firm yes/no as to whether a patient has suffered a brain injury. Rather, it’s an indicator of the likelihood that a CT scan will show intracranial lesions, and hence may be valuable in deciding whether CT scans are indicated.

Currently, it’s routine to order a CT scan for all patients with suspected closed head injuries, the FDA noted, but most scans do not show detectable lesions. The blood test is thus expected to cut down on these unhelpful scans and the associated radiation exposure.

Developed by Banyan Biomarkers, the Brain Trauma Indicator test is a quantitative assay for ubiquitin carboxy-terminal hydrolase L1 and glial fibrillary acidic protein, which are released into the blood following neural injury. The test should be performed within 12 hours of injury; results are available in 3-4 hours, the FDA said.

Trial data involving nearly 2,000 individuals with with suspected concussion or mild traumatic brain injury (mTBI) showed that the test was 97.5% accurate in identifying those with visible lesions on CT scans, and 99.6% accurate in predicting those who did not show such lesions.

“These findings indicate that the test can reliably predict the absence of intracranial lesions and that healthcare professionals can incorporate this tool into the standard of care for patients to rule out the need for a CT scan in at least one-third of patients who are suspected of having mTBI,” the agency said.

Brain-damaging vaccines, pesticides and medicines generate nearly $800 billion a year in medical revenues.

‘The current estimated annual cost for nine of the most common neurological disorders in the U.S. was a hefty $789 billion, a recent paper revealed. According to the paper, these conditions include Alzheimer’s disease and other forms of dementia, traumatic brain injury and Parkinson’s disease, as well as epilepsy, multiple sclerosis, and spinal cord injury.

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Researchers also projected that health care costs associated with brain damage will continue to increase as the number of elderly patients were expected to double between 2011 and 2050. Data showed that medical costs related to dementia and stroke alone were estimated to be more than $600 billion by 2030.

“The findings of this report are a wake-up call for the nation, as we are facing an already incredible financial burden that is going to rapidly worsen in the coming years. Although society continues to reap the benefits of the dramatic research investments in heart disease and cancer over the last few decades, similar levels of investment are required to fund neuroscience research focused on curing devastating neurological diseases such as stroke and Alzheimer’s, both to help our patients and also to avoid costs so large they could destabilize the entire health care system and the national economy,” said lead author Dr. Clifton Gooch, reports.’

fMRI finds changes in brain connectivity can help diagnose and predict outcomes of mild TBI

A new study shows that patients with mild traumatic brain injury (mTBI), even without evidence of brain lesions, may exhibit changes in brain connectivity detectable at the time of the injury that can aid in diagnosis and predicting the effects on cognitive and behavioral performance at 6 months. Brain connectivity maps showed differences between patients with mTBI and healthy controls, including different patterns depending on the presence of brain lesions, as reported in an article in Journal of Neurotrauma, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Neurotrauma website until March 23, 2017.

The article entitled “Resting-State Functional Connectivity Alterations Associated with Six-Month Outcomes in Mild Traumatic Brain Injury” describes the prospective multicenter TRACK-TBI pilot study. Eva Palacios and coauthors from University of California, San Francisco, San Francisco General Hospital and Trauma Center, University of Texas, Austin, University of Pittsburgh Medical Center (PA), Virginia Commonwealth University (Richmond), Icahn School of Medicine at Mount Sinai (New York, NY), and Antwerp University Hospital (Edegem, Belgium) concluded that resting state functional magnetic resonance imaging (MRI) to assess brain connectivity and compare spatial maps of resting state brain networks can serve as a sensitive biomarker for early diagnosis of mTBI and later patient performance.

“While, as the authors acknowledge, they are not the first group to explore the utility of resting state functional MRI in probing the morbidity associated with mild traumatic brain injury, they do elegantly capitalize on the TRACK-TBI study population to critically evaluate functional connectivity in a patient population that is well characterized and followed by traditional imaging approaches,” says John T. Povlishock, PhD, Editor-in-Chief of Journal of Neurotrauma and Professor, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond. “Their finding of altered patterns of functional connectivity even in that mild TBI patient population, revealing no CT/MRI abnormalities, is an extremely important observation, as is the fact that these same changes in functional connectivity portend the development of a persistent post-concussive syndrome.”

Dexmedetomidine as an adjunct for sedation in patients with traumatic brain injury

BACKGROUND: In patients with traumatic brain injury (TBI), optimizing sedation is challenging because maintaining a clinical examination is important in being able to detect neurological deterioration. Propofol (PROP) is frequently used as a sedative in TBI since it has been shown to reduce the cerebral metabolic rate, but it may lead to PROP-related infusion syndrome and hemodynamic compromise. Dexmedetomidine (DEX) is a sedative that produces minimal respiratory depression with opioid-sparing effects. The purpose of this study was to determine whether sedation with DEX would be safe in patients with severe TBI.

METHODS: This prospective observational single-center study was conducted from 2011 to 2013. Patients with severe TBI were treated according to standard of care per the Brain Trauma Foundation guidelines. Sedative agents were titrated using the Richmond Agitation Sedation Scale (RASS) while maintaining intracranial pressure of less than 20 mm Hg and cerebral perfusion pressure of greater than 60 mm Hg. The primary outcome measure was the mean time in target RASS (0 = alert and calm to −2 = light sedation).

RESULTS: A total of 198 patients were enrolled in the study. Patient-days (1,028 in total) were stratified into four groups: DEX only (n = 222), DEX + PROP (n = 148), PROP only (n = 599), and NEITHER (n = 59). Regression analyses indicated a significant difference in target RASS between sedative agents (p = 0.001). The DEX-only group had the highest adjusted mean daily estimate of 16.0 hours in target RASS. Hypotension was significantly higher in both the DEX only (p = 0.01) and DEX + PROP (p = 0.01) groups than in the PROP-only group.

CONCLUSIONS: Dexmedetomidine was found to be associated with significantly more hypotension. Therefore, larger studies are needed to identify the role of DEX in TBI.

Neuroimaging May Predict Recovery After Mild TBI

Researchers believe it may be possible to use neuroimaging to predict which patients with mild traumatic brain injury (mTBI) have a better chance of recovery.

Their study showed that patients with abnormally high fractional anisotropy (FA), as seen on diffuse tensor imaging (DTI) at the time of their injury, are more likely to have a good outcome.

The results could affect the development and targeting of treatments for patients after concussion, said author Michael L. Lipton, MD, PhD, associate director, Gruss Magnetic Resonance Research Center, Albert Einstein College of Medicine, Bronx, New York.

“Developing an effective intervention requires first identifying the people who need it,” said Dr Lipton, adding that most patients recover within a few months of a concussion with no intervention.

The study was published online June 9 in the American Journal of Neuroradiology.

The study included 39 adult patients (mean age, 38.5 years), who were evaluated in an emergency department and diagnosed with a concussion within 48 hours of their injury. Those with a previous concussion were excluded from the study.

The analysis also included 40 healthy volunteers. Patients and controls had similar preinjury intellectual functioning.

Study participants underwent DTI within 16 days of their injury. The healthy controls provided comparison imaging to allow the identification of abnormal FA.
FA is a measure of microstructural organization, Dr Lipton notes. “It’s a feature of what is sometimes called structural connectivity, but it per se does not really speak to the functionality of the connection but speaks to the presence of normally structured white matter.”

White Matter Regions

The researchers selected nine white matter regions known to be susceptible to mTBI and/or linked to functions associated with mTBI morbidity. These included the left and right frontal lobe, left and right temporal lobe, left and right thalamus, left and right cerebellum, and corpus callosum.

For each patient with mTBI, researchers developed an “EZ-MAP” to detect microstructural abnormalities. They separated these maps into images showing abnormally high FA (hFA) and abnormally low FA.

Cognitive function was assessed at 1 year by using the IntegNeuro, a computerized battery of tasks, with a summary z-score computed for each of the three domains (executive function, episodic memory, and attention).

Also at 1 year, researchers assessed postconcussion symptoms using the Rivermead Post-Concussive Symptom Questionnaire. On this instrument, patients rate the severity of 16 symptoms, with symptoms being categorized into cognitive, somatic and emotional factors.

As well, investigators measured health-related quality of life using the Sickness Impact Profile. On this scale, patients grade various aspects of daily functioning. The tool includes a physical dimension, psychological dimension, and social dimension.

The analysis included 26 of the patients with mTBI who returned for the 1-year follow-up. Six of the 26 had moved and were unavailable for onsite computerized assessments but completed the Rivermead and Sickness Impact assessments by phone.

The study showed that brain-wide imaging measures were significantly associated with memory performance at 1 year but not with attention or executive function. Mean FA, radial diffusivity, and mean diffusivity were significantly associated with health-related quality of life.

Researchers found several significant differences in 1-year assessments between participants with and without hFA in various white matter regions. For tasks of attention, those with hFA in the left frontal lobe performed significantly better (P = .008), as did those with hFA in the left temporal lobe (P = .004).

Participants with hFA in the right thalamus had significantly fewer emotional postconcussion symptoms (P = .003). Those with hFA in the left cerebellar white matter and those with hFA in the right cerebellar white matter had significantly fewer somatic postconcussion symptoms (P = .003 for both).

“We found that the presence of abnormally high FA was a predictor of better outcome,” said Dr Lipton.

He noted that the better outcomes were not just for cognitive function but also for “emotional function and what we call health-related quality of life.”

Patient characteristics did not seem to explain which participants had hFA and fared better.

“We looked at a whole range of characteristics, including age, sex, education, IQ, premorbid medical problems, and none accounted in any systematic way for the differences,” said Dr Lipton.

Brain Compensation

The researchers believe that areas of hFA may represent evidence of the brain compensating for the injury.

“The way the brain recovers from, or responds to, injury is through mechanisms like neuroplasticity,” said Dr Lipton. “What we are proposing here is that the areas of high FA that we are seeing may actually represent areas of compensatory or neuroplastic responses, not the actual injury itself.”

He stressed that the study group was small and the number of factors examined “limited.”

He also pointed out that there were also some areas of abnormally low FA.

To better understand the relationship between what’s going on in the brain at the time of the injury and long-term outcomes, researchers could use a similar approach to examine other groups of patients, said Dr Lipton.

If that supports the idea that hFA at the time of injury is a predictor of better outcome, it might change the focus of treatments for TBI, he said.

To date, most of that focus has been on trying to “fix the injury,” but it might prove more fruitful to enhance the compensatory mechanisms that are involved.

Dr Lipton used the example of stimulants, which are sometimes used to treat TBI. These drugs, he said, are believed to “ramp up” areas of the brain to compensate for dysfunctional networks elsewhere (as in attention-deficit/hyperactivity disorder).

Perhaps this and other treatments could be “revisited” in patients, such as those in the study with abnormal FA and less positive outcomes, who could potentially benefit.

But Dr Lipton stressed that researchers first have to better understand the mechanism of dysfunctional networks involved in TBI.

Another Notch

Asked to comment, Francis X. Conidi, MD, Florida Center for Headache and Sports Neurology, Port St Lucie, said this was “another good study supporting the use of DTI” in traumatic brain injury, or “another notch in the belt for DTI.”

 While other experts feel there’s not yet enough research on DTI, he said, “I’m a huge supporter of it; I think it’s the best biomarker for TBI.”

However, he noted some things he would have liked to have seen in the study. “I would have used more formal neuropsychological testing; I’m not a big fan of computerized testing.”

And he said he would have used “more of a symptoms checklist” to look for correlations between symptoms and FA values. “I would have liked to have known if headache, for example, is the more common problem.”

 A genetic component might help explain why some people with mild head trauma go on to have permanent sequelae while others recover with no problems, according to Dr Conidi.

“Maybe that’s what they’re seeing here,” he said. “That higher FA value may be a genetic response to the injury and that’s maybe why they have a better outcome.”

Blast TBI May Do Distinct Damage in Brain

Specific astroglial scar pattern seen in postmortem exams

Soldiers who sustain a blast traumatic brain injury (TBI) have a distinct pattern of astroglial scarring in their brains, which may account for the neurological and psychiatric symptoms that often accompany these injuries, researchers found.

In a postmortem analysis of brains from eight military personnel who survived explosive attacks — grenades, mortars, improvised explosive devices — all had astroglial scarring in the subpial glial plate, penetrating cortical blood vessels, grey-white matter junctions, and structures lining the ventricles, according to Daniel Perl, MD, of the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues.

None of the comparison cases — men with impact TBI, opiate use, or healthy controls — had any astroglial scarring in those areas, they reported online in Lancet Neurology.
“We believe this is the brain attempting to repair the damage produced during the exposure to the blast,” Perl told MedPage Today. “This pattern of scarring is exactly what biophysicists who study the effects of a blast wave on a biological structure would have predicted for the brain when they looked at our data.”
Blast TBI is thought to produce different damage in the brain than impact TBI, the kind of head injury currently in the spotlight because of concussions among football players and the probable link to chronic traumatic encephalopathy (CTE). Blast TBI occurs when a wave of compressed air, traveling faster than the speed of sound, propagates intense pressure and energy through the body, including the brain.
“It interacts with whatever it happens upon, including the service members who are standing in the range of the explosion,” Perl said. “Others have shown that a blast wave can penetrate the skull, and can be measured inside an intact skull. So it makes sense that it may damage the brain.”
Although soldiers with blast TBI often develop persistent neurological and psychiatric symptoms — including post-traumatic stress disorder (PTSD), headache, sleep disturbance, and memory problems — few brain abnormalities show up on conventional neuroimaging.

To get a better handle on the pathology, given that some 300,000 U.S. service members in Iraq and Afghanistan have sustained at least one TBI, and the U.S. military has spent more than $2 billion in the last decade on head injuries, Perl and colleagues analyzed the brains of eight military personnel exposed to explosive blasts. Three had acute blast exposure and died within a few days or months of the incident, and five had chronic blast exposure with death a few months to years afterward.
Perl and colleagues compared them with 13 control brains: five cases of chronic impact TBI, five cases of exposure to opiates, and three healthy controls.
Overall, they found the men exposed to acute or chronic blast TBI had a unique pattern of damage to the brain not seen in the controls, involving scarring in parts of the brain that are crucial for cognitive function, memory, sleep, and other important functions. These areas included the subpial glial plate, penetrating cortical blood vessels, grey-white matter junctions, and structures lining the ventricles.
The comparative civilian cases, with or without a history of impact TBI or opiate use, didn’t have any of this astroglial scarring, they found.
“The presence of reactive astrocytes in acute cases of blast TBI in the same neuroanatomical locations as the dense astroglial scar in cases of chronic blast TBI provides temporal and topographic evidence for a pathophysiological link to the blast event,” the researchers wrote.
The scarring may also be behind the neurological and psychiatric complications that can accompany blast TBI, Perl said.
He told MedPage Today that his team looked for tau protein deposits — which is suspected to play a role in the neurodegenerative complications of CTE — in all of the patients, but found only enough of the protein to make a diagnosis of CTE in one case. A second case was suggestive that a tauopathy was in the earliest stage of development.
“We speculate that we may see an increased risk of CTE down the road in those exposed to blast TBI,” he said.
The study was limited because its methodology precluded a determination on causality: it’s impossible to tell whether the brain scarring was a direct consequence of the blast, or if it resulted from some other mechanism. Some of those with blast injuries did have previous sports injuries, the researchers noted.
Perl also acknowledged that being exposed to a blast TBI is a very complex phenomenon: “There are blast winds that will not only knock you over, but propel the body over a considerable distance and produce an impact TBI if the body happens to land against a brick wall or other solid object. There is almost no pure blast TBI experience in real life.”
But that’s why they examined control brains, and they maintain that their findings are new and unique, and important to the Department of Defense given that a significant percentage of service members have been exposed to this kind of injury.
The researchers will continue to study additional cases of blast TBI exposures, and they’re looking into the magnitude of explosion that can lead to scarring, how various behavioral and neurologic areas might correlate to clinical damage, and whether there is a way to identify these kinds of changes in living service members, Perl said.
“Our study makes an important contribution in terms of understanding the nature of what a blast injury does to the brain,” he said, “but we need a great deal more work to better understand it.”
In an accompanying commentary, William Stewart, MD, of the University of Glasgow in Scotland, and Douglas Smith, MD, of the University of Pennsylvania in Philadelphia, wrote that this “short case series almost doubles the number of cases in the scientific literature describing the human neuropathology of blast TBI.”
“However, far from an answer to the question of what is blast traumatic brain injury, the work instead exposes the remarkable absence of robust human neuropathology studies in this field,” they wrote. “We must remain cautious in interpreting the significance of any single pathology as unique to blast-associated TBI based on a small and heterogeneous case series and little clinical information, and few control comparisons.”

Colorado Rancher Suffers Traumatic Brain Injury, Becomes Accidental Genius .

For most of her life, Leigh Erceg was an athlete who loved NASCAR, a bubbly tomboy who worked on a ranch in remote northwestern Colorado. She had boyfriends and a degree in physical education and zero interest in math or art.

A few years ago, Erceg, 47, suffered a traumatic brain injury and now she is a gifted artist and poet. She enjoys spending time puzzling over mathematical equations. She can “see” sounds and “hear” colors when she listens to music, although she is extremely sensitive to light.

She remembers nothing about her prior life. She doesn’t even recognize her own mother.

Erceg’s condition is so incredibly rare that it took numerous scientific studies and brain scans to diagnose her with what is called “savant syndrome.”

Savant Syndrome is described as vastly enhanced cognitive ability in an area such as art and math. Acquired savant syndrome is when a person isn’t born with the condition, which is the case with Erceg. She also suffers from “synesthesia,” a mixing of senses, where the person can see a sound, or hear a color as a series of numbers and letters.

“Leigh is the only woman in the world who has acquired savant syndrome and synesthesia following brain injury that I know of,” said Dr. Berit Brogaard, a neuroscientist at the University of Miami who has been studying her.

Leigh Erceg is shown here before the accident in this undated photo.

Leigh Erceg is shown here before the accident in this undated photo.

It was 2009 when Erceg, who was managing a ranch in Maybell, Colorado, said she was feeding chickens when she fell into a ravine and suffered catastrophic spine and brain injuries.

“I don’t know what type of fall it was but it must have been pretty dramatic,” she said. “I just remember them saying ‘Leigh, keep breathing.’ I remember it was a sheriff, and he said, ’Leigh keep breathing.’ There isn’t pictures, there is just words, ‘Leigh keep breathing.’”

Doctors were initially unsure she would ever walk again. What no one knew at the time was that her brain suffered the most severe damage, but in a unique way. Erceg has no memory of her old life, not even her childhood. She relies on Amber Anastasio, who she has been best friends with since the fifth grade, to help her understand who she used to be.

Leigh Erceg, right, and her friend Amber Anastasio, left, are shown here holding a picture of the two of them taken before Ercegs accident.

Leigh Erceg, right, and her friend Amber Anastasio, left, are shown here holding a picture of the two of them taken before Erceg’s accident.

In addition to her memories, Erceg also lost her ability to feel emotion, which doctors describe as “flat effect.” She has since learned to smile or chuckle as a response to social cues, but says she doesn’t feel or understand the reaction. She said she was initially misdiagnosed with bipolar disorder.

“Leigh was a total extrovert. She was very confident,” Anastasio said, “I just know that she is different now. It’s not a bad different. It’s just different. It’s who she is now.”

Erceg has a home now filled with mathematical equations and art — her interpretations of how she sees the world. All of her drawings are done with headphones on, music blaring and a Sharpie in hand. When she’s drawing, Erceg said “all the dimensions of the house” run through her mind.

“At one point, all theoretical designs come in occupancy of a triangle, of a linear line, of circulations,” she said, describing one of her drawings.

Leigh Ercegs home is now filled with mathematical equations and art -- her interpretations of how she sees the world.

Meredith Frost/ABC
Leigh Erceg’s home is now filled with mathematical equations and art — her interpretations of how she sees the world.

The birth of these strange new talents has left Erceg lonely at times and desperate to understand what happened to her, and questioning whether what she sees in her mind is real. She went to Dr. Brit Brogaard at the University of Miami, where she underwent two days of a rigorous series of tests.

After the first test, Erceg started to understand why she draws the way she does. And the way she describes seeing sounds or hearing colors is real, Broggad said.

“Most people, if you ask them to draw a house or a car, they will start with the outline of the car or house, and they will fill in the windows and door, and the wheels,” Brogaard said. “When you ask Leigh to draw something, she will start with the details. She will start with the windows or the wheels – the details, and fill out that way. She is attending to details before she is attending to the whole.”

Erceg’s genius may be accidental, but she has embraced it – a view of the world as colors and numbers, and a beautiful mind she is just beginning to understand.

Inflammation and Neuroprotection in Traumatic Brain Injury.

Importance  Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI.

Objectives  To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI.

Evidence Review  We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review.

Findings  Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed.

Conclusions and Relevance  The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.

Acute Traumatic Brain Injury

In a phase 3 trial, progesterone had no benefit as a neuroprotective agent in patients with blunt traumatic brain injury. Together with a second negative clinical trial of progesterone for acute TBI (SYNAPSE), the findings provide no support for this therapeutic approach.

More than 2.4 million emergency department visits, hospitalizations, or deaths are related to traumatic brain injury (TBI) annually, and approximately 5.3 million Americans are living with disability from TBI. The aggregate annual cost of TBI in the United States now approaches $76.5 billion. Survivors of severe TBI typically require 5 to 10 years of intensive therapy and are often left with substantial disability. Despite decades of research, no pharmacologic agent has been shown to improve outcomes after TBI.

Clinical Pearls

What is the basis for interest in the use of progesterone for acute traumatic brain injury?

Progesterone is a potent neurosteroid synthesized in the central nervous system. Preclinical studies in laboratory animals indicated that the early administration of progesterone after experimental TBI reduced cerebral edema, neuronal loss, and behavioral deficits. Enthusiasm for progesterone as a treatment for TBI was further stimulated by two single-center clinical trials showing decreased mortality and improved functional outcomes with progesterone as compared with placebo.

•What do the Extended Glasgow Outcome Scale (GOS-E) scores indicate with respect to functional outcome?

A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery.

Q: Does the early administration of progesterone (within 4 hours after injury) improve the outcome in patients with moderate-to-severe acute TBI when compared to placebo?

A: Despite extensive preclinical data and two promising single-center trials, progesterone was not associated with any benefit over placebo, as measured by the GOS-E score at 6 months, in this large, multicenter clinical trial. For the primary hypothesis comparing progesterone with placebo, favorable outcomes occurred in 51.0% of patients assigned to progesterone and in 55.5% of those assigned to placebo; the model estimated a relative benefit of 0.95 (95% confidence interval [CI], 0.85 to 1.06; P=0.35), with a relative benefit of less than 1.00 indicating fewer favorable outcomes in the progesterone group than in the placebo group.

Q: Was progesterone associated with more adverse events than placebo in this trial?

A: Progesterone was associated with an acceptable safety profile. Eight prospectively defined adverse events that were deemed to be potentially associated with the study drug were similar in frequency in the two groups. However, phlebitis or thrombophlebitis was significantly more frequent in the progesterone group than in the placebo group (relative risk, 3.03; 95% CI, 1.96 to 4.66). Episodes of phlebitis were frequently categorized as not serious and were self-limited