Traumatic Brain Injury (TBI) is the number one cause of death and chronic disability for those under the age of 45. Unfortunately there are few current treatments available and there has been a large failure to translate neuroprotective treatments from animal models. One potential reason is that metabolic dysfunction, a key part of TBI pathophysiology is not addressed. Ketogenic diets and exogenous ketones have been shown to have neuroprotective effects through multiple mechanisms in animal models of TBI, including the reversal of metabolic dysfunction. I will discuss the current evidence for the KD in the treatment of TBI. I will also briefly discuss other nutritional and lifestyle factors in the treatment of TBI.

1. Neuroprotective Effects of
Ketones in TBI
Bryan Barksdale MD/PhD student
PAH Winter Retreat 2016

2. Outline
● What is TBI?
● Epidemiology
● Pathophysiology
● Current Treatments and Focus
● Ketogenic Diets and Ketones
● TBI Studies using KD
● Other Fuel Sources
● Other Nutritional and Lifestyle Considerations
● Taking it to the Clinic and Potential Problems

3. What is TBI?
● Traumatic Brain Injury (TBI) is defined as an impact, penetration, or rapid
movement of the brain within the skull that results in an altered mental state
(Prins et al 2013)
● TBI is a very heterogenous disease (Kabadi and Faden 2014)
○ Every injury results from a unique set of circumstances (Meaney et al. 2014)
○ This leads to differences in severity and type of injury
○ Pre-injury conditions affect pathophysiology and outcome (UpToDate)

4. What is TBI?
● Generally TBI is classified by severity and injury type(UpToDate)
○ Mild (13-15), Moderate (9-12), and Severe (<8) by Glasgow Coma Scale
○ Concussion is often used synonymously with mild TBI (mTBI) but probably describes a subset of
milder brain injury
○ Diffuse or local, impact or nonimpact, closed or penetrating, blast related

5. What is TBI?
● Symptoms
○ mTBI is characterized by confusion and amnesia +/- preceding L.O.C.
○ Early: headache, dizziness, lack of awareness of surroundings, and nausea and vomiting
○ Late: mood and cognitive disturbances, sensitivity to light and noise, and sleep disturbances
(Post concussion syndrome)
○ Moderate and Severe TBI- persistent headache, focal neurologic symptoms, coma, problems
with speech and language, vision and other sensory perception, movement and balance
(Barkhoudarian et al. 2011)

6. What is TBI?
● Mild TBI usually has full recovery
● Moderate and Severe TBI are associated with permanent neurologic and
functional impairments
● Chronic disability due to TBI is common with a prevalence of 3.2-5.3 million
● TBI survivors can suffer from cognitive, behavioral, emotional,
endocrinological, and physical deficits
● Only 25% of survivors of severe TBI achieve long-term functional
independence
(UpToDate)

7. Epidemiology
● 1.74 million people
sustain a TBI in the
US every year
● The majority are of
TBIs are mild (75-
95%)
● Most prevalent cause
of death for those
under 45 and most
common cause of
long term disability
(CDC.GOV)
(UpToDate)

8. Epidemiology
● TBI caused by sports and military service are gaining attention more recently
due to:
○ TBI being considered the signature wound from Afghanistan and Iraq
conflicts
○ The link between sports related concussions and CTE
(Kabadi and Faden 2014, Hiebert et al. 2015)

9. Epidemiology
● The annual incidence of sports related concussions in the US is 1.6 to 3.8
million (Barkhoudarian et al. 2011)
● These numbers are likely underestimated as many cases go unreported
(Meaney et al. 2014)
● The likelihood of an athlete sustaining a concussion is as high as 20% per
season (UpToDate)
● There exists an opportunity for a second insult

10. Epidemiology
● From a survey of returning Iraq War vets, 5% reported injuries with loss of
consciousness and 10% with altered consciousness (UpToDate)
● The severity of combat related TBI tends to be higher compared to civilian
(Meaney et al. 2014)
● 67% of TBI injuries requiring hospitalization in US military operations in Iraq
and Afghanistan were from explosions (Meaney et al. 2014)

11. Pathophysiology of TBI
● Primary injury consists of the mechanical damage that happens at the time of
impact (or transfer of force)
● These forces tend to occur within 100 ms
● Shearing, stretching or compaction of axons and disruption of cell membranes
● Vascular injury which can cause intracerebral bleeding and hematoma
formation
● Focal: Vascular injury, Contusions, Lacerations
● Diffuse: Diffuse Axonal Injury (DAI)
(Mustafa and Al-Shboul 2013)

15. TBI
Pathophysiology
● Mechanoporation and opening
of K+
channels leads to K+
efflux
and depolarization
● Release of excitatory amino
acids, especially glutamate
● Activation of receptors,
particularly NMDARs which
allow Ca2+
influx as well as K+
efflux (feedback loop)
● Spreading depression
(neurologic deficits)
● Ca2+
is sequestered by
mitochondria which induces
oxidative stress and causes
mitochondrial dysfunction
(Barkhoudarian et al. 2011)

16. TBI
Pathophysiology
● Ca2+
also activates many
enzymes that increase oxidative
free radical production and
impair cytoskeletal integrity
● Increased ATP demand to
restore ionic homeostasis,
period of hyperglycolysis
● Decreased ATP production due
to defects in glycolysis and
mitochondrial dysfunction
● Leads to energy crisis and if
severe ultimately apoptosis
(Barkhoudarian et al. 2011)

17. TBI
Pathophysiology
● Hypometabolic state caused by:
○ Decreased glucose
uptake
○ Decreased glycolytic
processing (decreased
hexokinase, GAPDH, and
PDH activity)
○ Shunting to reparative
pentose phosphate
pathway
○ Decrease in ATP
production due to
damage of ETC
complexes
○ Increase in oxidative
damage
(Prins and Matsumoto 2014)

18. TBI
Pathophysiology
● Initial hypermetabolic
period followed by
prolonged metabolic
depression
● Prolonged increase in Ca2+
● Prolonged reduction in
blood flow
● Metabolic recovery time
correlates with severity of
injury and age
● Moderate and severe TBI
may take 2 weeks to
several months
(MacFarlane and Glenn 2015)

19. Current Treatments and Pipeline
● There are very few treatments for TBI
● The current focus is on:
○ Controlling CBF by reducing ICP
○ Preventing hypotension or hypoxia
○ Managing temperature and blood glucose
○ Preventing infection and seizures
● Surgical interventions exist for hematomas, penetrating injuries and depressed
skull fracture
● Neuroprotection is a huge field of study but clinical translation has been poor
(Algattas and Huang 2014, Kabadi and Faden 2014, Stocchetti et al 2015)
○ HBOT and Hypothermia- animal studies were positive but clinical trials are weak and mixed
○ Other failures include EPO, Magnesium, Progesterone, Citicoline

20. Current Treatments
and Pipeline
(Algattas and Huang 2014)

21. What Should We Target Instead?
● Multitargeted approach will likely translate better (Kabadi and Faden 2014)
● Consensus is that neuroinflammation, free radical formation and metabolic
dysfunction are key determinants of outcome (Gajavelli et al. 2014)
● Mitochondria have been shown to be a key participant in TBI pathophysiology
(Gajavelli et al. 2014, Yokobori et al. 2014, Hiebert et al. 2015)
● Even when hypoxia, hypotension, and low CBF are “corrected” there is still
substantial damage from other mechanisms (Bouzat et al. 2013, Jalloh et al. 2015)
● Decreased cerebral metabolism is a consistent finding after TBI and associated
with poor outcomes (Bouzat et al. 2013)
● Markers of mitochondrial dysfunction through microdialysis (lactate, pyruvate,
and glucose) and MRS (NAA) correlate with severity and outcome (Gajavelli et al. 2014,
Yokobori et al. 2014)

22. What Should We Target Instead?
(Bouzat et al. 2013)

23. Ketogenic diets and Ketone bodies
● Ketones are byproducts of fat metabolism produced during times of fasting or
starvation
● They are also produced when carbohydrates in the diet are severely restricted,
these are called ketogenic diets (KD)
● There are 3 main ketone bodies Beta-Hydroxybutyrate, Acetoacetate, and
Acetone.
● Ketone bodies enter the TCA cycle through conversion to Acetyl-CoA to
produce ATP
● Ketones can supply significant amount of brain’s energy demand
(Gano et al. 2014)

24. Ketogenic diets and Ketone bodies
(Gano et al. 2014)

25. Ketogenic Diets
(Gano et al. 2014)

26. Established Mechanisms of KD in Neurologic Disease
● Shown to be neuroprotective in models of epilepsy and other neurologic
disease
● Ketones provide an alternative energy substrate
● Reverse mitochondrial dysfunction, stimulate mitochondrial biogenesis and
mitophagy
● KD and ketone bodies have been shown to reduce oxidative stress
● Decrease apoptosis
● Anti-inflammatory
● Increases CBF
● Reduces seizure threshold and changes balance of neurotransmitters
(Maalouf et al. 2009, Gano et al. 2014)

27. Established Mechanisms
of KD in Neurologic
Disease
(Gano et al. 2014)

28. KD in TBI: Animal Studies
● These findings are from studies that have been done with multiple injury model
types and ages of rat
● Behaviorally KDs increase motor function and cognitive function after TBI
● KDs reduce lesion volume and edema
● Decrease number of apoptotic cells
● Decrease pro-apoptotic proteins such as BAX and Cytochrome C release
● Increase levels of ATP, creatinine, phosphocreatinine and normalizes NAA and
lactate
● Increase activity of ETC complex 2-3, bypass defects in complex 1
(White and Venkatesh 2011, Prins and Matsumoto 2014)

29. KD in TBI: Animal Studies
● Decrease markers of oxidative stress
● Increase levels of endogenous antioxidants
● Increase latency to seizure
● Protect against a second insult
● However one recent study showed that BHB did not prevent the BBB damage
after TBI (Orhan et al. 2016)
(White and Venkatesh 2011, Prins and Matsumoto 2014)

30. KD in TBI: Animal Studies
● However many of these findings are age dependent
● The neuroprotective effects are not seen as robustly in adult animals
● TBI physiology itself changes with age, the metabolic changes last longer
● KDs take longer to produce ketones in adults
● Older animals take longer to produces MCTs which transport ketone into the
brain
(Prins and Matsumoto 2014, Prins and Matsumoto 2014b)

31. KD in TBI: Human Studies
● There is only one published study in humans
● Ritter et al. placed 20 head injury patients on a carbohydrate free diet (KD) (Ritter
et al. 1996)
● Patients on the KD had stable blood sugar, lower blood lactate, and better
nitrogen balance
● However clinical outcomes were not reported on
● There is an ongoing clinical trial in pediatric TBI patients run by Matsumoto
○ ClinicalTrials.gov Identifier: NCT02174016
○ Estimated Primary Completion Date: December 2016
(White and Venkatesh 2011, Prins and Matsumoto 2014)

33. Other Fuels: Lactate, Pyruvate, Glucose
● New data indicates that lactate, directly and indirectly, is the primary fuel after
brain injury
● Lactate-animal and human studies have been positive, multiple pleiotropic
effects similar to ketones
● Pyruvate- animal studies have been positive but safety is questionable, is also
converted to lactate
● Glucose- post TBI hyperglycemia is beneficial, neutral or harmful depending on
the study
● However no adverse effects with exogenous glucose in animal or human
studies
(Prins et al 2013, Brooks and Martin 2015, Glenn et al 2015, Glenn et al 2015b)

34. Other Nutritional Aspects
● Adequate calories-recommendation is full feeding within 7 days, TBI leads to a
catabolic state (UpToDate, Brooks and Martin 2015)
● Omega 3s- contribute to the fluidity of function of neural and synaptic
membranes
● Have demonstrated benefit in animal studies of TBI
● May reduce inflammation, increase neurotrophic factors, improve
mitochondrial function
● Improved learning and cognition on animal models of TBI
● No human trials, but 2 are currently recruiting for pediatric mTBI
(Pillsbury et al 2011, Prins and Matsumoto 2014)

35. Other Nutritional Aspects
● Acetyl-L-Carnitine-improved behavioral outcome and decreased lesion volume
in animal model of TBI (Scafidi et al., 2010)
● Zinc-Patients with TBI are at higher risk for developing zinc deficiency.
However zinc supplementation studies haven’t been positive
● Choline
● Creatine
● Vitamin D
● Antioxidants-Vit C, Vit E, CoQ10
● Phytochemicals-Resveratrol, Curcumin
(Pillsbury et al 2011)

36. Other Lifestyle Factors: Exercise and Fasting
● Preconditioning with exercise may provide protection against ischemic injury
(Yokobori et al. 2013)
● Delayed exercise has been shown to improve outcomes in animal studies (Kabadi
and Faden 2014, Hiebert et al. 2015)
● Similarly intermittent fasting and caloric restriction are known to be
neuroprotective in many models of neurologic disease including TBI (Maalouf et al
2009, Pani 2015)

37. Bench to Bedside: Taking This to the Clinic
● KD is already established for epilepsy so it would be easier to implement
● Ketone salts are available and esters are in the pipeline
● The problem is how and when to initiate it, hard to translate from animal data
● Will it work in adults as well? can we improve it with fasting or using ketone
salts and esters
● Combine with lactate?
● How much evidence do we need? Is what we already have actionable?
● Pretreatment for athletes and military?
(White and Venkatesh 2011, Prins and Matsumoto 2014)

38. Potential Problems with KD
● In human trials high doses of ketone esters caused serious GI side effects,
headache, and dizziness
● Ketone salt solutions are alkalizing and a large sodium load
● Exogenous ketones may stimulate insulin release and inhibit hepatic
ketogenesis
● KD have the potential for hypoglycemia, excessive acidosis, GERD,
nephrolithiasis, increased in uric acid and hypercholesterolemia
● Prolonged use had been associated with growth retardations, obesity, nutrient
deficiency, decreased bone density, hepatic failure, and immune dysfunction
● Reports of dilated cardiomyopathy on KD
(White and Venkatesh 2011, Prins and Matsumoto 2014)

39. Summary
● TBI is the number one cause of death and chronic disability in those under 45
● There are few current treatment options and a failure to translate animal
research
● Metabolic dysfunction is a key part of TBI pathophysiology currently not
addressed
● Ketogenic diets and ketones have been shown to be neuroprotective because
they address metabolic dysfunction, and so much more
● The animal data for KD in TBI is very promising but is age dependent
● Human trials are desperately needed

40. Questions?

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