The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

      The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.
      Nationally, the incidence of traumatic brain injury (TBI) exceeds that of all other health diseases with an annual incidence of 1.7 million new cases (
      • Faul M.
      • Xu L.
      • Wald M.M.
      • Coronado V.G.
      Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006..
      ). It is an injury that affects both genders across all age groups, producing long-term disabilities that negatively impact families and society. Recent years have seen a substantial increase in public awareness of the long-term cognitive, emotional, and functional consequences of TBI. However, several potential neuroprotective treatments, such as therapeutic hypothermia, have produced disappointing results when tested in the clinical setting (
      • Clifton G.L.
      • Miller E.R.
      • Choi S.C.
      • Levin H.S.
      • McCauley S.
      • Smith Jr, K.R.
      • Muizelaar J.P.
      • Wagner Jr, F.C.
      • Marion D.W.
      • Luerssen T.G.
      • et al.
      Lack of effect of induction of hypothermia after acute brain injury.
      ,
      • Hutchison J.S.
      • Ward R.E.
      • Lacroix J.
      • Hébert P.C.
      • Barnes M.A.
      • Bohn D.J.
      • Dirks P.B.
      • Doucette S.
      • Fergusson D.
      • Gottesman R.
      • et al.
      Hypothermia therapy after traumatic brain injury in children.
      ). Thus, there is a significant need to identify better strategies to improve global outcome after TBI. In addition, given the inherent differences between the developing brain in which dynamic processes such as synaptogenesis, myelination, and plasticity are ongoing, and the mature adult brain in which these processes have been completed, any potential neuroprotective treatment must be evaluated in an age-specific manner. To that end, we discuss the changes in cerebral glucose metabolism, which have been described in the aftermath of TBI, the age-related variation of this metabolic dysfunction, and the potential of using the natural ketone metabolism mechanisms to ameliorate these problems and improve global outcome.

      METABOLIC DYSFUNCTIONS AFTER TBI

      Upon impact, rapid movement of the brain within the skull initiates a series of neurochemical disruptions that alter cerebral metabolism. Within minutes after injury, the ionic equilibrium across the neuronal membranes is disrupted, with injury severity-dependent increases in the concentration of extracellular potassium and glutamate, as well as intracellular calcium accumulation (
      • Fineman I.
      • Hovda D.A.
      • Smith M.
      • Yoshino A.
      • Becker D.P.
      Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study.
      ,
      • Katayama Y.
      • Becker D.P.
      • Tamura T.
      • Hovda D.A.
      Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury.
      ). This disruption of ionic equilibrium requires cellular energy to reestablish homeostasis, which is reflected by increases in cerebral glucose uptake observed within 30 min after adult rodent fluid percussion (FP) injury (
      • Yoshino A.
      • Hovda D.A.
      • Kawamata T.
      • Katayama Y.
      • Becker D.P.
      Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state.
      ) and within 8 days after human TBI (
      • Bergsneider M.
      • Hovda D.A.
      • Shalmon E.
      • Kelly D.F.
      • Vespa P.M.
      • Martin N.A.
      • Phelps M.E.
      • McArthur D.L.
      • Caron M.J.
      • Kraus J.F.
      • et al.
      Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study.
      ). This transient increase in glucose uptake is also known as “hyperglycolysis” and is followed by a prolonged period of glucose metabolic depression. These cerebral metabolic changes are a hallmark response described in both experimental and clinical brain trauma. 14C-2-deoxy-D-glucose autoradiography studies in adult rats following FP or controlled cortical impact (CCI) injury both show significant ipsilateral decreases in the cerebral metabolic rate of glucose (CMRglc) lasting 7–14 days depending on injury severity. Similarly, 18F-deoxyglucose positron emission tomography studies in human patients also reveal long-term glucose metabolic depression after TBI. Experimental studies have shown that the magnitude and duration of the glucose metabolic depression increases with injury severity and age (
      • Prins M.L.
      • Hovda D.A.
      Mapping cerebral glucose metabolism during spatial learning: interactions of development and traumatic brain injury.
      ,
      • Thomas S.
      • Prins M.L.
      • Samii M.
      • Hovda D.A.
      Cerebral metabolic response to traumatic brain injury sustained early in development: a 2-deoxy-D-glucose autoradiographic study.
      ,

      HovdaD. A.LifshitzJ.BerryJ. A.BadieH.YoshinoA.LeeS. M.. 1994. Long-term changes in metabolic rates for glucose following mild, moderate, and severe concussive head injuries in adult rats. Soc. Neurosci. Abstract. 20: 845.

      ).
      The duration of CMRglc depression increases from 5 days in adult mild FP injury to 14 days in severe FP injury (

      HovdaD. A.LifshitzJ.BerryJ. A.BadieH.YoshinoA.LeeS. M.. 1994. Long-term changes in metabolic rates for glucose following mild, moderate, and severe concussive head injuries in adult rats. Soc. Neurosci. Abstract. 20: 845.

      ). The FP model generates a more generalized concussive injury, whereas the CCI model produces a more severe injury with a predictable cortical contusion. Corresponding to this increased severity, greater magnitude and duration of glucose metabolic depression are observed with the CCI injury model (
      • Sutton R.L.
      • Hovda D.A.
      • Adelson P.D.
      • Benzel E.C.
      • Becker D.P.
      Metabolic changes following cortical contusion: relationships to edema and morphological changes.
      ,
      • Prins M.L.
      • Hovda D.A.
      The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats.
      ). In human TBI patients, the level of consciousness (as measured by Glasgow Coma Scale) shows significant correlation with CMRglc in thalamic, brainstem, and cerebellar structures (
      • Hattori N.
      • Huang S-C.
      • Wu H-M.
      • Yeh E.
      • Glenn T.C.
      • Vespa P.M.
      • McArthur D.
      • Phelps M.E.
      • Hovda D.A.
      • Bergsneider M.
      Correlation of regional metabolic rates of glucose with Glasgow coma scale after traumatic brain injury.
      ).
      The duration of post-TBI CMRglc depression also increases with cerebral maturation. Postnatal day (PND)17 rat pups given the same FP injury as adult rats showed faster recovery (3 days) of CMRglc depression (
      • Thomas S.
      • Prins M.L.
      • Samii M.
      • Hovda D.A.
      Cerebral metabolic response to traumatic brain injury sustained early in development: a 2-deoxy-D-glucose autoradiographic study.
      ). Adolescent PND35 rats showed earlier recovery of glucose metabolic rates in subcortical structures than adult PND90 rats (
      • Prins M.L.
      • Hovda D.A.
      The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats.
      ). In general, animal models have demonstrated age-dependent recovery of CMRglc after TBI, but comparison of glucose metabolic recoveries after TBI within the human pediatric population have not yet been studied.
      Other biochemical changes that occur in the aftermath of TBI further disrupt glucose uptake and metabolism. For instance, proton NMR spectroscopy of [1,2-13C]-labeled glucose demonstrates a 9–12% increase in glucose processing through the pentose phosphate pathway between 3 and 24 h after CCI injury, thereby decreasing the available glucose supply for energy production (
      • Bartnik B.L.
      • Sutton R.L.
      • Fukushima M.
      • Harris N.G.
      • Hovda D.A.
      • Lee S.M.
      Upregulation of pentose phosphate pathway and preservation of tricarboxylic acid cycle flux after experimental brain injury.
      ). TBI also has been shown to generate early increases in reactive oxygen species (ROS) which damage lipids, protein, and DNA (
      • Hall E.D.
      • Andrus P.K.
      • Yonkers P.A.
      Brain hydroxyl radical generation in acute experimental head injury.
      ,
      • Althaus J.S.
      • Andrus P.K.
      • Williams C.M.
      • VonVoigtlander P.F.
      • Cazers A.R.
      • Hall E.D.
      The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury. Reversal by tirilazad mesylate (U-74006F).
      ,
      • Marklund N.
      • Lewander T.
      • Clausen F.
      • Hillered L.
      Effects of the nitrone radical scavengers PBN and S-PBN on in vivo trapping of reactive oxygen species after traumatic brain injury in rats.
      ,
      • Sen S.
      • Goldman H.
      • Morehead M.
      • Murphy S.
      • Phillis J.W.
      Oxypurinol inhibits free radical release from the cerebral cortex of closed head injured rats.
      ,
      • Sen S.
      • Goldman H.
      • Morehead M.
      • Murphy S.
      • Phillis J.W.
      Alpha-phenyl-tert-butyl-nitrone inhibits free radical release in brain concussion.
      ). ROS-induced DNA damage activates DNA repair enzymes, such as poly-ADP ribose polymerase (PARP). In the presence of DNA strand breaks, pathological activation of PARP depletes cytosolic NAD+, which ultimately inhibits glycolytic processing of glucose at the glyceraldehyde phosphate dehydrogenase step (
      • Sheline C.T.
      • Behrens M.M.
      • Choi D.W.
      Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis.
      ). Collectively, these series of biochemical changes divert and obstruct processing of glucose through the glycolytic pathway. The consequent decrease in glucose oxidation and ATP concentrations (
      • Singh I.N.
      • Sullivan P.G.
      • Deng Y.
      • Mbye L.H.
      • Hall E.D.
      Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy.
      ,
      • Lee S.M.
      • Wong M.D.
      • Samii A.
      • Hovda D.A.
      Evidence for energy failure following irreversible traumatic brain injury.
      ) make glucose an inefficient energy substrate in the post-TBI brain.

      KETONES AS ALTERNATIVE SUBSTRATE EARLY AFTER TBI

      Cerebral ketone metabolism has been demonstrated to contribute significantly to brain metabolism under various conditions of energy challenges (
      • Prins M.L.
      Cerebral metabolic adaptation and ketone metabolism after brain injury.
      ). Observations that suckling rats, who rely upon ketone bodies in addition to glucose as necessary metabolic substrates (
      • Cotter D.G.
      • d'Avignon D.A.
      • Wentz A.E.
      • Weber M.L.
      • Crawford P.A.
      Obligate role for ketone body oxidation in neonatal metabolic homeostasis.
      ,
      • Hawkins R.A.
      • Williamson D.H.
      • Krebs H.A.
      Ketone-body utilization by adult and suckling rat brain in vivo.
      ), recover metabolically and behaviorally faster than adults following TBI led to the idea that alternative substrates may be protective (
      • Thomas S.
      • Prins M.L.
      • Samii M.
      • Hovda D.A.
      Cerebral metabolic response to traumatic brain injury sustained early in development: a 2-deoxy-D-glucose autoradiographic study.
      ). Utilizing cerebral ketone metabolism as a therapeutic approach is not only appealing because it can bypass the early glucose metabolic derangements after TBI, but it offers numerous other consequences that are beneficial after brain injury (Fig. 1). Ketone bodies require only three enzymatic steps to enter the TCA cycle, have been shown to improve metabolic efficiency (
      • Kashiwaya Y.
      • Sato K.
      • Tsuchiya N.
      • Thomas S.
      • Fell D.A.
      • Veech R.L.
      • Passonneau J.V.
      Control of glucose utilization in working perfused rat heart.
      ,
      • Sato K.
      • Kashiwaya Y.
      • Keon C.A.
      • Tsuchiya N.
      • King M.T.
      • Radda G.K.
      • Chance B.
      • Clarke K.
      • Veech R.L.
      Insulin, ketone bodies, and mitochondrial energy transduction.
      ,
      • Lardy H.A.
      • Phillips P.H.
      Studies of fat and carbohydrate oxidation in mammalian spermatozoa.
      ), and increase the ΔG′ of ATP hydrolysis (
      • Veech R.L.
      • Chance B.
      • Kashiwaya Y.
      • Lardy H.A.
      • Cahill Jr, G.F.
      Ketone bodies, potential therapeutic uses.
      ). Ketone metabolism can also decrease the production of free radicals in both the mitochondria and cytosol (

      .The Energy and Metabolic Control in Mitochondria. S. Papa, J. M. Tager, E. Quagliariello, et al., editors. Adriatica Editrice, Bari, Italy. 329–382.

      ,
      • Ziegler D.R.
      • Ribeiro L.C.
      • Hagenn M.
      • Siqueira I.R.
      • Araújo E.
      • Torres I.L.S.
      • Gottfried C.
      • Netto C.A.
      • Gonçalves C-A.
      Ketogenic diet increases glutathione peroxidase activity in rat hippocampus.
      ,
      • Sullivan P.G.
      • Rippy N.A.
      • Dorenbos K.
      • Concepcion R.C.
      • Agarwal A.K.
      • Rho J.M.
      The ketogenic diet increases mitochondrial uncoupling protein levels and activity.
      ). The multiple target action of ketones makes it a powerful tool in injuries that activate a multitude of cascades simultaneously; and consequently, there have been an increasing number of studies which demonstrate beneficial consequences of the ketogenic diet, calorie restriction, and fasting after brain trauma.
      Figure thumbnail gr1
      Fig. 1Diagram of the ketogenic sites of action. White diamonds with numbers indicate the metabolic changes that occur after TBI and their consequent changes in energy production and cellular damage. The black diamonds with letters indicate the sites where ketone metabolism can improve cellular energy production and decrease damage.
      One of the earliest studies exploring the potential use of alternative metabolic substrates following TBI demonstrated that intravenous infusion of 14C-3-β-hydroxybutyrate (βHB) 3 h following CCI injury in the adult rat resulted in greater cerebral uptake of βHB with greater production of 14CO2 (
      • Prins M.L.
      • Lee S.M.
      • Fujima L.S.
      • Hovda D.A.
      Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats.
      ). The increase in ketone metabolism improved regional ATP concentrations, demonstrating the potential for alternative substrate therapy after trauma. To avoid the plasma osmolarity changes associated with long-term intravenous ketone infusions, subsequent studies utilized a 4:1 ketogenic diet (Bioserve F6666). The high-fat low-carbohydrate ketogenic diet is already clinically established as a treatment for pediatric epilepsy (
      • Neal E.G.
      • Chaffe H.
      • Schwartz R.H.
      • Lawson M.S.
      • Edwards N.
      • Fitzsimmons G.
      • Whitney A.
      • Cross J.H.
      The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial.
      ). The strength of diet therapy is measured by the ratio of grams of fat: carbohydrate + protein, with the “dose” typically ranging from 1:1 to 4:1. In contrast, a standard American diet is roughly equivalent to a 0.3:1 diet ratio (
      • Kossoff E.H.
      • Dorward J.L.
      The modified Atkins diet.
      ). Variations of the ketogenic diet have been administered after TBI to induce early ketosis. When the ketogenic diet was given to PND17, -35, -45, and -65 rats after CCI injury for 1 week, an age-dependent neuroprotective effect was observed (
      • Prins M.L.
      • Fujima L.S.
      • Hovda D.A.
      Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury.
      ). PND35 rats (analogous to an adolescent age group) fed the ketogenic diet had increases in plasma βHB levels within 6 h, which was sustained for the week (
      • Prins M.L.
      • Fujima L.S.
      • Hovda D.A.
      Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury.
      ,
      • Prins M.L.
      • Giza C.C.
      Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats.
      ). However, plasma ketone levels did not increase until 24 h postinjury in adult rats. Ketone metabolism significantly decreased lesion volume and number of degenerating fluoro-jade positive cells in PND35 and -45 rats, but not in the younger or older age groups. The same ketogenic diet, given immediately after CCI injury for 1 week, also showed improved motor and cognitive function in the PND35 age group (
      • Appelberg K.S.
      • Hovda D.A.
      • Prins M.L.
      The effects of a ketogenic diet on behavioral outcome after controlled cortical impact injury in the juvenile and adult rat.
      ). The PND35 rats on the ketogenic diet showed a significant reduction in the number of hindlimb footslips off the beam walking task and showed shorter latencies in the Morris water maze relative to adult rats. Age differences in metabolic responses to the Bioserv F6666 ketogenic diet were also observed after TBI. Cortical tissue from PND35 rats on the ketogenic diet after CCI injury had improved ATP, creatine, and phosphocreatine levels and normalization of N-acetylaspartate and lactate levels at 24 h postinjury, which were not observed in adult ketogenic diet rats (
      • Deng-Bryant Y.
      • Prins M.L.
      • Hovda D.A.
      • Harris N.G.
      Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury.
      ). Administration of this diet immediately after CCI injury has been shown to have age-dependent effects of CMRglc changes, with the ketogenic diet further reducing TBI depression of CMRglc in adolescents to a greater extent than in adults (
      • Prins M.L.
      • Hovda D.A.
      The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats.
      ).
      The age difference in uptake of ketones (as reflected by the decrease in glucose uptake) may reflect either actual differences in transporters or differences in timing of plasma substrate increases. In fact, both may play a role in the efficacy of ketones in mitigating TBI-induced cascades. Cerebrovascular expression of monocarboxylate transporter (MCT)1 and MCT2 is 80–88% greater in microvessels from CCI-injured PND35 rats compared with CCI-injured adult rats, which may enhance cerebral uptake of ketones after injury (
      • Prins M.L.
      • Giza C.C.
      Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats.
      ). However, the time course of plasma ketone concentrations is delayed in the adults, which may delay the ability of cerebral ketones to counteract ongoing pathological processes. While intravenous administration of βHB could be an alternative approach, fasting for 24 h has been shown to increase plasma ketones and elevate MCTs in the adult brain (
      • Matsuyama S.
      • Ohkura S.
      • Iwata K.
      • Uenoyama Y.
      • Tsukamura H.
      • Maeda K-I.
      • Kimura K.
      Food deprivation induces monocarboxylate transporter 2 expression in the brainstem of female rat.
      ). Given the rapid pathological progression following TBI, alterations that increase ketone availability and delivery could help resolve this issue.
      The 4:1 ketogenic diet (Teklad 96355) has also been used to reduce cell loss after weight drop injury (
      • Hu Z-G.
      • Wang H-D.
      • Qiao L.
      • Yan W.
      • Tan Q-F.
      • Yin H-X.
      The protective effect of the ketogenic diet on traumatic brain injury-induced cell death in juvenile rats.
      ,
      • Hu Z.G.
      • Wang H.D.
      • Jin W.
      • Yin H.X.
      Ketogenic diet reduces cytochrome c release and cellular apoptosis following traumatic brain injury in juvenile rats.
      ). In these studies PND35 rats were placed on the ketogenic diet immediately after injury, and edema and apoptosis were quantified. Animals on the ketogenic diet also showed decreases in the Bcl-2 associated X protein (Bax) mRNA (48%) and protein (44%), thereby decreasing cellular apoptosis (30%) and brain swelling (1%). Animals on the ketogenic diet also showed a decrease in mitochondrial release of the electron transport enzyme, cytochrome c, into the cytosol. Normally this action initiates apoptotic signaling cascades, which are inhibited by cerebral ketone metabolism.
      In addition to the CCI and weight drop models that produce evolving contusions, the ketogenic diet has also been used after a concussive FP brain injury. PND56 rats were given FP injury 3 weeks after the standard or ketogenic diet (Bioserv F6666) was initiated to test the seizure threshold (
      • Schwartzkroin P.A.
      • Wenzel H.J.
      • Lyeth B.G.
      • Poon C.C.
      • Delance A.
      • Van K.C.
      • Campos L.
      • Nguyen D.V.
      Does ketogenic diet alter seizure sensitivity and cell loss following fluid percussion injury?.
      ). Animals on the ketogenic diet showed longer latencies for flurothyl-induced seizures and had less hippocampal cell loss than standard-fed FP-injured animals. Collectively, ketosis induced by the ketogenic diet has been shown to confer neuroprotection after various types of TBI in the adolescent/young adult rat.
      Induction of ketosis via fasting has been shown to provide protection from brain injury in adult animals (
      • Davis L.M.
      • Pauly J.R.
      • Readnower R.D.
      • Rho J.M.
      • Sullivan P.G.
      Fasting is neuroprotective following traumatic brain injury.
      ). Fasting adult rats for 24 h increased cortical tissue sparing, decreased markers of oxidative stress, and decreased mitochondrial calcium loading after moderate CCI injury, but not after severe injury. Interestingly, animals fasted for 48 h did not show significant cortical tissue protection. Despite the fact that fasting induced ketosis 24 h postinjury, a protective effect was still observed in the moderately injured adult animal. At this time, the interaction between injury types, severity, age, and type of ketosis induction remain unclear.

      KETONES AND CONCUSSION

      Concussion awareness has increased in the national media, bringing new attention to the milder forms of TBI. Concussive brain injuries have been shown to produce a similar metabolic pattern of derangements, but with faster recovery than severe injuries. A closed head injury model developed to deliver a concussive injury to the adolescent rat brain reveals that even an injury that produces no cell loss, contusion, or bleeding results in a measurable period of decreased CMRglc (
      • Prins M.L.
      • Alexander D.
      • Giza C.C.
      • Hovda D.A.
      Repeated mild traumatic brain injury: mechanisms of cerebral vulnerability.
      ). PND35 rats given a single concussive injury showed recovery of cortical metabolic rates between 3 and 5 days postinjury. Introduction of a second concussion during the metabolic recovery of the first injury resulted in prolonged CMRglc depression. These results indicate the cumulative nature of concussive injuries and emphasize the significance of the state of brain metabolism after injuries. There is evidence that administration of the ketogenic diet immediately after the first concussive injury improves cognitive function after the second concussive injury (

      .SalameN.GrecoT.RodriguezA.AlexanderD.JonesM.PrinsM. L.. 2012. Ketogenic neuroprotection of repeat TBI in juvenile rats. Soc. Neurotrauma..

      ). PND35 rats given two concussions separated by 24 h showed significant deficits in the novel object recognition task when tested 1 day after the last injury. However, animals that received the ketogenic diet for the 24 h interval between the two injuries visited the novel object first and spent more time with the new object, showing better cognitive performance. The effects of ketone administration prior to repeat mild TBI has also been recently examined in adult rats (
      • Wang T.
      • Van K.C.
      • Gavitt B.J.
      • Grayson J.K.
      • Lu Y-C.
      • Lyeth B.G.
      • Pichakron K.O.
      Effect of fish oil supplementation in a rat model of multiple mild traumatic brain injuries.
      ). Standard diets supplemented with 6% fish oil were given for 4 weeks prior to repetitive FP injury. Animals were maintained on the diet for another 2 weeks postinjury before undergoing Morris water maze testing and histological assessment. Adult rats given the modified omega-3 fatty acid diet showed improved cognitive performance.
      The usefulness of ketogenic therapy in concussive injuries needs to be further studied, but the idea is already gaining attention (
      • Maroon J.C.
      • Bost J.
      Concussion management at the NFL, college, high school, and youth sports levels.
      ). This year there are two clinical trials examining the effectiveness of omega-3 fatty acids on sports-related concussions in Division I National Collegiate Athletic Association (NCAA) athletes (
      • Trojian T.H.
      • Jackson E.
      Ω-3 polyunsaturated fatty acids and concussions: treatment or not?.
      ,

      .BicaD.2013. High dose omega-3 fatty acids in the treatment of sports related concussions. Accessed August 26, 2014, at http://clinicaltrials.gov/show/NCT01814527.

      ) and children (

      .MillerS.2013. DHA for the treatment of pediatric concussion related to sports injury. Accessed August 26, 2014, at http://clinicaltrials.gov/show/NCT01903525.

      ). The concept of utilizing alternative cerebral metabolic substrates to support brain function during pathological processes is gradually expanding from neurodegenerative diseases to all severities of TBI and even spinal cord trauma as well.

      KETONES AS ALTERNATIVE SUBSTRATE EARLY AFTER TRAUMATIC SPINAL CORD INJURY

      Ketosis induced by diet or fasting has also been shown to be beneficial after spinal cord injury. Adult male rats given a 3:1 ratio ketogenic diet (Bioserv F5848) for 12 weeks starting 4 h after cervical injury had decreased spinal lesions, increased expression of GLUT1 and MCT1 vascular transporters, and improved forelimb motor function (
      • Streijger F.
      • Plunet W.T.
      • Lee J.H.T.
      • Liu J.
      • Lam C.K.
      • Park S.
      • Hilton B.J.
      • Fransen B.L.
      • Matheson K.A.J.
      • Assinck P.
      • et al.
      Ketogenic diet improves forelimb motor function after spinal cord injury in rodents.
      ). Ketosis induced by every other day fasting for 2–4 weeks improved functional recovery, decreased lesion size, and increased corticospinal tract sprouting in adult male rats with thoracic or cervical injury (
      • Jeong M.A.
      • Plunet W.
      • Streijger F.
      • Lee J.H.
      • Plemel J.R.
      • Park S.
      • Lam C.K.
      • Liu J.
      • Tetzlaff W.
      Intermittent fasting improves functional recovery after rat thoracic contusion spinal cord injury.
      ,
      • Plunet W.T.
      • Streijger F.
      • Lam C.K.
      • Lee J.H.T.
      • Liu J.
      • Tetzlaff W.
      Dietary restriction started after spinal cord injury improves functional recovery.
      ). In contrast, every other day fasting in adult mice after thoracic compression failed to show histological or behavioral neuroprotection (
      • Streijger F.
      • Plunet W.T.
      • Plemel J.R.
      • Lam C.K.
      • Liu J.
      • Tetzlaff W.
      Intermittent fasting in mice does not improve hindlimb motor performance after spinal cord injury.
      ). In the adult mice, the plasma βHB levels did not show significant increases until postinjury day 3, which may have contributed to the lack of neuroprotection. It should also be noted that binge eating in mice is greater than in rats, with mice almost doubling their food intake on the feeding days. This difference in feeding behaviors may also contribute to the different neuroprotective response. This suggests that early alternative substrate intervention is critical in rapidly evolving states of metabolic crisis.

      KETONES AS A CEREBRAL SUBSTRATE DURING LONG-TERM RECOVERY

      Recovery from TBI is a dynamic process, with the initial postinjury period occupied by complex ionic and neurochemical perturbations, and later stages of recovery reliant more on the brain's properties of plasticity and reorganization to ameliorate the severity of residual neurologic deficits. Consequently, therapies which prevent maladaptive processes in the immediate aftermath of TBI may in later stages of recovery impair long-term potentiation and learning processes which are necessary for effective rehabilitation. Any putative neuroprotective strategy for TBI must therefore be evaluated in the context of appropriate timing following the injury.
      While preclinical studies of ketogenic diet treatment acutely following TBI have demonstrated improved outcome, the optimal timing and duration of postinjury treatment remains unclear. Studies of the ketogenic diet's effects on plasticity and long-term potentiation have been somewhat inconsistent. Although Zhao et al. (
      • Zhao Q.
      • Stafstrom C.E.
      • Fu D.D.
      • Hu Y.
      • Holmes G.L.
      Detrimental effects of the ketogenic diet on cognitive function in rats.
      ) demonstrated impaired visual-spatial memory and reduced brain growth in rats fed a ketogenic diet, both with and without prior status epilepticus, this study employed an extremely high fat:carbohydrate + protein ratio of 8.6:1, which is more than 2-fold higher than the maximum ratio typically used in clinical practice (
      • Zhao Q.
      • Stafstrom C.E.
      • Fu D.D.
      • Hu Y.
      • Holmes G.L.
      Detrimental effects of the ketogenic diet on cognitive function in rats.
      ,
      • Cunnane S.C.
      • Likhodii S.S.
      Claims to identify detrimental effects of the ketogenic diet (KD) on cognitive function in rats.
      ). This extreme diet ratio was associated with lower overall caloric intake, poor weight gain, and inadequate protein consumption to meet growth requirements. This emphasizes the need for body weight controls to be included in experimental designs to monitor response to changes in diet.
      Studies addressing the effects of long-term ketone consumption on synapse, axonal sprouting, and innervation have not provided consensus on the role of ketone metabolism during long-term TBI recovery. Differential synaptic changes have been observed in senescent rats after 8 weeks of 10 or 20% medium chain triglyceride diet (Bioserv) (
      • Balietti M.
      • Giorgetti B.
      • Fattoretti P.
      • Grossi Y.
      • Di Stefano G.
      • Casoli T.
      • Platano D.
      • Solazzi M.
      • Orlando F.
      • Aicardi G.
      • et al.
      Ketogenic diets cause opposing changes in synaptic morphology in CA1 hippocampus and dentate gyrus of late-adult rats.
      ). In these aged rats, the diet showed opposing morphologic modifications with the stratum moleculare layer of Cornu Ammonis (CA)1, showing lower synaptic density and fewer synaptic mitochondria, while the outer molecular layer of the dentate gyrus showed greater synaptic density and mitochondrial concentrations. These data bring up an interesting possibility that cellular responses to ketosis may differ regionally, and vulnerability associated with aging or trauma may make some cells unable to adapt to different fuel sources (
      • Hawkins R.A.
      • Biebuyck J.F.
      Ketone bodies are selectively used by individual brain regions.
      ). Changes in synaptic function, as measured by long-term potentiation, have also been examined, though inconclusively. The ketogenic diet or calorie restriction for 2–3 weeks in seizure-naïve PND21 rats demonstrated no diet-related impact on short-term plasticity (using paired-pulse modulation) or long-term plasticity (measured through long-term potentiation of the medial perforant pathway) (
      • Thio L.L.
      • Rensing N.
      • Maloney S.
      • Wozniak D.F.
      • Xiong C.
      • Yamada K.A.
      A ketogenic diet does not impair rat behavior or long-term potentiation.
      ). In contrast, PND51–73 rats maintained on the Bioserv ketogenic diet for 3 weeks showed diminished long-term potentiation for at least 48 h (
      • Koranda J.L.
      • Ruskin D.N.
      • Masino S.A.
      • Blaise J.H.
      A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats.
      ). In normal adult rats, 8 weeks of ketogenic diet did not alter the baseline electrophysiological measures (
      • Stafstrom C.E.
      • Wang C.
      • Jensen F.E.
      Electrophysiological observations in hippocampal slices from rats treated with the ketogenic diet.
      ). It is unclear, based on these two studies, whether age alone can account for the differential response.
      In addition to the direct effects of ketosis on synaptic plasticity, there is evidence that ketosis can affect neurotransmitters and growth factors involved in these processes. Cultured neurons utilizing βHB have reduced malate-aspartate shuttle activity and diminished glutamate release upon stimulation (
      • Lund T.M.
      • Risa O.
      • Sonnewald U.
      • Schousboe A.
      • Waagepetersen H.S.
      Availability of neurotransmitter glutamate is diminished when beta-hydroxybutyrate replaces glucose in cultured neurons.
      ). While decreased excitatory neurotransmission may be desirable for seizure prevention, it could be inhibitory during establishment of new connections during recovery. PND30 rats fed the ketogenic diet for 2 months showed reduced brain-derived neurotrophic factor (BDNF) levels in the striatum but not in the hippocampus (
      • Vizuete A.F.
      • de Souza D.F.
      • Guerra M.C.
      • Batassini C.
      • Dutra M.F.
      • Bernardi C.
      • Costa A.P.
      • Gonçalves C-A.
      Brain changes in BDNF and S100B induced by ketogenic diets in Wistar rats.
      ). BDNF plays an important role in plasticity and recovery after TBI, which may be altered for some cerebral regions after ketosis.
      Collectively these effects of ketones provide researchers with insight into the effects of ketosis on brain synaptic function and plasticity, but the mechanisms and how the addition of TBI will complicate these outcomes remain unknown. While research has shown that ketone metabolism is beneficial during the acute phase of TBI, more research is needed to address the cellular changes in gene expression and the role of long-term ketone use after TBI to ensure that the optimal cerebral substrate is available during rehabilitation and recovery.

      OTHER FATTY ACIDS AND TBI

      Independent of ketone body action, ω-3 PUFAs, such as DHA and EPA, have also demonstrated benefit in animal and clinical studies of TBI. α-Linolenic acid (ALA) can serve as a precursor to EPA, and subsequently to DHA (
      • Sprecher H.
      • Chen Q.
      • Yin F.Q.
      Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.
      ). Because <1% of ALA is converted to DHA in humans, the majority of DHA is obtained through dietary sources such as fish, seafood, and poultry (
      • Burdge G.C.
      • Finnegan Y.E.
      • Minihane A.M.
      • Williams C.M.
      • Wootton S.A.
      Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]alpha-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men.
      ,
      • Burdge G.C.
      • Jones A.E.
      • Wootton S.A.
      Eicosapentae­noic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men.
      ,
      • Burdge G.C.
      • Wootton S.A.
      Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women.
      ). The most prominent ω-3 PUFA in the mammalian brain is DHA, which is highly concentrated in gray matter and, due to its flexible structure, contributes to the fluidity and function of neural and synaptic membranes (
      • Klenk E.
      • Montag W.
      The C22 polyenoic acids in the glycerophosphatides of the brain [Article in German].
      ,
      • Mohrhauer H.
      • Holman R.T.
      Alteration of the fatty acid composition of brain lipids by varying levels of dietary essential fatty acids.
      ,
      • Sastry P.S.
      Lipids of nervous tissue: composition and metabolism.
      ,
      • Innis S.M.
      Dietary (n-3) fatty acids and brain development.
      ). DHA is essential for normal fetal neurologic development, and has roles in neuronal differentiation, regulating gene expression, learning and memory, and neuronal plasticity (
      • Hashimoto M.
      • Hossain S.
      • Shimada T.
      • Sugioka K.
      • Yamasaki H.
      • Fujii Y.
      • Ishibashi Y.
      • Oka J-I.
      • Shido O.
      Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats.
      ,
      • Katakura M.
      • Hashimoto M.
      • Okui T.
      • Shahdat H.M.
      • Matsuzaki K.
      • Shido O.
      Omega-3 polyunsaturated fatty acids enhance neuronal differentiation in cultured rat neural stem cells.
      ,
      • Green P.
      • Yavin E.
      Mechanisms of docosahexaenoic acid accretion in the fetal brain.
      ,
      • Kitajka K.
      • Puskás L.G.
      • Zvara A.
      • Hackler Jr, L.
      • Barceló-Coblijn G.
      • Yeo Y.K.
      • Farkas T.
      The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids.
      ,
      • Barceló-Coblijn G.
      • Högyes E.
      • Kitajka K.
      • Puskás L.G.
      • Zvara A.
      • Hackler Jr, L.
      • Nyakas C.
      • Penke Z.
      • Farkas T.
      Modification by docosahexaenoic acid of age-induced alterations in gene expression and molecular composition of rat brain phospholipids.
      ).
      In the aftermath of TBI, not only are normal patterns of energy homeostasis disrupted, but factors involved in synaptic transmission, plasticity, and learning, such as BDNF and synapsin I, are also decreased. ω-3 PUFA supplementation normalized levels of these depleted neurochemicals, and furthermore improved performance on functional measures of learning and cognition in animal models of TBI (
      • Wu A.
      • Ying Z.
      • Gomez-Pinilla F.
      Omega-3 fatty acids supplementation restores mechanisms that maintain brain homeostasis in traumatic brain injury.
      ,
      • Wu A.
      • Ying Z.
      • Gomez-Pinilla F.
      Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats.
      ). Bailes and Mills (
      • Bailes J.E.
      • Mills J.D.
      Docosahexaenoic acid reduces traumatic axonal injury in a rodent head injury model.
      ) found that DHA supplementation for 30 days following impact acceleration injury was associated with a dose-dependent decrease in axons positively staining for β-amyloid precursor protein (APP), which is a marker for diffuse axonal injury.
      Several studies have also examined the potential neuroprotective effects of preinjury supplementation with ω-3 PUFAs. DHA supplementation for 30 days prior to impact acceleration injury was associated with decreased markers of cellular apoptosis and diffuse axonal injury, as well as improved water maze performance (
      • Mills J.D.
      • Hadley K.
      • Bailes J.E.
      Dietary supplementation with the omega-3 fatty acid docosahexaenoic acid in traumatic brain injury.
      ). Pu et al. (
      • Pu H.
      • Guo Y.
      • Zhang W.
      • Huang L.
      • Wang G.
      • Liou A.K.
      • Zhang J.
      • Zhang P.
      • Leak R.K.
      • Wang Y.
      • et al.
      Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury.
      ) found that mice pretreated with ω-3 PUFAs, including DHA and EPA, for 2 months prior to CCI injury had similar cortical lesion volume to those fed a diet inherently poor in ω-3 PUFAs, but that hippocampal neuronal loss within the CA3 region and cognitive/behavior performance were improved. In addition, ω-3 PUFA pretreatment resulted in white matter preservation through decreased inflammatory response to injury, improved levels of myelin basic protein, more intact myelinated fibers, and improved postinjury conduction velocity of action potentials stimulated across portions of the corpus callosum (
      • Pu H.
      • Guo Y.
      • Zhang W.
      • Huang L.
      • Wang G.
      • Liou A.K.
      • Zhang J.
      • Zhang P.
      • Leak R.K.
      • Wang Y.
      • et al.
      Omega-3 polyunsaturated fatty acid supplementation improves neurologic recovery and attenuates white matter injury after experimental traumatic brain injury.
      ).

      THE USE OF KETONES IN CLINICAL TBI

      In spite of the extensive preclinical evidence supporting the neuroprotective benefits of ketones, the ketogenic diet and ω-3 PUFA supplementation, clinical trials are sorely needed to validate the impact of these treatments on global outcome in humans. To our knowledge, only one clinical study has examined the short-term effects of ketogenic therapy in the acute hospital setting. 20 adult patients with severe TBI were randomized to receive either standard enteral feeds or a ketogenic-like diet which was carbohydrate-free with moderately high fat content (
      • Ritter A.M.
      • Robertson C.S.
      • Goodman J.C.
      • Contant C.F.
      • Grossman R.G.
      Evaluation of a carbohydrate-free diet for patients with severe head injury.
      ). Those receiving the carbohydrate-free diet demonstrated lower blood lactate concentration, higher ketone body levels, and better urinary nitrogen balance. Long-term follow-up and global outcome measures were not reported. The authors additionally noted that the carbohydrate-free diet was associated with consistent euglycemia, whereas several episodes of hyperglycemia occurred in the group receiving standard nutritional formula. Hyperglycemia has been repeatedly associated with poorer outcome in both pediatric and adult TBI (
      • Béjot Y.
      • Aboa-Eboulé C.
      • Hervieu M.
      • Jacquin A.
      • Osseby G-V.
      • Rouaud O.
      • Giroud M.
      The deleterious effect of admission hyperglycemia on survival and functional outcome in patients with intracerebral hemorrhage.
      ,
      • Lam A.M.
      • Winn H.R.
      • Cullen B.F.
      • Sundling N.
      Hyperglycemia and neurological outcome in patients with head injury.
      ,
      • Melo J.R.T.
      • Di Rocco F.
      • Blanot S.
      • Laurent-Vannier A.
      • Reis R.C.
      • Baugnon T.
      • Sainte-Rose C.
      • Olveira-Filho J.
      • Zerah M.
      • Meyer P.
      Acute hyperglycemia is a reliable outcome predictor in children with severe traumatic brain injury.
      ). It is also important to note that the majority of ketone neuroprotective experimental studies thus far have been conducted in rodents and dose-dependent efficacy and therapeutic windows will likely need to be established in each species.

      POTENTIAL PROBLEMS WITH KETONE THERAPY

      To translate the extensive experimental data supporting the benefits of ketone metabolism for TBI into clinical practice, an easily implemented method must be identified to safely and quickly increase cerebrospinal fluid (CSF) ketone levels, and induce a shift to cerebral ketone metabolism. In addition, research and development costs must also be taken into consideration, because the safety and efficacy of any novel therapeutic agent must be validated in extensive clinical trials prior to approval for standard clinical use. In contrast, therapies which have already been approved and established can be much more rapidly deployed into clinical use for other indications.
      Direct ketone infusion represents one potential therapeutic avenue. In one study using magnetic resonance spectroscopy (MRS) to measure cerebral ketone levels in healthy human adults, intravenous βHB infusion achieving plasma levels of 2.12 mmol/l were associated with approximate cerebral βHB levels of 0.24 mmol/l (
      • Pan J.W.
      • Telang F.W.
      • Lee J.H.
      • de Graaf R.A.
      • Rothman D.L.
      • Stein D.T.
      • Hetherington H.P.
      Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain.
      ). A separate group testing a novel hypertonic intravenous βHB solution in adult rats achieved cerebral βHB levels up to 0.28 mmol/l (
      • White H.
      • Venkatesh B.
      • Jones M.
      • Worrall S.
      • Chuah T.
      • Ordonez J.
      Effect of a hypertonic balanced ketone solution on plasma, CSF and brain beta-hydroxybutyrate levels and acid-base status.
      ). In contrast, more substantial increases in CSF βHB levels are achieved by prolonged fasting. βHB levels of 0.05 mmol/l, detected via MRS in nonfasted adults, increased to 0.60 mmol/l after 2 days of fasting and 0.98 mmol/l after 3 days of fasting (
      • Pan J.W.
      • Rothman T.L.
      • Behar K.L.
      • Stein D.T.
      • Hetherington H.P.
      Human brain beta-hydroxybutyrate and lactate increase in fasting-induced ketosis.
      ). Therefore, intravenous ketone administration may be an inefficient method for inducing changes in cerebral energy metabolism. Strategies designed to primarily increase plasma ketone levels must also target increased ketone transport across the blood brain barrier by MCTs.
      Recently, a phase 1 trial tested the pharmacokinetics, safety, and tolerability of orally administering a ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, to healthy adult human volunteers. In the highest dose group of 12 adults drinking a 714 mg/kg ketone monoester solution three times daily, βHB levels averaging 3.30 mmol/l were achieved (
      • Clarke K.
      • Tchabanenko K.
      • Pawlosky R.
      • Carter E.
      • Todd King M.
      • Musa-Veloso K.
      • Ho M.
      • Roberts A.
      • Robertson J.
      • VanItallie T.B.
      • et al.
      Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.
      ). This approaches therapeutic plasma ketone levels typically achieved during clinical use of the ketogenic diet for epilepsy (
      • van Delft R.
      • Lambrechts D.
      • Verschuure P.
      • Hulsman J.
      • Majoie M.
      Blood beta-hydroxybutyrate correlates better with seizure reduction due to ketogenic diet than do ketones in the urine.
      ). However, 12 of 12 subjects who were administered this high dose reported side effects such as nausea, abdominal distention, headache, diarrhea, and dizziness. Two individuals were discontinued from the study; one due to severe vomiting and the other due to nausea, diarrhea, chest pain, abdominal distention, and upper abdominal pain (
      • Clarke K.
      • Tchabanenko K.
      • Pawlosky R.
      • Carter E.
      • Todd King M.
      • Musa-Veloso K.
      • Ho M.
      • Roberts A.
      • Robertson J.
      • VanItallie T.B.
      • et al.
      Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects.
      ). In light of these significant side effects, this strategy of direct ketone body infusion may also prove problematic due to its effect on the insulin/glucagon balance. Both βHB and acetoacetate infusion in diabetic dogs stimulated pancreatic insulin secretion, which may counteract the ability of glucagon to promote hepatic ketogenesis and maintain the protective ketotic state (
      • Madison L.L.
      • Mebane D.
      • Unger R.H.
      • Lochner A.
      The hypoglycemic action of ketones. II. Evidence for a stimulatory feedback of ketones on the pancreatic beta cells.
      ).
      In light of the many regulatory obstacles and clinical trial expenses required to obtain approval for direct oral or intravenous ketone body administration in the clinical setting, acute post-TBI ketogenic diet initiation provides an attractive alternative. In essence, implementation of postinjury ketogenic diet simply involves a straightforward substitution of a ketogenic enteral formula such as Ketocal (Nutricia North America) or Ross Carbohydrate Free (Abbott Nutrition) for the standard carbohydrate-based formulas used for tube feeding. Following an initial period of postinjury fasting in anticipation of possible urgent surgical intervention, prompt advancement to full caloric feeds are typically recommended for improved outcome (
      • Bratton S.L.
      • Chestnut R.M.
      • Ghajar J.
      • McConnell Hammond F.F.
      • Harris O.A.
      • Hartl R.
      • Manley G.T.
      • Nemecek A.
      • Newell D.W.
      • Rosenthal G.
      • et al.
      Guidelines for the management of severe traumatic brain injury. XII. Nutrition.
      ,
      • Taha A.A.
      • Badr L.
      • Westlake C.
      • Dee V.
      • Mudit M.
      • Tiras K.L.
      Effect of early nutritional support on intensive care unit length of stay and neurological status at discharge in children with severe traumatic brain injury.
      ). However, in some cases, concurrent injury to the gastrointestinal tract may preclude enteral feeding. Additionally, in clinical practice for the treatment of epilepsy, ketogenic diet implementation requires close monitoring for side effects and complications such as excessive hypoglycemia, excessive acidosis, gastroesophageal reflux, nephrolithiasis, and hypercholesterolemia (
      • Kossoff E.H.
      • Zupec-Kania B.A.
      • Amark P.E.
      • Ballaban-Gil K.R.
      • Christina Bergqvist A.G.
      • Blackford R.
      • Buchhalter J.R.
      • Caraballo R.H.
      • Helen Cross J.
      • Dahlin M.G.
      • et al.
      Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.
      ). The ketogenic diet has been urgently initiated in the intensive care unit for refractory status epilepticus in children and adults (
      • Nabbout R.
      • Mazzuca M.
      • Hubert P.
      • Peudennier S.
      • Allaire C.
      • Flurin V.
      • Aberastury M.
      • Silva W.
      • Dulac O.
      Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES).
      ,
      • Nam S.H.
      • Lee B.L.
      • Lee C.G.
      • Yu H.J.
      • Joo E.Y.
      • Lee J.
      • Lee M.
      The role of ketogenic diet in the treatment of refractory status epilepticus.
      ,
      • Cervenka M.C.
      • Hartman A.L.
      • Venkatesan A.
      • Geocadin R.G.
      • Kossoff E.H.
      The ketogenic diet for medically and surgically refractory status epilepticus in the neurocritical care unit.
      ,
      • O'Connor S.E.
      • Richardson C.
      • Trescher W.H.
      • Byler D.L.
      • Sather J.D.
      • Michael E.H.
      • Urbanik K.B.
      • Richards J.L.
      • Davis R.
      • Zupanc M.L.
      • et al.
      The ketogenic diet for the treatment of pediatric status epilepticus.
      ). However, the effect of ketogenic diet implementation on TBI-related conditions such as cerebral edema, intracerebral hemorrhage, and other systemic injuries must be further evaluated.

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