Article | Published:

Evaluation of a ketogenic diet for improvement of neurological recovery in individuals with acute spinal cord injury: a pilot, randomized safety and feasibility trial

Spinal Cord Series and Casesvolume 4, Article number: 88 (2018) | Download Citation

Abstract

Study design

Longitudinal, randomized study.

Objectives

(1) Test the safety and feasibility of a ketogenic diet (KD) intervention in the acute stages of spinal cord injury (SCI), (2) assess the effects of a KD on neurological recovery, and (3) identify potential serum biomarkers associated with KD-induced changes in neurological recovery.

Setting

Acute care and rehabilitation facility.

Methods

The KD is a high-fat, low-carbohydrate diet that includes ≈70–80% total energy as fat. Seven participants with acute complete and incomplete SCI (AIS A–D) were randomly assigned to KD (n = 4) or standard diet (SD, n = 3). Neurological examinations, resting energy expenditure analysis, and collection of blood for evaluation of circulating ketone levels were performed within 72 h of injury and before discharge. Untargeted metabolomics analysis was performed on serum samples to identify potential serum biomarkers that may explain differential responses between groups.

Results

Our pilot findings primarily demonstrated that KD is safe and feasible to be administered in acute SCI. Furthermore, upper extremity motor scores were higher (p < 0.05) in the KD vs. SD group and an anti-inflammatory lysophospholipid, lysoPC 16:0, was present at higher levels, and an inflammatory blood protein, fibrinogen, was present at lower levels in the KD serum samples vs. SD serum samples.

Conclusion

Taken together, these preliminary results suggest that a KD may have anti-inflammatory effects that may promote neuroprotection, resulting in improved neurological recovery in SCI. Future studies with larger sample size are warranted for demonstrating efficacy of KD for improving neurological recovery.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and causes of death among persons with spinal cord injury. Arch Phys Med Rehabil. 1999;80:1411–9.

  2. 2.

    Jensen MP, Molton IR, Groah SL, Campbell ML, Charlifue S, Chiodo A, et al. Secondary health conditions in individuals aging with SCI: terminology, concepts and analytic approaches. Spinal Cord. 2012;50:373–8.

  3. 3.

    Strauss DJ, Devivo MJ, Paculdo DR, Shavelle RM. Trends in life expectancy after spinal cord injury. Arch Phys Med Rehabil. 2006;87:1079–85.

  4. 4.

    Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol. 2006;17:431–9.

  5. 5.

    Prins ML, Matsumoto JH. The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. J Lipid Res. 2014;55:2450–7.

  6. 6.

    Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB. Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology. 2005;64:728–30.

  7. 7.

    Freeman J, Veggiotti P, Lanzi G, Tagliabue A, Perucca E, Institute of Neurology ICMF. The ketogenic diet: from molecular mechanisms to clinical effects. Epilepsy Res. 2006;68:145–80.

  8. 8.

    Freeman JM, Vining EP, Pillas DJ, Pyzik PL, Casey JC, Kelly LM. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics. 1998;102:1358–63.

  9. 9.

    Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging. 2004;25:311–4.

  10. 10.

    Veyrat-Durebex C, Reynier P, Procaccio V, Hergesheimer R, Corcia P, Andres CR, et al. How can a ketogenic diet improve motor function? Front Mol Neurosci. 2018;11:15.

  11. 11.

    Bough KJ, Gudi K, Han FT, Rathod AH, Eagles DA. An anticonvulsant profile of the ketogenic diet in the rat. Epilepsy Res. 2002;50:313–25.

  12. 12.

    Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot Essent Fat Acids. 2004;70:309–19.

  13. 13.

    Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241–7.

  14. 14.

    Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc Natl Acad Sci USA. 2000;97:5440–4.

  15. 15.

    Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J Clin Invest. 2003;112:892–901.

  16. 16.

    Noh HS, Kim DW, Kang SS, Cho GJ, Choi WS. Ketogenic diet prevents clusterin accumulation induced by kainic acid in the hippocampus of male ICR mice. Brain Res. 2005;1042:114–8.

  17. 17.

    Noh HS, Hah YS, Nilufar R, Han J, Bong JH, Kang SS, et al. Acetoacetate protects neuronal cells from oxidative glutamate toxicity. J Neurosci Res. 2006;83:702–9.

  18. 18.

    Ziegler DR, Ribeiro LC, Hagenn M, Siqueira IR, Araujo E, Torres IL, et al. Ketogenic diet increases glutathione peroxidase activity in rat hippocampus. Neurochem Res. 2003;28:1793–7.

  19. 19.

    Cullingford TE. The ketogenic diet; fatty acids, fatty acid-activated receptors and neurological disorders. Prostaglandins Leukot Essent Fat Acids. 2004;70:253–64.

  20. 20.

    Mabon PJ, Weaver LC, Dekaban GA. Inhibition of monocyte/macrophage migration to a spinal cord injury site by an antibody to the integrin alphaD: a potential new anti-inflammatory treatment. Exp Neurol. 2000;166:52–64.

  21. 21.

    Popovich PG, Wei P, Stokes BT. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol. 1997;377:443–64.

  22. 22.

    Farooque M, Hillered L, Holtz A, Olsson Y. Changes of extracellular levels of amino acids after graded compression trauma to the spinal cord: an experimental study in the rat using microdialysis. J Neurotrauma. 1996;13:537–48.

  23. 23.

    Beattie MS, Farooqui AA, Bresnahan JC. Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma. 2000;17:915–25.

  24. 24.

    Streijger F, Plunet WT, Lee JH, Liu J, Lam CK, Park S, et al. Ketogenic diet improves forelimb motor function after spinal cord injury in rodents. PLoS ONE. 2013;8:e78765.

  25. 25.

    Kobayakawa K, Kumamaru H, Saiwai H, Kubota K, Ohkawa Y, Kishimoto J, et al. Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans. Sci Transl Med. 2014;6:256ra137.

  26. 26.

    Sala F, Menna G, Bricolo A, Young W. Role of glycemia in acute spinal cord injury. Data from a rat experimental model and clinical experience. Ann N Y Acad Sci. 1999;890:133–54.

  27. 27.

    Kirshblum SC, O’Connor KC. Predicting neurologic recovery in traumatic cervical spinal cord injury. Arch Phys Med Rehabil. 1998;79:1456–66.

  28. 28.

    Pollard ME, Apple DF. Factors associated with improved neurologic outcomes in patients with incomplete tetraplegia. Spine (Phila PA 1976). 2003;28:33–9.

  29. 29.

    Waters RL, Adkins RH, Yakura JS. Definition of complete spinal cord injury. Paraplegia. 1991;29:573–81.

  30. 30.

    Ditunno JF Jr., Young W, Donovan WH, Creasey G. The international standards booklet for neurological and functional classification of spinal cord injury. American Spinal Injury Association. Paraplegia. 1994;32:70–80.

  31. 31.

    Prasain JK, Wilson LS, Arabshahi A, Grubbs C, Barnes S. Mass spectrometric evidence for the modification of small molecules in a cobalt-60-irradiated rodent diet. J Mass Spectrom. 2017;52:707.

  32. 32.

    Barnes S, Benton HP, Casazza K, Cooper SJ, Cui X, Du X, et al. Training in metabolomics research. II. Processing and statistical analysis of metabolomics data, metabolite identification, pathway analysis, applications of metabolomics and its future. J Mass Spectrom. 2016;51:535–48.

  33. 33.

    Barnes S, Benton HP, Casazza K, Cooper SJ, Cui X, Du X, et al. Training in metabolomics research. I. Designing the experiment, collecting and extracting samples and generating metabolomics data. J Mass Spectrom. 2016;51:461–75.

  34. 34.

    Marino RJ, Burns S, Graves DE, Leiby BE, Kirshblum S, Lammertse DP. Upper- and lower-extremity motor recovery after traumatic cervical spinal cord injury: an update from the national spinal cord injury database. Arch Phys Med Rehabil. 2011;92:369–75.

  35. 35.

    Steeves JD, Kramer JK, Fawcett JW, Cragg J, Lammertse DP, Blight AR, et al. Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury. Spinal Cord. 2011;49:257–65.

  36. 36.

    Waters RL, Adkins RH, Yakura JS, Sie I. Motor and sensory recovery following complete tetraplegia. Arch Phys Med Rehabil. 1993;74:242–7.

  37. 37.

    Waters RL, Adkins RH, Yakura JS, Sie I. Motor and sensory recovery following incomplete tetraplegia. Arch Phys Med Rehabil. 1994;75:306–11.

  38. 38.

    Waters RL, Adkins RH, Yakura JS, Sie I. Motor and sensory recovery following incomplete paraplegia. Arch Phys Med Rehabil. 1994;75:67–72.

  39. 39.

    Bardehle S, Rafalski VA, Akassoglou K. Breaking boundaries-coagulation and fibrinolysis at the neurovascular interface. Front Cell Neurosci. 2015;9:354.

  40. 40.

    Davalos D, Baeten KM, Whitney MA, Mullins ES, Friedman B, Olson ES, et al. Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol. 2014;75:303–8.

  41. 41.

    Ryu JK, Davalos D, Akassoglou K. Fibrinogen signal transduction in the nervous system. J Thromb Haemost. 2009;7(Suppl 1):151–4.

  42. 42.

    Cunningham TJ, Yao L, Lucena A. Product inhibition of secreted phospholipase A2 may explain lysophosphatidylcholines’ unexpected therapeutic properties. J Inflamm (Lond). 2008;5:17.

  43. 43.

    Treede I, Braun A, Sparla R, Kuhnel M, Giese T, Turner JR, et al. Anti-inflammatory effects of phosphatidylcholine. J Biol Chem. 2007;282:27155–64.

  44. 44.

    Triggiani M, Granata F, Frattini A, Marone G. Activation of human inflammatory cells by secreted phospholipases A2. Biochim Biophys Acta. 2006;1761:1289–300.

  45. 45.

    Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition. 2012;28:1016–21.

  46. 46.

    Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015;31:1–13.

Download references

Acknowledgements

The authors sincerely thank the participants and their families for their tireless dedication. We also thank Rhonda Pierce, RD, Margaret Peoples, RD, and the UAB Bionutrition Kitchen for development and delivery of KDs, as well as the UAB Department of Emergency Medicine Research Assistant Program for their assistance with study coordination and data collection.

Funding

This work was supported by KL2TR001419-01 (CY-F) and UAB Center for Clinical and Translational Science (UL1-TR-001417).

Author information

Affiliations

  1. Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    • Ceren Yarar-Fisher
    • , Jia Li
    • , Cassandra Renfro
    •  & Hammad Aslam
  2. School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    • Adarsh Kulkarni
  3. Department of Emergency Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    • Paige Farley
  4. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    • Patrick Bosarge
  5. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    • Landon Wilson
    •  & Stephen Barnes

Authors

  1. Search for Ceren Yarar-Fisher in:

  2. Search for Adarsh Kulkarni in:

  3. Search for Jia Li in:

  4. Search for Paige Farley in:

  5. Search for Cassandra Renfro in:

  6. Search for Hammad Aslam in:

  7. Search for Patrick Bosarge in:

  8. Search for Landon Wilson in:

  9. Search for Stephen Barnes in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Ceren Yarar-Fisher.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41394-018-0121-4