Abstract
We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child’s Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments.
References
| 1. |
Jozwiak, S, Kossoff, EH, Kotulska-Jozwiak, K. Dietary treatment of epilepsy: rebirth of an ancient treatment. Neurol Neurochir Pol. July-August 2011;45(4):370–378. Google Scholar | Crossref | Medline | ISI |
| 2. |
Huffman, J, Kossoff, EH. State of the ketogenic diet(s) in epilepsy. Curr Neurol Neurosci Rep. July 2006;6(4):332–340. Google Scholar | Crossref | Medline | ISI |
| 3. |
Spence, SJ, Schneider, MT. The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr Res. June 2009;65(6):599–606. Google Scholar | Crossref | Medline | ISI |
| 4. |
Frye, RE, Butler, I, Strickland, D, Castillo, E, Papanicolaou, A. Electroencephalogram discharges in atypical cognitive development. J Child Neurol. May 2010;25(5):556–566. Google Scholar | SAGE Journals | ISI |
| 5. |
Tuchman, R, Cuccaro, M, Alessandri, M. Autism and epilepsy: historical perspective. Brain Dev. October 2010;32(9):709–718. Google Scholar | Crossref | Medline | ISI |
| 6. |
Li, BM, Liu, XR, Yi, YH. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav. July 2011;21(3):291–295. Google Scholar | Crossref | Medline | ISI |
| 7. |
Parmeggiani, A, Barcia, G, Posar, A, Raimondi, E, Santucci, M, Scaduto, MC. Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev. October 2010;32(9):783–789. Google Scholar | Crossref | Medline | ISI |
| 8. |
Frye, RE, Sreenivasula, S, Adams, JB. Traditional and non-traditional treatments for autism spectrum disorder with seizures: an on-line survey. BMC Pediatr. 2011;11:37. Google Scholar | Crossref | Medline | ISI |
| 9. |
Rossignol, DA . Novel and emerging treatments for autism spectrum disorders: a systematic review. Ann Clin Psychiatry. October-December 2009;21(4):213–236. Google Scholar | Medline | ISI |
| 10. |
Vojdani, A, Bazargan, M, Vojdani, E. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease. Clin Diagn Lab Immunol. May 2004;11(3):515–524. Google Scholar | Crossref | Medline |
| 11. |
Vojdani, A, Campbell, AW, Anyanwu, E, Kashanian, A, Bock, K, Vojdani, E. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol. August 2002;129(1-2):168–177. Google Scholar | Crossref | Medline | ISI |
| 12. |
Vojdani, A, O'Bryan, T, Green, JA. Immune response to dietary proteins, gliadin and cerebellar peptides in children with autism. Nutr Neurosci. June 2004;7(3):151–161. Google Scholar | Crossref | Medline | ISI |
| 13. |
Vojdani, A, Pangborn, JB, Vojdani, E, Cooper, EL. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. September-December 2003;16(3):189–199. Google Scholar | SAGE Journals | ISI |
| 14. |
Jyonouchi, H, Geng, L, Ruby, A, Reddy, C, Zimmerman-Bier, B. Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders. J Pediatr. May 2005;146(5):605–610. Google Scholar | Crossref | Medline | ISI |
| 15. |
Barcia, G, Posar, A, Santucci, M, Parmeggiani, A. Autism and coeliac disease. J Autism Dev Disord. February 2008;38(2):407–408. Google Scholar | Crossref | Medline | ISI |
| 16. |
Jyonouchi, H, Geng, L, Streck, DL, Toruner, GA. Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes. J Neuroimmunol. September 15 2011;238(1-2):73–80. Google Scholar | Crossref | Medline | ISI |
| 17. |
Jyonouchi, H . Food allergy and autism spectrum disorders: is there a link? Curr Allergy Asthma Rep. May 2009;9(3):194–201. Google Scholar | Crossref | Medline | ISI |
| 18. |
Jyonouchi, H . Autism spectrum disorders and allergy: observation from a pediatric allergy/immunology clinic. Expert Rev Clin Immunol. May 2010;6(3):397–411. Google Scholar | Crossref | Medline | ISI |
| 19. |
Lucarelli, S, Frediani, T, Zingoni, AM. Food allergy and infantile autism. Panminerva Med. September 1995;37(3):137–141. Google Scholar | Medline | ISI |
| 20. |
Evangeliou, A, Vlachonikolis, I, Mihailidou, H. Application of a ketogenic diet in children with autistic behavior: pilot study. J Child Neurol. February 2003;18(2):113–118. Google Scholar | SAGE Journals | ISI |
| 21. |
Blades, M . Autism: an interesting dietary case history. Nutr Food Sci. 2000;30(3):137–140. Google Scholar | Crossref |
| 22. |
Reichelt, KL, Ekrem, J, Scott, H. Gluten, milk proteins and autism: dietary intervention effects on behavior and peptide secretion. J Appl Nutr. 1990;42(1):1–11. Google Scholar |
| 23. |
Knivsberg, AM, Wiig, K, Lind, G, NØDland, M, Reichelt, KL. Dietary intervention in autistic syndromes. Brain Dysfunction. 1990;3(5-6):315–327. Google Scholar |
| 24. |
Knivsberg, AM, Reichelt, KL, Nodland, M, Hoien, T. Autistic symptoms and diet: a follow-up study. Scand J Ed Res. 1995;39:223–236. Google Scholar | Crossref |
| 25. |
Whiteley, P, Rodgers, J, Savery, D, Shattock, P. A gluten-free diet as an intervention for autism and associated spectrum disorders: preliminary findings. Autism. 1999;3(1):45. Google Scholar | SAGE Journals |
| 26. |
Cade, R, Privette, M, Fregly, M. Autism and schizophrenia: intestinal disorders. Nutritional Neuroscience. 2000;3:57–72. Google Scholar | Crossref | Medline | ISI |
| 27. |
Goin-Kochel, R, Mackintosh, V, Myers, B. Parental reports on the efficacy of treatments and therapies for their children with autism spectrum disorders. Res Autism Spectrum Dis. 2009;3:528–261. Google Scholar | Crossref | ISI |
| 28. |
Pennesi, CM, Klein, LC. Effectiveness of the gluten-free, casein-free diet for children diagnosed with autism spectrum disorder: based on parental report. Nutr Neurosci. March 2012;15(2):85–91. Google Scholar | Crossref | Medline | ISI |
| 29. |
Christison, GW, Ivany, K. Elimination diets in autism spectrum disorders: any wheat amidst the chaff? J Dev Behav Pediatr. April 2006;27(2 suppl): S162–S171. Google Scholar | Crossref | Medline | ISI |
| 30. |
Sponheim, E. [Gluten-free diet in infantile autism. A therapeutic trial]. Tidsskr Nor Laegeforen. February 28, 1991;111(6):704–707. Google Scholar | Medline |
| 31. |
Millward, C, Ferriter, M, Calver, S, Connell-Jones, G. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008(2):CD003498. Google Scholar | Medline | ISI |
| 32. |
Whiteley, P, Haracopos, D, Knivsberg, AM. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. April 2010;13(2):87–100. Google Scholar | Crossref | Medline | ISI |
| 33. |
Whiteley, P, Shattock, P, Knivsberg, AM. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2012;6:344. Google Scholar | Medline | ISI |
| 34. |
Masino, SA, Kawamura, M, Wasser, CD, Pomeroy, LT, Ruskin, DN. Adenosine, ketogenic diet and epilepsy: the emerging therapeutic relationship between metabolism and brain activity. Curr Neuropharmacol. September 2009;7(3):257–268. Google Scholar | Crossref | Medline | ISI |
| 35. |
Stafstrom, CE, Bough, KJ. The ketogenic diet for the treatment of epilepsy: a challenge for nutritional neuroscientists. Nutr Neurosci. April 2003;6(2):67–79. Google Scholar | Crossref | Medline | ISI |
| 36. |
Bjelland, I, Tell, GS, Vollset, SE, Refsum, H, Ueland, PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. June 2003;60(6):618–626. Google Scholar | Crossref | Medline |
| 37. |
Armstrong, DJ, Meenagh, GK, Bickle, I, Lee, AS, Curran, ES, Finch, MB. Vitamin D deficiency is associated with anxiety and depression in fibromyalgia. Clin Rheumatol. April 2007;26(4):551–554. Google Scholar | Crossref | Medline | ISI |
| 38. |
Berk, M, Jacka, FN, Williams, LJ, Ng, F, Dodd, S, Pasco, JA. Is this D vitamin to worry about? Vitamin D insufficiency in an inpatient sample. Aust N Z J Psychiatry. October 2008;42(10):874–878. Google Scholar | SAGE Journals | ISI |
| 39. |
Alramadhan, E, Hanna, MS, Goldstein, TA, Avila, SM, Weeks, BS. Dietary and botanical anxiolytics. Med Sci Monit. April 2012;18(4):RA40–48. Google Scholar | Medline | ISI |
| 40. |
Weeks, BS. Formulations of dietary supplements and herbal extracts for relaxation and anxiolytic action: Relarian. Med Sci Monit. November 2009;15(11):RA256–262. Google Scholar | Medline | ISI |
| 41. |
Papakostas, GI, Cassiello, CF, Iovieno, N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry. July 2012;57(7):406–413. Google Scholar | SAGE Journals | ISI |
| 42. |
Papakostas, GI, Shelton, RC, Zajecka, JM. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry. December 1, 2012;169(12):1267–1274. Google Scholar | Crossref | Medline | ISI |
| 43. |
Devinsky, O, Schachter, SC, Pacia, S, eds. Complementary and Alternative Therapies for Epilepsy. New York, NY: Demos; 2005. Google Scholar |
| 44. |
Farnalls, SL, Rennick, J. Parents’ caregiving approaches: facing a new treatment alternative in severe intractable childhood epilepsy. Seizure. January 2003;12(1):1–10. Google Scholar | Crossref | Medline | ISI |
| 45. |
Kneen, R, Appleton, RE. Alternative approaches to conventional antiepileptic drugs in the management of paediatric epilepsy. Arch Dis Child. November 2006;91(11):936–941. Google Scholar | Crossref | Medline | ISI |
| 46. |
McElroy-Cox, C . Alternative approaches to epilepsy treatment. Curr Neurol Neurosci Rep. July 2009;9(4):313–318. Google Scholar | Crossref | Medline | ISI |
| 47. |
Gaby, AR . Natural approaches to epilepsy. Altern Med Rev. March 2007;12(1):9–24. Google Scholar | Medline |
| 48. |
Semmler, A, Moskau-Hartmann, S, Stoffel-Wagner, B, Elger, C, Linnebank, M. Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism. Clin Chem Lab Med. February 1, 2013:1–5. Google Scholar | Medline | ISI |
| 49. |
Morrell, MJ . Folic Acid and Epilepsy. Epilepsy Curr. March 2002;2(2):31–34. Google Scholar | SAGE Journals |
| 50. |
Coppola, G, Ingrosso, D, Operto, FF. Role of folic acid depletion on homocysteine serum level in children and adolescents with epilepsy and different MTHFR C677 T genotypes. Seizure. June 2012;21(5):340–343. Google Scholar | Crossref | Medline | ISI |
| 51. |
Linnebank, M, Moskau, S, Semmler, A. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. February 2011;69(2):352–359. Google Scholar | Crossref | Medline | ISI |
| 52. |
Freeman, JM, Kossoff, EH, Hartman, AL. The ketogenic diet: one decade later. Pediatrics. March 2007;119(3):535–543. Google Scholar | Crossref | Medline | ISI |
| 53. |
Pan, JW, Williamson, A, Cavus, I. Neurometabolism in human epilepsy. Epilepsia. 2008;49(suppl 3):31–41. Google Scholar | Crossref | Medline | ISI |
| 54. |
Chuang, YC . Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell death. Acta Neurol Taiwan. March 2010;19(1):3–15. Google Scholar | Medline |
| 55. |
Liang, LP, Patel, M. Seizure-induced changes in mitochondrial redox status. Free Radic Biol Med. January 15, 2006;40(2):316–322. Google Scholar | Crossref | Medline | ISI |
| 56. |
Patel, M . Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med. December 15, 2004;37(12):1951–1962. Google Scholar | Crossref | Medline | ISI |
| 57. |
Oliveira, G, Diogo, L, Grazina, M. Mitochondrial dysfunction in autism spectrum disorders: a population-based study. Dev Med Child Neurol. March 2005;47(3):185–189. Google Scholar | Crossref | Medline | ISI |
| 58. |
Weissman, JR, Kelley, RI, Bauman, ML. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS One. 2008;3(11): e3815. Google Scholar | Crossref | Medline | ISI |
| 59. |
Rossignol, DA, Frye, RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012;17(3):290–314. Google Scholar | Crossref | Medline | ISI |
| 60. |
Rose, S, Melnyk, S, Pavliv, O. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2012;2:e134. Google Scholar | Crossref | Medline | ISI |
| 61. |
Ghanizadeh, A, Akhondzadeh, S, Hormozi, Makarem A, Abotorabi, M, Firoozabadi, A. Glutathione-related factors and oxidative stress in autism, a review. Curr Med Chem. 2012;19(23):4000–4005. Google Scholar | Crossref | Medline | ISI |
| 62. |
Frustaci, A, Neri, M, Cesario, A. Oxidative stress-related biomarkers in autism: Systematic review and meta-analyses. Free Radic Biol Med. May 15, 2012;52(10):2128–2141. Google Scholar | Crossref | Medline | ISI |
| 63. |
Chauhan, A, Audhya, T, Chauhan, V. Brain region-specific glutathione redox imbalance in autism. Neurochem Res. August 2012;37(8):1681–1689. Google Scholar | Crossref | Medline | ISI |
| 64. |
Rossignol, DA, Frye, RE. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry. 2012;17(4):389–401. Google Scholar | Crossref | Medline | ISI |
| 65. |
Damodaran, LP, Arumugam, G. Urinary oxidative stress markers in children with autism. Redox Rep. 2011;16(5):216–222. Google Scholar | Crossref | Medline | ISI |
| 66. |
Chauhan, A, Chauhan, V, Brown, T, eds. Autism: Oxidative Stress, Inflammation and Immune Abnormalities. Boca Raton, FL: Taylor & Francis; 2009. Google Scholar | Crossref |
| 67. |
Cardenas-Rodriguez, N, Huerta-Gertrudis, B, Rivera-Espinosa, L. Role of oxidative stress in refractory epilepsy: evidence in patients and experimental models. Int J Mol Sci. 2013;14(1):1455–1476. Google Scholar | Crossref | Medline | ISI |
| 68. |
Menon, B, Ramalingam, K, Kumar, RV. Oxidative stress in patients with epilepsy is independent of antiepileptic drugs. Seizure. December 2012;21(10):780–784. Google Scholar | Crossref | Medline | ISI |
| 69. |
Aguiar, CC, Almeida, AB, Araujo, PV. Oxidative stress and epilepsy: literature review. Oxid Med Cell Longev. 2012;2012:795259. Google Scholar | Crossref | Medline | ISI |
| 70. |
Shin, EJ, Jeong, JH, Chung, YH. Role of oxidative stress in epileptic seizures. Neurochem Int. August 2011;59(2):122–137. Google Scholar | Crossref | Medline | ISI |
| 71. |
Waldbaum, S, Patel, M. Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy? J Bioenerg Biomembr. December 2010;42(6):449–455. Google Scholar | Crossref | Medline | ISI |
| 72. |
James, SJ, Melnyk, S, Jernigan, S. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. December 5, 2006;141B(8):947–956. Google Scholar | Crossref | Medline | ISI |
| 73. |
Weisberg, I, Tran, P, Christensen, B, Sibani, S, Rozen, R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. July 1998;64(3):169–172. Google Scholar | Crossref | Medline | ISI |
| 74. |
Mohammad, NS, Jain, JM, Chintakindi, KP, Singh, RP, Naik, U, Akella, RR. Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. August 2009;19(4):171–176. Google Scholar | Crossref | Medline | ISI |
| 75. |
Schmidt, RJ, Hansen, RL, Hartiala, J. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. July 2011;22(4):476–485. Google Scholar | Crossref | Medline | ISI |
| 76. |
Ramaekers, VT, Sequeira, JM, Blau, N, Quadros, EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol. May 2008;50(5):346–352. Google Scholar | Crossref | Medline | ISI |
| 77. |
Hall, EH, Crowe, SE. Environmental and lifestyle influences on disorders of the large and small intestine: implications for treatment. Dig Dis. 2011;29(2):249–254. Google Scholar | Crossref | Medline | ISI |
| 78. |
Ribaldone, DG, Astegiano, M, Fagoonee, S, Rizzetto, M, Pellicano, R. Epilepsy and celiac disease: review of literature. Panminerva Med. December 2011;53(4):213–216. Google Scholar | Medline | ISI |
| 79. |
Miskiewicz, P, Kepczynska-Nyk, A, Bednarczuk, T. Coeliac disease in endocrine diseases of autoimmune origin. Endokrynol Pol. 2012;63(3):240–249. Google Scholar | Medline | ISI |
| 80. |
Visser, J, Rozing, J, Sapone, A, Lammers, K, Fasano, A. Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms. Ann N Y Acad Sci. May 2009;1165:195–205. Google Scholar | Crossref | Medline | ISI |
| 81. |
Sellitto, M, Bai, G, Serena, G. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PLoS One. 2012;7(3):e33387. Google Scholar | Crossref | Medline | ISI |
| 82. |
Gonzalez, A, Stombaugh, J, Lozupone, C, Turnbaugh, PJ, Gordon, JI, Knight, R. The mind-body-microbial continuum. Dialogues Clin Neurosci. 2011;13(1):55–62. Google Scholar | Crossref | Medline |
| 83. |
Kallus, SJ, Brandt, LJ. The intestinal microbiota and obesity. J Clin Gastroenterol. January 2012;46(1):16–24. Google Scholar | Crossref | Medline | ISI |
| 84. |
Greenblum, S, Turnbaugh, PJ, Borenstein, E. Metagenomic systems biology of the human gut microbiome reveals topological shifts associated with obesity and inflammatory bowel disease. Proc Natl Acad Sci USA. January 10, 2012;109(2):594–599. Google Scholar | Crossref | Medline | ISI |
| 85. |
Tilg, H, Kaser, A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest. June 2011;121(6):2126–2132. Google Scholar | Crossref | Medline | ISI |
| 86. |
Maccaferri, S, Biagi, E, Brigidi, P. Metagenomics: key to human gut microbiota. Dig Dis. 2011;29(6):525–530. Google Scholar | Crossref | Medline | ISI |
| 87. |
Bach, A, Schirardin, H, Weryha, A, Bauer, M. Ketogenic response to medium-chain triglyceride load in the rat. J Nutr. October 1977;107(10):1863–1870. Google Scholar | Crossref | Medline | ISI |
