Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Piotr Duda
 -- 1882 2022-11-30 21:47:22 |
2 Reference format revised.
Lindsay Dong
Meta information modification 1882 2022-12-01 10:34:58 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Skrobas, U.;  Duda, P.;  Bryliński, �.;  Drożak, P.;  Pelczar, M.;  Rejdak, K. Ketogenic Diets in the Management of Lennox-Gastaut Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/37405 (accessed on 27 July 2024).
Skrobas U,  Duda P,  Bryliński �,  Drożak P,  Pelczar M,  Rejdak K. Ketogenic Diets in the Management of Lennox-Gastaut Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/37405. Accessed July 27, 2024.
Skrobas, Urszula, Piotr Duda, Łukasz Bryliński, Paulina Drożak, Magdalena Pelczar, Konrad Rejdak. "Ketogenic Diets in the Management of Lennox-Gastaut Syndrome" Encyclopedia, https://encyclopedia.pub/entry/37405 (accessed July 27, 2024).
Skrobas, U.,  Duda, P.,  Bryliński, �.,  Drożak, P.,  Pelczar, M., & Rejdak, K. (2022, November 30). Ketogenic Diets in the Management of Lennox-Gastaut Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/37405
Skrobas, Urszula, et al. "Ketogenic Diets in the Management of Lennox-Gastaut Syndrome." Encyclopedia. Web. 30 November, 2022.
Ketogenic Diets in the Management of Lennox-Gastaut Syndrome
Edit
This entry is adapted from the peer-reviewed paper 10.3390/nu14234977

Epilepsy is an important medical problem with approximately 50 million patients globally. No more than 70% of epileptic patients will achieve seizure control after antiepileptic drugs, and several epileptic syndromes, including Lennox-Gastaut syndrome (LGS), are predisposed to more frequent pharmacoresistance. Ketogenic dietary therapies (KDTs) are a form of non-pharmacological treatments used in attempts to provide seizure control for LGS patients who experience pharmacoresistance. In general, KDTs are diets rich in fat and low in carbohydrates that put the organism into the state of ketosis. A classic ketogenic diet (cKD) is the best-evaluated KDT, while alternative KDTs, such as the medium-chain triglyceride diet (MCT), modified Atkins diet (MAD), and low glycemic index treatment (LGIT) present several advantages due to their better tolerability and easier administration. The literature reports regarding LGS suggest that KDTs can provide ≥50% seizure reduction and seizure-free status in a considerable percentage of the patients.

Keywords: epilepsy epileptic syndromes Lennox-Gastaut syndrome diet therapy ketogenic diets

1. Introduction

Epilepsy is a common neurological disease with approximately 50 million patients globally. Only fewer than 70% of epileptic patients can achieve seizure control with anti-epileptic drugs [1]. There are certain syndromes in which that percentage is significantly lower, e.g., Lennox-Gastaut syndrome (LGS). LGS is a rare, severe, early-onset developmental epileptic encephalopathy characterized by a triad of multiple drug-resistant seizure types, a specific electroencephalography pattern showing bursts of slow spike-wave complexes or generalized paroxysmal fast activity, and intellectual impairment. Not all patients have all of the core seizure types (e.g., tonic, atonic, and atypical absences), especially at onset [2]. The tonic type of seizure is seen in all patients with LGS, but may not be present at the time of its onset [3]. The incidence of LGS is estimated at 0.1 to 0.28 per 100,000 people per year; the lifetime prevalence at the age of ten years amounts to 0.26 per 1000 children [4]. It is estimated that LGS patients account for 1–10% of cases of childhood epilepsy and 1–2% of all epilepsy patients [2]. There are identifiable and non-identifiable causes of LGS. Approximately, 65 to 75% of patients have an identifiable cause. These include brain damage (e.g., head injury), perinatal complications (e.g., birth asphyxia, intrauterine growth retardation, kernicterus), congenital central nervous system malformations (e.g., tuberous sclerosis), infections (e.g., meningitis, sepsis), or metabolic disorders [2][3]. When LGS has no apparent cause, a genetic predisposition or etiology is probable [2]. The mutation of genes involved in human brain development (e.g., the forkhead box G1 (FOXG1), or chromodomain-helicase-DNA-binding protein 2 (CHD2) genes) and the gene for presynaptic protein dynamin 1 (DNM 1) have been found to be associated with this syndrome. Valproate, lamotrigine, and topiramate are considered the first-choice drugs. According to randomized control trials, other anti-epileptics reported to be effective are clobazam, felbamate, and rufinamide. It is important to start with as few drugs at a time as possible, in the lowest possible doses. If the first drug fails, change to another drug, but if the second drug is also not effective, a second agent can be added to the existing regimen [3]. As available pharmacologic treatments for seizures are limited in their efficacy, several non-pharmacological methods are used, including surgical and dietary interventions. Surgical procedures can lead to control in a select subset of patients suitable for that kind of treatment but still, a significant number of patients are left with uncontrolled seizures. The ketogenic diet and related diets have proven to be useful in drug-resistant childhood epilepsy [5].

2. Ketogenic Dietary Therapies

KDTs are well-established, nonpharmacological treatments used for children and adults with pharmacoresistant epilepsy [6]. Their mechanisms of action rely on putting the organism into a ketogenic state, similar to starvation, which has been reported as a treatment for epilepsy since ancient times [7]. KDT refers to any diet therapy in which dietary composition results in a ketogenic state of human metabolism. The diet generally refers to a high-fat, low-carbohydrate, and moderate-protein diet. Following the development of the classic ketogenic diet (cKD), new diets have been proposed in an attempt to increase retention and savoriness while imitating the effects produced by the original diet. Currently, there are four major KDTs—cKD, the modified Atkins diet (MAD), the medium-chain triglyceride diet (MCT), and the low glycemic index treatment (LGIT). 

The cKD and the MCT diet have been in existence the longest and are typically started in the hospital by a dietitian and neurologist. cKD is the oldest and the most researched diet among dietary therapies for epilepsy. It was designed in the year 1923 by doctor Russell Wilder from the Mayo Clinic and was designed to particularly treat this disease [8][9]. In the cKD, the fat source is largely long-chain triglycerides (LCT), which are gained mainly from standard foods. cKD is typically administered in a 4:1 ratio of fat to carbohydrate and protein, providing 90% of the total calories from the fat. MCT oils provide more ketones per kilocalorie of energy than LCTs. This enlarged ketogenic potential means less total fat is needed in the MCT diet, which allows the inclusion of more carbohydrates and protein and more potential food choices [6]. In both of the above-mentioned KDTs, calculations and arrangements concerning the diet and education of a patient and their family should be conducted by a dietitian [6][10].
As the cKD and MCT can be too restrictive, alternative diets were created. They are more liberal versions of the cKD, which are less restrictive on protein and calorie intake, more affordable for patients, and can be similarly effective in the treatment of epilepsy. The MAD was created at Johns Hopkins Hospital in 2003, primarily for children with behavioral difficulties and adolescents whose parents and neurologists were unwilling to start on the cKD [11]. The MAD is a high-fat, low-carbohydrate therapy which typically provides approximately a 1:1–1.5:1 ketogenic ratio, but no set ratio is required and some children can achieve a ratio as high as 4:1. The initial daily carbohydrate consumption on the MAD is approximately 10–15 g with a possible increase to 20 g per day after 1–3 months. In addition, there is no restriction on protein, fluids, or calories, making meal planning easier. Detailed calculations are not required [6].
The LGIT was introduced as an elasticized version of the cKD and was first found to be successful in Massachusetts General Hospital in 2005 [12]. The diet is more liberal and allows 40 to 60 g of carbohydrates per day, but restricts sources of carbohydrates to a glycemic index of less than 50 to prevent postprandial increases in blood glucose. Fats and proteins are unrestricted. This diet is preferred by adolescents because of their difficulty in following the cKD. Admission to hospital is not required to implement the treatment [13].

3. Mechanisms of KDTs’ Antiseizure Effect

Despite the antiseizure effect of ketosis being known from ancient times [7], the mechanisms of KDTs’ action have not been fully elucidated [14]. Among proposed theories, the abundance of ketone bodies (KBs) and fatty acids, the decreased glucose supply, and the impact on gut microbiota are mainly considered, inducing the modifications of neuronal metabolism, neurotransmitters, and ion channels [15][16][17].

KBs and fatty acids can generate direct changes in organism homeostasis. Acetoacetate [18] and beta-hydroxybutyrate [18][19] were shown to induce activation of ATP-sensitive potassium (KATP) channels [18][19], while polyunsaturated fatty acids (PUFA) and, presumably, KBs activate two-pore domain potassium (K2P) channels [20], increasing the seizure threshold via neuronal hyperpolarization [18][19][20]. A medium-chain fatty acid—decanoic acids—was shown to independently contribute to seizure control through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition [21].

KDTs conditions also promote neuronal stability via their effects on the neurotransmitters mainly affecting gamma-aminobutyric acid (GABA) [15]. Upregulation of glutamic acid decarboxylase [22] and reduction in GABA transaminase activity [23] were suggested to result in enhanced GABA concentration. Regarding glutamate, the impact of KDTs on its levels is inconstant, and further research in this field is needed. Norepinephrine, dopamine, serotonin, galanine, and neuropeptide Y are highlighted among other neurotransmitters presumably involved in the antiseizure effect of KDTs [15].

Regarding energy metabolism, prolonged KDT implementation promotes mitochondria synthesis and concentration, increasing adenosine triphosphate (ATP) generation and enhancing the brain’s resistance to metabolic stress [15][24]. Reduced glycolysis presumably contributes to the antiseizure effect, as an intravenous glucose bolus reverses ketonemia and the antiseizure effects of KDTs rapidly [25]. 

4. Efficacy of cKD

The efficacy of cKD in the treatment of LGS is well-documented in scientific research. A literature review conducted by Lemmon ME et al. [26], which included 18 papers from the years 1989–2010 concerning applying cKD in, overall, 189 children with LGS, showed that after 3–36 months of using this diet, 47% of investigated children experienced ≥50% seizure reduction, whereas 16% of children achieved seizure-free status. Moreover, it was proven that the cKD causes a reduction in multiple types of epileptic seizures, including tonic, atonic, or atypical absence seizures.
No predictive factors were found for the reduction in the number of seizures after using cKD in LGS. Research by Lemmon ME et al. [26] showed that age, gender, presence of side effects, etiology of LGS, number of previously taken anticonvulsants, and history of seizures during infancy were not predictive of >90% seizure reduction after 12 months of using cKD [26]. 

5. Efficacy of Alternative Ketogenic Diets

Although alternative ketogenic diets were introduced to provide better tolerability and palatability than cKD, their efficacy is the most important issue. The comparison of the efficacy of MAD and cKD was assessed among the general population of children and adolescents with epilepsy. In a meta-analysis conducted by Razaei et al. [27], no statistically significant differences in efficacy were reported between MAD and cKD. Regarding LGS patients, a study conducted by Sharma S et al. [28] comprised of 25 pediatric LGS patients treated with MAD. After three months, nearly half of the patients had a ≥50% reduction in seizure frequency. After six months, 14 children discontinued the diet; however, all of the children who remained on the diet had more than a 50% reduction in seizure frequency both at the 6th and 12th month of the study [28].

6. Safety and Tolerability of Ketogenic Dietary Therapies

The literature reports from the general epileptic population show that KDTs are generally considered as safe treatment options [29][30][31]. They are applied in adults, as well as in children [32], showing good tolerability for patients as young as six weeks [33]. Additionally, cKD may be used in groups of LGS patients presenting certain metabolic abnormalities.
In the case of LGS, the use of cKD could have certain side effects including gastrointestinal disturbances, such as diarrhea, constipation or vomiting, hypocalcemia, kidney stones, hyperuricemia, and metabolic acidosis [34]. Patients subjected to cKD also experience problems with the cardiovascular system, kidneys, and skeletal system [35]. Moreover, research shows that this diet could cause growth retardation in children [36][37]; however, the data regarding growth retardation is mixed [6]. It was proven that patients who experience side effects have a higher risk of non-adherence to this diet [38].
Compared to cKD, a lower occurrence of side effects is an advantage of LGIT. As a result, this diet is reported as easier to use and continue [15][39]. The side effect among all patients in one of the reported studies was transient diarrhea. In addition, laboratory abnormalities were observed—reduced serum total carbon dioxide, hypercholesterolemia, increased alanine aminotransferase, increased lipase, and increased blood urea nitrogen. However, mentioned conditions did not require additional management or medication [40].

7. Conclusions

KDTs are effective in LGS treatment. KDTs are reported as safe treatment options and can be administered to different populations of epileptic patients. The most common complications include constipation, diarrhea, and vomiting, while severe adverse effects are rarely reported. Several less-restrictive KDTs, including MCT, MAD, and LGIT, are worth considering, due to their better tolerability, lower treatment costs, and easier administration.

References

  1. Epilepsy. Available online: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy (accessed on 23 February 2022).
  2. Asadi-Pooya, A.A. Lennox-Gastaut Syndrome: A Comprehensive Review. Neurol. Sci. 2018, 39, 403–414.
  3. Jahngir, M.U.; Ahmad, M.Q.; Jahangir, M. Lennox-Gastaut Syndrome: In a Nutshell. Cureus 2018, 10, e3134.
  4. Orphanet: Lennox Gastaut Syndrome. Available online: https://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=2382 (accessed on 9 May 2022).
  5. Winesett, S.P.; Bessone, S.K.; Kossoff, E.H.W. The Ketogenic Diet in Pharmacoresistant Childhood Epilepsy. Expert Rev. Neurother. 2015, 15, 621–628.
  6. Kossoff, E.H.; Zupec-Kania, B.A.; Auvin, S.; Ballaban-Gil, K.R.; Christina Bergqvist, A.G.; Blackford, R.; Buchhalter, J.R.; Caraballo, R.H.; Cross, J.H.; Dahlin, M.G.; et al. Optimal Clinical Management of Children Receiving Dietary Therapies for Epilepsy: Updated Recommendations of the International Ketogenic Diet Study Group. Epilepsia Open 2018, 3, 175–192.
  7. Wheless, J.W. History of the Ketogenic Diet. Epilepsia 2008, 49, 3–5.
  8. Pinto, A.; Bonucci, A.; Maggi, E.; Corsi, M.; Businaro, R. Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease. Antioxidants 2018, 7, 63.
  9. Misiewicz Runyon, A.; So, T.-Y. The Use of Ketogenic Diet in Pediatric Patients with Epilepsy. ISRN Pediatr. 2012, 2012, 263139.
  10. Pfeifer, H.H.; Lyczkowski, D.A.; Thiele, E.A. Low Glycemic Index Treatment: Implementation and New Insights into Efficacy. Epilepsia 2008, 49 (Suppl. S8), 42–45.
  11. Kossoff, E.H.; Dorward, J.L. The Modified Atkins Diet. Epilepsia 2008, 49, 37–41.
  12. Pfeifer, H.H.; Thiele, E.A. Low-Glycemic-Index Treatment: A Liberalized Ketogenic Diet for Treatment of Intractable Epilepsy. Neurology 2005, 65, 1810–1812.
  13. Wells, J.; Swaminathan, A.; Paseka, J.; Hanson, C. Efficacy and Safety of a Ketogenic Diet in Children and Adolescents with Refractory Epilepsy-A Review. Nutrients 2020, 12, 1809.
  14. Fan, Y.; Wang, H.; Liu, X.; Zhang, J.; Liu, G. Crosstalk between the Ketogenic Diet and Epilepsy: From the Perspective of Gut Microbiota. Mediat. Inflamm. 2019, 2019, 8373060.
  15. Barzegar, M.; Afghan, M.; Tarmahi, V.; Behtari, M.; Rahimi Khamaneh, S.; Raeisi, S. Ketogenic Diet: Overview, Types, and Possible Anti-Seizure Mechanisms. Nutr. Neurosci. 2021, 24, 307–316.
  16. D’Andrea Meira, I.; Romão, T.T.; Do Prado, H.J.P.; Krüger, L.T.; Pires, M.E.P.; Da Conceição, P.O. Ketogenic Diet and Epilepsy: What We Know so Far. Front. Neurosci. 2019, 13, 5.
  17. Lindefeldt, M.; Eng, A.; Darban, H.; Bjerkner, A.; Zetterström, C.K.; Allander, T.; Andersson, B.; Borenstein, E.; Dahlin, M.; Prast-Nielsen, S. The Ketogenic Diet Influences Taxonomic and Functional Composition of the Gut Microbiota in Children with Severe Epilepsy. NPJ Biofilms Microbiomes 2019, 5, 5.
  18. Yellen, G. Ketone Bodies, Glycolysis, and KATP Channels in the Mechanism of the Ketogenic Diet. Epilepsia 2008, 49, 80.
  19. Tanner, G.R.; Lutas, A.; Martínez-François, J.R.; Yellen, G. Single K ATP Channel Opening in Response to Action Potential Firing in Mouse Dentate Granule Neurons. J. Neurosci. 2011, 31, 8689–8696.
  20. Vamecq, J.; Vallée, L.; Lesage, F.; Gressens, P.; Stables, J.P. Antiepileptic Popular Ketogenic Diet: Emerging Twists in an Ancient Story. Prog. Neurobiol. 2005, 75, 1–28.
  21. Boison, D. New Insights into the Mechanisms of the Ketogenic Diet. Curr. Opin. Neurol. 2017, 30, 187–192.
  22. Cheng, C.M.; Hicks, K.; Wang, J.; Eagles, D.A.; Bondy, C.A. Caloric Restriction Augments Brain Glutamic Acid Decarboxylase-65 and -67 Expression. J. Neurosci. Res. 2004, 77, 270–276.
  23. Suzuki, Y.; Takahashi, H.; Fukuda, M.; Hino, H.; Kobayashi, K.; Tanaka, J.; Ishii, E. Beta-Hydroxybutyrate Alters GABA-Transaminase Activity in Cultured Astrocytes. Brain Res. 2009, 1268, 17–23.
  24. Nylen, K.; Likhodii, S.; Burnham, W.M.I. The Ketogenic Diet: Proposed Mechanisms of Action. Neurotherapeutics 2009, 6, 402.
  25. Huttenlocher, P.R. Ketonemia and Seizures: Metabolic and Anticonvulsant Effects of Two Ketogenic Diets in Childhood Epilepsy. Pediatr. Res. 1976, 10, 536–540.
  26. Lemmon, M.E.; Terao, N.N.; Ng, Y.T.; Reisig, W.; Rubenstein, J.E.; Kossoff, E.H. Efficacy of the Ketogenic Diet in Lennox-Gastaut Syndrome: A Retrospective Review of One Institution’s Experience and Summary of the Literature. Dev. Med. Child Neurol. 2012, 54, 464–468.
  27. Rezaei, S.; Abdurahman, A.A.; Saghazadeh, A.; Badv, R.S.; Mahmoudi, M. Short-Term and Long-Term Efficacy of Classical Ketogenic Diet and Modified Atkins Diet in Children and Adolescents with Epilepsy: A Systematic Review and Meta-Analysis. Nutr. Neurosci. 2019, 22, 317–334.
  28. Sharma, S.; Jain, P.; Gulati, S.; Sankhyan, N.; Agarwala, A. Use of the Modified Atkins Diet in Lennox Gastaut Syndrome. J. Child Neurol. 2015, 30, 576–579.
  29. Wu, Q.; Wang, H.; Fan, Y.Y.; Zhang, J.M.; Liu, X.Y.; Fang, X.Y.; Yang, F.H.; Cao, Q.J.; Qi, Y. Ketogenic Diet Effects on 52 Children with Pharmacoresistant Epileptic Encephalopathy: A Clinical Prospective Study. Brain Behav. 2018, 8, e00973.
  30. Na, J.H.; Kim, H.D.; Lee, Y.M. Effective and Safe Diet Therapies for Lennox-Gastaut Syndrome with Mitochondrial Dysfunction. Ther. Adv. Neurol. Disord. 2020, 13, 1–12.
  31. Sharawat, I.K.; Panda, P.K.P.; Sihag, R.K.; Panda, P.K.P.; Dawman, L. Efficacy and Safety of Corpus Callosotomy and Ketogenic Diet in Children with Lennox Gastaut Syndrome: A Systematic Review and Meta-Analysis. Childs Nerv. Syst. 2021, 37, 2557–2566.
  32. Williams, T.J.; Cervenka, M.C. The Role for Ketogenic Diets in Epilepsy and Status Epilepticus in Adults. Clin. Neurophysiol. Pract. 2017, 2, 154–160.
  33. Thompson, L.; Fecske, E.; Salim, M.; Hall, A. Use of the Ketogenic Diet in the Neonatal Intensive Care Unit-Safety and Tolerability. Epilepsia 2017, 58, e36–e39.
  34. Azevedo de Lima, P.; Baldini Prudêncio, M.; Murakami, D.K.; Pereira de Brito Sampaio, L.; Figueiredo Neto, A.M.; Teixeira Damasceno, N.R. Effect of Classic Ketogenic Diet Treatment on Lipoprotein Subfractions in Children and Adolescents with Refractory Epilepsy. Nutrition 2017, 33, 271–277.
  35. Cai, Q.-Y.; Zhou, Z.-J.; Luo, R.; Gan, J.; Li, S.-P.; Mu, D.-Z.; Wan, C.-M. Safety and Tolerability of the Ketogenic Diet Used for the Treatment of Refractory Childhood Epilepsy: A Systematic Review of Published Prospective Studies. World J. Pediatr. 2017, 13, 528–536.
  36. Ferraris, C.; Guglielmetti, M.; Pasca, L.; De Giorgis, V.; Ferraro, O.E.; Brambilla, I.; Leone, A.; De Amicis, R.; Bertoli, S.; Veggiotti, P.; et al. Impact of the Ketogenic Diet on Linear Growth in Children: A Single-Center Retrospective Analysis of 34 Cases. Nutrients 2019, 11, 1442.
  37. Bertoli, S.; Masnada, S.; De Amicis, R.; Sangiorgio, A.; Leone, A.; Gambino, M.; Lessa, C.; Tagliabue, A.; Ferraris, C.; De Giorgis, V.; et al. Glucose Transporter 1 Deficiency Syndrome: Nutritional and Growth Pattern Phenotypes at Diagnosis. Eur. J. Clin. Nutr. 2020, 74, 1290–1298.
  38. Martin-McGill, K.J.; Bresnahan, R.; Levy, R.G.; Cooper, P.N. Ketogenic Diets for Drug-Resistant Epilepsy; John Wiley and Sons Ltd.: Hoboken, NJ, USA, 2020; Volume 2020.
  39. Kumada, T.; Hiejima, I.; Nozaki, F.; Hayashi, A.; Fujii, T. Glycemic Index Treatment Using Japanese Foods in a Girl with Lennox-Gastaut Syndrome. Pediatr. Neurol. 2013, 48, 390–392.
  40. Kim, S.H.; Kang, H.C.; Lee, E.J.; Lee, J.S.; Kim, H.D. Low Glycemic Index Treatment in Patients with Drug-Resistant Epilepsy. Brain Dev. 2017, 39, 687–692.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Clinical Neurology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Urszula Skrobas
,
Piotr Duda
,
Łukasz Bryliński
,
Paulina Drożak
,
Magdalena Pelczar
,
Konrad Rejdak
View Times: 470
Revisions: 2 times (View History)
Update Date: 01 Dec 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback