Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KD-fed rats, with or without SE, had significantly impaired visual-spatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development.

[1]  G. Holmes,et al.  Long‐term Effects of Status Epilepticus in the Immature Brain Are Specific for Age and Model , 2003, Epilepsia.

[2]  S. Kang,et al.  The protective effect of a ketogenic diet on kainic acid-induced hippocampal cell death in the male ICR mice , 2003, Epilepsy Research.

[3]  P. Thavendiranathan,et al.  The effect of the ‘classic’ ketogenic diet on animal seizure models , 2003, Brain Research.

[4]  E. Vining,et al.  Growth of children on the ketogenic diet. , 2002, Developmental medicine and child neurology.

[5]  G. Holmes,et al.  Beneficial effects of enriched environment following status epilepticus in immature rats , 2002, Neurology.

[6]  S. Cunnane,et al.  Epilepsy and the Ketogenic Diet: Assessment of Ketosis in Children Using Breath Acetone , 2002, Pediatric Research.

[7]  G. Holmes,et al.  Memory impairment following status epilepticus in immature rats: time‐course and environmental effects , 2002, The European journal of neuroscience.

[8]  S. S. Almeida,et al.  Early postnatal protein malnutrition affects learning and memory in the distal but not in the proximal cue version of the Morris water maze , 2002, Behavioural Brain Research.

[9]  K. Bough,et al.  An anticonvulsant profile of the ketogenic diet in the rat , 2002, Epilepsy Research.

[10]  R. Schuller,et al.  Growth retardation in children with epilepsy on the ketogenic diet: a retrospective chart review. , 2002, Journal of the American Dietetic Association.

[11]  G. Holmes,et al.  Anticonvulsant action and long-term effects of gabapentin in the immature brain , 2001, Neuropharmacology.

[12]  N Burgess,et al.  Unilateral temporal lobectomy patients show lateralized topographical and episodic memory deficits in a virtual town. , 2001, Brain : a journal of neurology.

[13]  G. Holmes,et al.  Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus. , 2001, Brain research. Developmental brain research.

[14]  K. Bough,et al.  Comparison of the Anticonvulsant Efficacies and Neurotoxic Effects of Valproic Acid, Phenytoin, and the Ketogenic Diet , 2001, Epilepsia.

[15]  P. Pyzik,et al.  The ketogenic diet: a 3- to 6-year follow-up of 150 children enrolled prospectively. , 2001, Pediatrics.

[16]  C. Lazarus,et al.  Cognitive Performances and Locomotor Activity Following Dentate Granule Cell Damage in Rats: Role of Lesion Extent and Type of Memory Tested , 2001, Neurobiology of Learning and Memory.

[17]  J. Brandt,et al.  Effects of ketogenic diet on development and behavior: preliminary report of a prospective study. , 2001, Developmental medicine and child neurology.

[18]  G. Holmes,et al.  Timing of ketogenic diet initiation in an experimental epilepsy model. , 2000, Brain research. Developmental brain research.

[19]  D. Gilbert,et al.  The Ketogenic Diet: Seizure Control Correlates Better With Serum β-Hydroxybutyrate Than With Urine Ketones , 2000, Journal of child neurology.

[20]  W. Burnham,et al.  Dietary Fat, Ketosis, and Seizure Resistance in Rats on the Ketogenic Diet , 2000, Epilepsia.

[21]  J. P. Andrade,et al.  Behavioral effects of protein deprivation and rehabilitation in adult rats: relevance to morphological alterations in the hippocampal formation , 2000, Behavioural Brain Research.

[22]  K. Bough,et al.  A ketogenic diet has different effects upon seizures induced by maximal electroshock and by pentylenetetrazole infusion , 2000, Epilepsy Research.

[23]  P. Schwartzkroin,et al.  Age-dependent differences in flurothyl seizure sensitivity in mice treated with a ketogenic diet , 1999, Epilepsy Research.

[24]  K. Bough,et al.  Path Analysis Shows That Increasing Ketogenic Ratio, but Not β-Hydroxybutyrate, Elevates Seizure Threshold in the Rat , 1999, Developmental Neuroscience.

[25]  G. Winocur,et al.  The effects of high fat diets and environmental influences on cognitive performance in rats , 1999, Behavioural Brain Research.

[26]  G. Holmes,et al.  Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model. , 1999, Neuroreport.

[27]  K. Bough,et al.  Seizure resistance is dependent upon age and calorie restriction in rats fed a ketogenic diet , 1999, Epilepsy Research.

[28]  G. Holmes,et al.  Mossy fiber sprouting after recurrent seizures during early development in rats , 1999 .

[29]  K. Bough,et al.  A Ketogenic Diet Increases the Resistance to Pentylenetetrazole‐Induced Seizures in the Rat , 1999, Epilepsia.

[30]  J M Freeman,et al.  The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. , 1998, Pediatrics.

[31]  Y. Ben-Ari,et al.  Consequences of neonatal seizures in the rat: Morphological and behavioral effects , 1998, Annals of neurology.

[32]  J M Freeman,et al.  A multicenter study of the efficacy of the ketogenic diet. , 1998, Archives of neurology.

[33]  R. Sankar,et al.  Patterns of Status Epilepticus-Induced Neuronal Injury during Development and Long-Term Consequences , 1998, The Journal of Neuroscience.

[34]  G. Holmes,et al.  Ketogenic Diet: Effects on Expression of Kindled Seizures and Behavior in Adult Rats , 1997, Epilepsia.

[35]  P. Rogers,et al.  Acute Effects on Mood and Cognitive Performance of Breakfasts Differing in Fat and Carbohydrate Content , 1996, Appetite.

[36]  G. Winocur,et al.  Cognitive impairment in rats fed high-fat diets: a specific effect of saturated fatty-acid intake. , 1996, Behavioral neuroscience.

[37]  J. LaManna,et al.  Diet‐Induced Ketosis Does Not Cause Cerebral Acidosis , 1996, Epilepsia.

[38]  G. Holmes,et al.  Alternative Epilepsy Therapies: The Ketogenic Diet, Immunoglobulins, and Steroids , 1996, Epilepsia.

[39]  R. Wing,et al.  Cognitive effects of ketogenic weight-reducing diets. , 1995, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[40]  B. Strupp,et al.  Enduring cognitive effects of early malnutrition: a theoretical reappraisal. , 1995, The Journal of nutrition.

[41]  J. Galler,et al.  An analysis of spatial navigation in prenatally protein malnourished rats , 1994, Physiology & Behavior.

[42]  G. Holmes,et al.  Effects of quisqualic acid and glutamate on subsequent learning, emotionality, and seizure susceptibility in the immature and mature animal , 1993, Brain Research.

[43]  G. Holmes,et al.  Age‐Dependent Cognitive and Behavioral Deficits After Kainic Acid Seizures , 1993, Epilepsia.

[44]  E. Vining,et al.  Efficacy of the Ketogenic Diet for Intractable Seizure Disorders: Review of 58 Cases , 1992, Epilepsia.

[45]  K. Bedi.  Spatial learning ability of rats undernourished during early postnatal life , 1992, Physiology & Behavior.

[46]  K. Bedi.  Effects of undernutrition during early life on granule cell numbers in the rat dentate gyrus , 1991, The Journal of comparative neurology.

[47]  H. Romijn,et al.  At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? , 1991, Early human development.

[48]  J. P. Andrade,et al.  Long-term low-protein diet reduces the number of hippocampal mossy fiber synapses , 1991, Experimental Neurology.

[49]  J. Galler,et al.  Prenatal protein malnutrition and working memory performance in adult rats , 1990, Behavioural Brain Research.

[50]  K. Bedi,et al.  The effects of undernutrition during early life on spatial learning , 1989, Physiology & Behavior.

[51]  C. A. Castro,et al.  Early-life undernutrition impairs the development of the learning and short-term memory processes mediating performance in a conditional-spatial discrimination task , 1989, Behavioural Brain Research.

[52]  C. A. Castro,et al.  Early-life malnutrition selectively retards the development of distal- but not proximal-cue navigation. , 1987, Developmental psychobiology.

[53]  E. Vining,et al.  Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. , 1987, Pediatrics.

[54]  P. Morgane,et al.  Behavioral effects of severe and moderate early malnutrition , 1986, Physiology & Behavior.

[55]  J. Bronzino,et al.  Prenatal protein malnutrition affects synaptic potentiation in the dentate gyrus of rats in adulthood. , 1986, Brain research.

[56]  R. Morris.  Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[57]  R. Morris,et al.  Place navigation impaired in rats with hippocampal lesions , 1982, Nature.

[58]  T. Kemper,et al.  The effects of protein malnutrition on the developing central nervous system in the rat , 1978, Neuroscience & Biobehavioral Reviews.

[59]  R N Walsh,et al.  The Open-Field Test: a critical review. , 1976, Psychological bulletin.

[60]  A. Neims,et al.  Anticonvulsant properties of the ketogenic diet in mice. , 1972, The Journal of pharmacology and experimental therapeutics.

[61]  R. Zimmermann,et al.  Influence of nutritional deprivations in early life on learning behavior of rats as measured by performance in a water maze. , 1966, The Journal of nutrition.

[62]  J. P. Andrade,et al.  Evidence of reorganization in the hippocampal mossy fiber synapses of adult rats rehabilitated after prolonged undernutrition , 2004, Experimental Brain Research.

[63]  C. Stafstrom.  Assessing the behavioral and cognitive effects of seizures on the developing brain. , 2002, Progress in brain research.

[64]  J. P. Andrade,et al.  Chronic food restriction is associated with subtle dendritic alterations in granule cells of the rat hippocampal formation , 2002, Hippocampus.

[65]  N Burgess,et al.  Bilateral hippocampal pathology impairs topographical and episodic memory but not visual pattern matching , 2001, Hippocampus.

[66]  P. Morgane,et al.  Spatial cue utilization in chronically malnourished rats: task-specific learning deficits. , 1986, Developmental psychobiology.

[67]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[68]  N. McNaughton,et al.  Effects of early undernutrition on hippocampal development and function , 1982, Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie.