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Nutrition ResearchVol. 18. No. 2. pp. 402416.1998 Copyright 1998 Elsevier @ ScienceInc. F’ rinted theUSA.

All tights in reserved 0271-5317m $19.00 + .oo ELSEVIER

PI1 s0271-5317(98)00030-x

DIETARY

THERAPY OF EPILEPSY

IN THE NINETIES; KETOGENIC DIET

RENEWED EXPERIENCE WITH THE

Asuri

N. Prasad', M.D. MRCP(UK), FRCPC Carl E. Stafstrom'M.D., Ph.D.

From the Division of Pediatrics (Neurology), The Charles A. Janeway Child Health Centre, St.John's, Newfoundland, Canada, and the Division of Pediatric Neurology', The Floating Hospital for Children at New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Boston, MA.

ABSTRACT serendipitous fasting From a observation that temporarily suppresses epileptic seizures, arose the idea that a diet would mimic the metabolic effects of ketosis. The so named "ketogenic diet“ has enjoyed a renewal of interest amongst physicians and the public in recent years, partly because of dramatic proclamation by the media that a miracle cure has been long ignored by the medical establishment. The efficacy of the ketogenic diet until recently has not been rigorously examined through scientific trials. We examine the historical precedent to the use of the ketogenic diet treatment for epileptic seizures, as and critically review current research previous and regarding its efficacy and mechanisms of action. Despite the efficacy of the diet in a wide variety of difficult to treat epileptic seizures in children and adults, there remain several limitations. Although a metabolic adaptation within the brain is thought to be responsible for its action, the precise mechanisms at a cellular level remain poorly understood. Further research on the ketogenic diet needs to focus on precisely defining indications, mechanisms of action, safety and impact on quality of life in epilepsy. 0 *998ElsNicrsdaIcxInc. words: Ketone bodies, epilepsy, myoclonic Key therapy, side effects, Antiepileptic drugs. seizures, Diet

'Address for correspondence and reprint requests Dr. Asuri N. Prasad at the Division of Pediatrics The Charles A. Janeway Child Health Centre St.John's, Newfoundland, Canada. AlAlR8

to: (Neurology)

403

404

A.N. PRASAD and C.E. STAFSTROM

INTRODUCTION

Throughout history, persons with have epilepsy been persecuted, castigated and stigmatized. Not only have they had to deal with the dramatic and unpredictable nature of their seizures, but also with society's reaction to their mysterious ailment. Individuals with epilepsy and their physicians have resorted to all sorts of therapies in their attempts to tame this condition. As noted by Ternkin( some such therapies are now considered bizarre(e.g powdered human skull, liver of a recently slain gladiator). Other treatments that might seem strange at first glance are finding their way into conventional epilepsy treatment regimens (e.g. vagal nerve stimulation). When considered against this historical backdrop, dietary approaches to therapy cannot be considered all that unusual, and indeed, an epilepsy diet might provide an attractive alternative to standard antiepileptic drugs and their attendant side effects. The concept that we might be able to control epileptic seizures simply by altering nutritional intake is a radical one, yet deeply rooted in medical history. As we enter the new millennium, dietary approaches are likely to emerge as important and increasingly used therapeutic adjuncts in our battle against epilepsy. In this article, we review the state of our current knowledge about the best known dietary treatment for epilepsy, the ketogenic diet. Although the ketogenic diet has proven efficacy, its mechanism of action remains unknown. Suffice it to say, considerable more research is needed to clarify the indications and consequences of this treatment modality. mechanisms,

HISTORICAL

PERSPECTIVE

Dietary manipulations to treat epilepsy were used as early as the 5t" century BC when Hippocrates described a man whose seizures were completely cured by total abstinence from food and drink. Galen suggested a role for diet in the etiology of epilepsy, and recommended an "attenuating diet" for some patients. In biblical times, Jesus cast demons out of epileptic children and told his followers that a cure would come through prayer and fasting. In 8th century, the renowned physician Avicenna recommended a seizure the mainly of avoidance treatment consisting of certain foods. The earliest to induce ketosis for treatment of seizures are not precisely attempts but the impetus appears to have come from the observation that established, seizures temporarily remitted during fasting(2-4). Geyelin suggested that the beneficial results of fasting might be due to acidosis which develops(3). Wilder (5)first speculated that a diet with a high fat content and low percentages of protein and carbohydrate would mimic the effect of fasting in producing ketosis, but could be maintained for much longer periods than could fasting. He and others showed subsequently that such a diet was indeed useful for control of seizures (5-10). Dietary therapy became less popular with the advent of effective antiepileptic drugs. Although the ketogenic diet's use continued over the years, its popularity as a therapeutic option has until recently taken a back seat to drug therapy. increasing concerns about side effects of antiepileptic drugs, in However, particular the effects of antiepileptic medication on cognitive function, have prompted physicians to evaluate alternative therapies. Recent research publications and media interest have renewed much debate on the merits of the ketogenic diet(2, 4, 11). Several questions remain unanswered, despite several decades of experience with the ketogenic diet: How does the diet work? What are the optimal indications for use? In which seizure types is it most effective?

KETOGENIC DIET IN EPILEPSY

Should it be used as a first or second line therapy for some seizure disorders in childhood? What are the effects of the diet on cognitive function? Are there any significant long-term side effects? None of the available clinical studies satisfactorily answer these questions. The very nature of the diet precludes a blinded trial design. Attempts to study the efficacy of the diet prospective randomized through trials have not been possible until recently(l2, 13).

DEVELOPMENT

OF THE DIET

Based on the assumption that fasting improved seizure control through the twin changes of ketosis and acidosis, Wilder devised a diet that would mimic the biochemical changes of fasting. This ketogenic diet consisted of a combined with small amounts of carbohydrate high proportion of fats and protein. While fat was "ketogenic" the other two components tend to be Wilder's calculations indicated that a ratio of the foods "antiketogenic". producing a ketogenic effect to the foods producing an antiketogenic effect should be of the order of 1.5:1 or higher(5). Subsequent studies showed that the optimum seizure control was achieved when the diet had a ketogenic potential of 3 or higher, thus giving rise to the current nomenclature of a 3:l or 4:l diet. Modifications of the "classic diet" include the medium chain triglyceride (MCT) diet, and a "modified" MCT diet(l4, 15).

INDICATIONS

FOR USE

Two broad indications for the use of the ketogenic diet have found general acceptance among neurologists and their patients, namely: 1) seizures refractory to drug therapy, and 2) drug toxicity. The diet seems to have the greatest beneficial effects in young children, who produce and utilize ketones rapidly (2 -3 days), and whose dietary intake can be more closely more In older children, it is more difficult (though not impossible) supervised. to prepare a palatable diet with the appropriate ratio of fat, carbohydrate and protein necessary to produce the desired level of ketosis(l1). Also, older children usually have well-established dietary likes and dislikes, and these can become a limiting factor in compliance, which must be strict. The diet has traditionally been used in the treatment of refractory epilepsy, where conventional antiepileptic medications have failed. The role of the diet as a first or second line treatment against newly diagnosed seizure disorders remains to be evaluated.

KETOGENIC

DIET

PROTOCOLS

The early ketogenic diets recommended by Wilder (5)and Livingston (16) were based on the consumption of a high percentage long-chain saturated fats with a fat to carbohydrate ratio of 4:l. Some consider the classical diet to which may lead to poor compliance. be relatively unpalatable, A modification of the standard ketogenic diet was proposed by Huttenlocher and colleagues 1 compares some of the features of the classic and the MCT (14). Table ketogenic diets. The specific details of day to day dietary adjustments must be worked out between the parents and the dietitian. Indeed the collaboration of an interested and experienced dietitian is essential if the ketogenic diet is to succeed. Parental education requires constant attention to ensure the

406

A.N. PRASAD and C.E. STAFSTROM

TABLE 1. COMPARISON OF CLASSIC KETOGENIC DIET VERSUS MCT DIET; PROS AND CONS

CLASSIC

DIET

MCT

DIJ3T

Introduced by Wilder (1921)

COMPOSITION MCT 60%, long chain saturated fat (1 I%), protein (IO%), Carbohydrate (19%). Allows more carbohydrate than classic diet. Fat is mostly octanoic and decanoic acids which are more ketogenic. BIOCHEMICAL CHANGES Rapid absorption and earlier attainment of ketotic state. Equally ketogenic to a 3: 1Classic diet.

Diet effectiveness depends on the degree of carbohydrate restriction. Fat to carbohydrate-protein ratio of 3:1- 4:l works best. No restriction on the composition of fat.

In comparison

to the MCT diet; higher ketone body

levels achieved, higher glycerol values achieved. No difference in lactate or pyruvate values. No significant increase in cholesterol, HDL, LDL or VLDL.

No significant effect on plasma lipids, lactate, pyrovate.

Low blood alaoine levels, but not as marked as with Lower blood alanine levels most marked with the classical diet. classical diet.

ADVANTAGES & DISADVANTAGES Severe carbohydrate restriction makes it less palatable, less acceptable to older children. More palatable since more carbohydrate permitted. Fewer side effects. More side effects reported (abdominal pain, diarrhea). Equal efficacy with MCT. Rapid induction of ketosis. Equal efficacy with classic 3:l diet.

Table

reproduced diet,

by permission imnunoglobulins,

from

Prasad

AN et al. Alternative Epilepsia 1996;

epilepsy 37 Suppl

therapies: l:SSl-95.

the

ketogenic

and steroids.

KETOGENIC DIET IN EPILEPSY

the ketotic state. General achievement maintenance of successful and guidelines are provided in textbooks( review articles(l2, 17)and on the all of which Internet(URL-http://www-leland.stanford.edu/group/ketodiet/), address the calculation of the diet and specific steps in its initiation. provided medications continued concurrently Anticonvulsant may be they may be tapered once seizure carbohydrate-free formulations are used(l6); remission is achieved with the diet.

MECHANISM

OF ACTION

The precise mechanism of action of the ketogenic diet remains unknown. some based on animal experiments. The Several theories have been expounded, following factors have been hypothesized to produce an anticonvulsant effect: the acidosis accompanying the ketotic the ketosis generated by ketone bodies, in brain lipid in fluid and electrolyte balance, changes state, changes concentrations and diet induced metabolic energy adaptation in the brain(l9). brain metabolism may be altered so that ketone bodies are During starvation, The ketogenic diet utilized as an energy source rather than glucose(20). possibly seeks to imitate this effect. Wilder (5) attributed the anticonvulsant effect of the ketogenic diet to Infusion of acetoacetic ketosis and the sedative effect of acetoacetic acid. acid and its sodium salts has a protective effect in rabbits against thujone emphasized the and Lennox(22) role of acidosis induced seizures(21). increase in administration of bicarbonate may cause an that suggested A lowering of though this was not borne out in subsequent studies. seizures, the serum pH with the ketogenic diet was reported by one study (23) but this was not corroborated (15),(24). There are important age related differences in the effect of the A rise in the plasma concentration of the ketone bodies Oketogenic diet. hydroxybutyrate and acetoacetate has been shown in patients on the ketogenic in plasma rose equally with the classic diet. Ketone body concentrations The rise was less pronounced in older children in ketogenic diet or MCT diet. Similar increases have also been whom the diet seemed less effective(l5). demonstrated in the spinal fluid and the brain(25). The ketogenic diet seems to work more effectively in younger subjects in both human (14, 26) and animal studies(27, 28) Ketosis has been shown to have an anticonvulsant effect in experimental by elevating resistance to maximum electroshock seizures (MES) and animals, conferring protection against bicuclline induced seizures. Mice pups 16 days old and adult mice were fed on a diet containing 70% lipids(27). The immature mice became more ketonemic and were more resistant to maximum electroshock seizures(MES), than were the adults. This study demonstrates the age related differences in response to the diet as is seen in humans as well. Another significant observation was the rapidity with which this protective effect was lost(within 3.5 hours), when the mice resumed a normal diet. This loss of effect is also seen in children previously controlled on the ketogenic diet. seizures resumed 45 minutes after an intravenous For example, glucose infusion(l5). Chronically ketotic rats demonstrate an increase in the cerebral energy reserve and energy charge(24). Decreased glucose utilization and glycogenolysis, enhanced glycogen synthesis and possible augmentation of the hexose transport system all result in a glucose sparing effect. The increased brain energy reserve (ATP/ADP ratio) is central to the increased neuronal stability that accompanies chronic ketosis(24, 29). Some evidence supports the hypothesis that elevated lipid levels might have an anticonvulsant effect(30). Dekaban showed a sharp increase in all classes of plasma lipids in diets with different ketogenic potentials. The

A.N. PRASAD and C.E. STAFSTROM

hyperlipidemia took 2-3 weeks to reach a steady state with higher levels achieved with diets of higher ketogenic potential. Yehuda et al(31) report that an essential fatty acid preparation raises the seizure threshold in rats. The long term the relationship between plasma lipid levels and the ketogenic diet is unpredictable(30, 32). Reduction in serum alanine concentrations have been reported with the classical ketogenic diet but not with the MCT diet Alanine plays an important role in gluconeogenesis, but it is unclear (32). whether this reduction occurs due to increased consumption or decreased production. Previous models of the ketogenic diet have used acute methods of seizure induction (maximal electroshock, chemical convulsants) and have thus been measures of acute seizure threshold. The first study assessing the effect of an experimental ketogenic diet on the process of epileptogenesis has recently appeared(33). Using the kindling model of epilepsy, these authors gave an experimental ketogenic diet to adult rats for five weeks. The threshold to afterdischarges (an electrophysiologic measure of hyperexcitability but not associated with clinical seizure) and to behavioral kindled seizures were assessed before, each week while on the diet and several weeks after the diet was discontinued. Compared to control rats receiving a standard diet, those getting the ketogenic diet had significantly elevated afterdischarge and seizure threshold for the first three weeks of diet treatment. This is the first evidence that the ketogenic diet can inhibit the process of epileptogenesis, at least temporarily. It will be critical to now test this protocol on immature animals, to determine whether the beneficial effect is more robust during development, as seems to be the case in humans. In summary, the ketogenic diet results in a prompt elevation of plasma ketone bodies and after an interval of several days, a metabolic shift to preferential utilization of ketone bodies as an energy source occurs within the brain. an increase in seizure threshold follows. This As this occurs, otherwise the anticonvulsant effect effect is simply not one of sedation, would be maximal within the first few days when ketone body concentrations are the highest. Sustained ketosis appears to be the most important factor in Ketosis is necessary but not sufficient modifying the convulsive threshold. to explain the antiepileptic mechanism of the ketogenic diet. A latency of 10 the convulsive threshold rises, - 21 days seems to be necessary before suggesting a metabolic adaptation within the CNS. The fact that this change can be rapidly reversed suggests a labile cerebral metabolic system. There is relative paucity of information on the action of ketone bodies on cortical excitability. EFFICACY OF THE DIET

The scientific literature over the last 75 years includes a number of (summarized in Table 2). Each of the studies has clinical studies Most have been uncontrolled and retrospective methodological limitations. making a metanalysis difficult. The lack of a uniform with small numbers, system of seizure nomenclature and classification makes comparisons difficult. what is meant by a "good" or not defined, e.g., The end point is often Despite these difficulties, a few tentative conclusions "partial" response. can be drawn. Overall, results from 19 studies were analyzed and the major findings

KETOGENIC DIET IN EPILEPSY

of 19 studies used the classic ketogenic diet presented in Table 2. Twelve the classic vs. the MCT alone, 4/19 used the MCT diet alone, and 3/19 compared The consensus view is that the ketogenic diet improves seizure control diets. Both the classic and MCT diet appear to be in some children with seizures. equally effective in the treatment of refractory seizures of all types. About one third of children appear to achieve near complete cessation of seizures, The remainder do while another one third achieve a less complete response. not appear to benefit from the ketogenic diet. Improvement in the level of alertness and behavior are also reported(34, 35). There is a clear age dependent window of responsiveness to the diet. Children under the age of one year are more resistant to developing ketosis, and tend not to respond favorably although success in this age group has been Teenagers and adults do not fare as well as young children and reported(36). factor in determining the diets success dietary compliance may be a decisive or failure. Both the classic and the MCT diet appear to be effective in treating irrespective of seizure type(26). When seizures are of a "mixed seizures rate varies from 29% to 55%. However when patients with type" the remission of 70%-80% are seizures are considered, remission rates alone myoclonic Later studies use a modified definition of remission in terms reported (37). from complete of degree of seizure control on dietary t:>":o"s"y, varying good response reduction). seizures) to When the remission(n0 than 50% reduction in seizures frequency" is therapeutic endpoint of "greater taken as an index of successful remission, rates as high as 81% are achieved (26, 35). to be most effective for control of myoclonic Dietary therapy appears atonic/akinetic seizures, and the Lennox-Gastaut syndrome, followed seizures, in all other refractory seizure types (partial by varying degrees of success and generalized tonic clonic seizures). The diet appears to be least effective in controlling temporal lobe and absence seizures. Some of the or minor motor seizures, earlier reports equate "petit mal" with myoclonic rather than the modern nomenclature of absence epilepsy. EEG changes may or may not parallel the clinical improvement on the ketogenic diet. Nellhaus claimed that the normalization of the EEG coincided with development of ketosis and clinical improvement(38), but these results Janaki et al (1976) reported that EEG have only appeared in abstract form. improvement in petit ma1 and minor motor seizures, changes mirrored clinical but this association did not hold true for grand ma1 or focal epilepsy(39). Huttenlocher demonstrated similar EEG improvement in several patients treated On the other hand, Schwartz with the MCT diet(l5). and colleagues reported EEG changes clinical correlation between and response(26). No poor comprehensive studies of the EEG changes of large numbers of patients before, and after the ketogenic diet have been reported. during, the interest in ketogenic diet, Since resurgence of the planned prospective studies have been conducted and preliminary results are available. Multicenter and single center studies the conclusions of (12, 13)support older studies that the ketogenic diet is effective in substantial a number of patients with difficult to control seizures. However it is interesting that about half of the patients discontinue the diet before a year of use, two thirds because of a poor response (<50% control of seizures), and one third because of poor tolerance(l2). While many studies report a subjective improvement in alertness and behavior as a positive gain from the ketogenic diet, none has reported any formal neuropsychological assessments to document such changes(35, 40, 41). Such a study of effects of the diet on cognition and behavior would be invaluable in distinguishing the adverse cognitive effects of anticonvulsants from those of seizures.

410

A.N. PRASAD and C.E. STAFSTROM

Table 2. Comparison Study Number of patients (age range) Seizure type Diet of studies evaluating the efficacy of the ketogenic diet. NO response I Failures Special Comments Study conclusion Comments

’ Complete
response/ >90% reduction in seizures

Partial response/ MO% reduction in seizures
w37

Peterman (1925)

:35-l,

y)

Idiooathic (GM, PM)

Classic 4:l

19137

2i37

Remainina

lost to
follow up

84% were seizure f?ee or substantially improved Remission rate of 3004 70% continue to have seizures Effective in petit mal. Transient response observed

Retrospective study

Helmholz (1927), (1930)

141 (2-15 Y)

(Gti, PM)

Classic 4:l

431141

32/141

661141

PM (1928) k, 13)

Classic 4:l

Anecdotal experience

Barborka (1929)

100 (16-51 y)

?

Classic

12llOO

441100

441100

Response rate of 66%

Study based on adult patients

Eley (1933)

29 (1.5-1 I y)

Idiopathic (GM, PM)

Classic 2.5-3.5:1

2ol29

6RO remissions only when ketosis was maintained.

Retrospective smdy. Normal EEG predicted favorable response to diet. Remission rate of 45% Study also reported consistent rise in plasma total lipids and cholesterol; other components showed unpredictable behavior. Retrospective study

Dekaban (1966)

ill-6 yr.)

Intractable idiopathic 8, symptomatic 3

Classic 4:1

5/l I

4111

Failed to establish ketosis in 2

Wilkins (1937)

iirn-12 yr.)

Mixed PM 3/S, GM 418, Minor motor seizures 118.

Classic 3:l

S/30

7130

15/30

Remission rate of 26%. No benefit in 50%.

GM =

grand

mal,

PM = petit

ma1

(Table contrnued)

KETOGENIC DIET IN EPILEPSY

411

Table 2. Continued Study Number of patients (age range) Hopkins and Lynch (1970) 34 Refractory Classic 3:1 Seizure type Diet Complete response/ >90% reduction in seizures 10134 “satisfactory
FCSpOllSe”

(O-12 Y)

Partial response/ =50% reduction in seizures 4134 “modest KSpOW”

No response / Failures

Special notes

Study conclusion

Comments

--

1l/34

Inadequate trial in 4

Remission rate of 29%

(all had minor motor seizures

No clear cut differences between responders and non responders. End points not defined. In “petit mal” and myoclonic epilepsy EEG changes paralleled clinical improvement. First study to demonstrate efficacy of a dietary alternative to the classic diet.

Janaki et al (1976)

15 (O-30 Y)

GM 9, PM 1, focal 3, Myoclonic 2

Classic 4:l

3115 Good control

12115 partial control

Best results in minor seizures in children ~8 yr.

Huttenlocher (1976)

12 (2.5-16~)

Myoclonic epilepsy 6, complex partial seizures 4, grand mal 1, infantile spasms 1. Myoclonic, Infantile spasms: 1225 LennoxGastaUt 375

MCT

416

6112

116 75% reduction in seizure frequency

116seizure free but had to discontinue diet due to side effects

MCT diet is especially effective in minor motor seizures, and is tolerated better

Livingston et al (1977)

MCT: 25 Classic (3:1): 1600

Classic 3:1 And MCT

Complete control in 526,

Marked improve ment in 254.

25 on MCT were non responders.

No response in 195

Classic diet works best for myoclonic seizures, and is superior to the MCT diet. MCT diet less effective than the classic diet

Uncontrolled study, too large a difference in sample size for results to be analyzed statistically Uncontrolled retrospective study, sample size too small for results to be statistically significant supports effectiveness of the MCT diet

BWIIXM (1978)

Classic 4:l: 8 MCT: 18

Mixed refractory

Classic 4:1 vs. MCT

418

218

218

l/l8

6118

11118

TraWW (1985)

17

Intractable seizures

MCT

5117

5117

2117

Discontinued in 5117

Complete remission in 29%, partial remission in 29%.

(Table contintled)

A.N. PRASAD and C.E. STAFSTROM

Table 2. Continued Study Number of patients (age range) 50 23(<lO y) l7(>10 y) Seizure type Diet Complete response/ >90% reduction in seizures 8122 Partial response/ >50% reduction in seizures >90% reduction in 4122. >50% reduction in 10/22. NO response I Failures Special notes Study conclusion Comments

Sills (1986)

Myoclonic 18150, PM 7150, GM 17/50. Complex Partial s/50.

MCT

6 failures

44 tolerated diet, 318 who responded refused to continue.

ROS Perez (1989)

9

Refractory: Lennox-Gastaut (5); epilepsy with myoclonic absences (1); “intermediary petit mall’ (1); benign atypical partial epilepsy in infancy (1) and epilepsy with myoclonic -astatic seizure(l) Drop attacks 24, absence 9, generalized seizures 17, partial sz 9.

MCT

5/8

3/8

MCT most effective in myoclonic and absence seizures, but may also work in other seizure types. High response rates can be achieved with careful patient selection.

Small study group.

Schwartz etal. (1989)

58 2w5 Y) 25(5-10 y) 9(11-15y) 5 (‘15 Y)

MCT, classic and modified MCT

>50% reduction in seizure 51

<50 % reduction in seizure frequency 12

Some children received mcwethan one type of diet

All three diets arc effective, response was statistically significant. More unpalatabilit y and side effects with MCT diet seen in older children and adolescents. Study supports effectiveness of the diet in patients who are well selected and motivated.

Prospective study shows similar
HXCXY

between the two diets in the short term.

Kinsman (1992)

58 l-20 y

Multiple seizure types SO%, 88% were treated with multiple AEDs

Classic 4:1

17139 (29%)

22/39 (38%) >50% reduction in seizure frequency.

75% of responders continued the diet for at least 18 months. AEDs reduced 27158, (64%), increased
dWtll~SS

Retrospective study, confirms efficacy and long term acceptability and efficacy of the diet.

21158 (36%), improved behavior 13/58 (23%).

KETOGENIC DIET IN EPILEPSY

413
drug regimens), so cost

MCT diet can considerations

be quite high must be taken

(but less than into account.

some

antiepileptic

There is a potential theoretical risk for patients who may have an underlying metabolic disorder involving mitochondrial dysfunction, or are being treated with Introduction of the ketogenic diet in such instances (46). valproic acid, a fatty acid contributing to clinical deterioration. Patients should may worsen the metabolic burden, oxidation defects prior to commencement of ketogenic be prescreened for fatty acid because of the theoretical risk that the ketogenic diet may cause Also, diet(47). a carnitine profile should be obtained and supplementation with Lcarnitine deficiency, If clinical worsening is noted when valproic acid therapy is carnitine considered (47). its discontinuation should be considered. used concurrently,

LONG

TERM

EFFECTS

40 and 45 years of age who had been Livingston(37) examined many adults between Be found no evidence of treated during childhood with the classical 4:l ketogenic diet. including arteriosclerosis, hypertension or adverse effects on cardiovascular function, Blood cholesterol determinations were performed on many of these cardiac abnormalities. However studies using modern evaluation techniques and long adults, and all were normal. term follow up of large numbers of children should be performed.

DIRECTIONS

FOR

FUTURS

RESEARCH

Despite several decades of use of the ketogenic diet, many issues regarding its mechanism of action and efficacy remain to be elucidated. There have been few well controlled prospective studies looking at the efficacy of the diet in achieving planned, Optimum conditions under which the diet is maximally effective remain seizure remission. There have been no studies looking at comparative efficacy of diet versus to be defined. Better data is needed on the optimum duration of traditional antiepileptic therapy. The effects of the diet treatment and on relapse rates after treatment discontinuation. will be remain to be investigated. Studies on animal models on the EEG patterns Although most imperative to better define the mechanism of action of the diet(29,33). of the diet in improving mental alertness and authors are impressed with the effect effects through are available on documenting cognitive behavior, no studies neuropsychological testing. Questions such as these must await the results of well planned prospective multicenter studies that are amenable to statistical analysis.

SUMfARY

AND

CONCLUSIONS

The ketogenic diet is effective as one of the modalities for management of The ketogenic diet works best in the young child intractable seizures in childhood. l-10 years with several forms of refractory epilepsy irrespective of between age and also affords improvement in behavior and alertness in many cases. While it etiology, is devoid of some of the more toxic side effects associated with standard anticonvulsant the ketogenic diet poses its own set of challenges to the physician, dietitian therapy, Both the classic and the MCT diets are probably equally effective in and family. The MCT diet has more of reported side effects compared to the controlling seizures. The ketogenic diet can be expected to induce a remission in at least a classical diet. depending on several variables, including patient age, seizure third to half of cases, is defined. When seizure frequency improves, there may or type, and how "effectiveness" Rigid dietary restriction of carbohydrate and protein is may not be EEG improvement. Because of the low incidence of side effects and improvement in necessary for success. the ketogenic diet is an attractive alternative in some patients alertness and behavior, when conventional medications fail. For dietary management to be successful, highly close liaison with an experienced dietitian, motivated parents, and patience are key virtues.

414

A.N. PRASAD and C.E. STAFSTROM

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