Emma and Barbara - paper including ree dx etc - found it finally....

[Guest guest]

Here it is, I have put asterixes on the relevant part about the diff between

cal need assessments after giving the ree dx (termed calorimetry here - same

thing) as opposed to using tables to calculate cal needs instead.

PS - Barbara - Doesn't Claire go to CHOP now for the diet, would have thought

would already have done a ree dx test for her? Congrats on the latest

EEG btw, that is fabulous news, any direction upwards has to be a good one....

The Ketogenic Diet

Eileen P.G. Vining, MD

The popularity of the ketogenic diet has waxed and waned over the years, but

most recently the diet has been found to be particularly useful for patients

with medically refractory epilepsy. Classically, the diet is high in fat and low

in carbohydrates and protein. The resulting ketosis exerts an antiepileptic

effect, though the precise mechanism of action has not been defined.

Fifteen poster sessions presented new research on the ketogenic diet at the

2002 Annual Scientific Meeting of the American Epilepsy Society, and a special

interest group met to discuss new basic-science observations in a more informal

setting.

Efficacy Studies

Two groups reported on efficacy of the diet. Snively and colleagues[1] from

the University of Florida, Gainesville, provided additional retrospective

evidence of the efficacy of the diet in 17 children under 2 years of age. Two

patients quickly withdrew; of the 15 who remained on the diet, 40% became almost

seizure-free and 53% experienced more than a 50% reduction in seizure frequency.

The durability of this outcome is not clear, but these investigators continue to

demonstrate the lack of difficulty in using the diet in very young children.

In another study, Sotero de Menezes and Saneto[2] of the University of

Washington and Children's Hospital and Regional Medical Center, Seattle,

Washington, reported 4 patients with " epileptic spasms, " an entity clinically

similar to infantile spasms but occurring in older children. One of these

patients achieved partial control (> 50% reduction) of spasms using the

ketogenic diet. This would not be surprising, given the diet's recently reported

efficacy in infantile spasms.

Initiating the Diet

Two studies examined aspects of diet initiation. Classically, patients are

admitted to the hospital for fasting before introduction of the diet; at this

time they also receive instruction in its use. Wirrell's group[3] at Alberta

Children's Hospital, Calgary, Alberta, Canada, reviewed the records of 14

children who began the classic diet without a fast. Eight of the children began

as inpatients, on a 1:1 ratio diet, and advanced to a 3-4:1 ratio diet over 3-4

days; the 6 children who started as outpatients advanced from a 1-2:1 ratio to a

3-4:1 ratio also over 3-4 days. Thirteen of the 14 children tolerated this well.

Good ketosis was achieved at a mean of 58 hours. This is clearly later than

would be seen if children had been fasting before beginning the diet, but it

remains unclear whether a more, or less, rapid introduction of ketosis is

important in the long-term management of these patients. The investigators

reported success with the diet in 42%, although the definition of success and

durability of the effect of the diet is unclear. This group had discussed the

issue of defining success and durability of effect in an earlier publication,[4]

in which they also relate that they have decided to hospitalize all of their

patients for diet initiation.

Schultz and colleagues[5] from Stanford University Medical Center and the

Lucile Packard Children's Hospital, Stanford, California, provided new insights

into the calorie requirement of children at diet initiation. Usually, this

estimate is made clinically and is based on the current nutritional status of

the child using a percentage (75%-80%) of the recommended daily allowance (RDA)

and expected energy demands.

*****These investigators performed indirect calorimetry, measuring oxygen

consumption and carbon dioxide production on 21 older and cooperative patients.

One third of the patients had calorimetry-based calorie requirements that

differed by more than 25% from the RDA-based values. The provision of calories

based on this measurement led to a very stable weight picture at follow-up.

Although stability of weight is not always clinically indicated (eg, in patients

who are overweight), this may be a useful technique in preparing the initial

diet plan.******

Side Effects and Complications

Several presentations described monitoring, side effects, and potential

complications of the diet. In a very interesting attempt to document how various

centers monitor and implement the diet, Frantz and colleagues[6] from The

Children's Hospital of Philadelphia, Pennsylvania, reported questionnaire

responses from 14 centers. Almost half did not restrict protein on the diet, 20%

did not restrict calories, almost a third did not provide education classes, and

almost half the centers did not evaluate lipid or prealbumin levels before

initiating the diet. This study highlights how variable the approach to the diet

can be and the need for better standards of care if we hope to use this therapy

optimally.

Bergqvist and the group from The Children's Hospital of Philadelphia have also

begun to examine bone density in children on the ketogenic diet.[7] Using a

cross-sectional (rather than longitudinal) design they showed that males on the

ketogenic diet for 12-24 months experienced a significantly worse osteopenia

than females. This is part of an ongoing prospective study that may clarify

observations made in 1979, when Hahn and colleagues[8] reported that children on

the diet had a significant reduction in serum 25OHD as well as loss of bone

mass, which can be partially reversed by vitamin D treatment. This work will be

important to providing optimal care for children who are on the diet for an

extended period of time.

A broad review of both early- and late-onset complications of the diet was

presented by Kang and colleagues[9] from Sang-gye Paik Hospital, Seoul, South

Korea. They reported their experience with 117 patients. Typical early problems

included GI intolerance, hypertriglyceridemia, and transient hyperuricemia.

Other early problems of interest included lipoid pneumonia in 5%, suggesting

aspiration. Late complications (after 2 months) were seen in 30% of patients and

included infections, dyslipidemia, hepatitis (6%), and single cases of

cardiomyopathy, acute pancreatitis, and secondary hypocarnitinemia. Of interest

is that most children who experienced growth failure showed normalization of

growth when the diet was discontinued. Diet-related deaths were presumed in 4

cases (sepsis in 2, cardiomyopathy, and lipoid pneumonia).

Carnitine deficiency was also addressed in a study by Werner and

associates[10] from Children's Hospital of Wisconsin, in Milwaukee. Although the

clinical relevance of measuring free carnitine remains in question, the

investigators conducted a retrospective chart review and found that 61% of 20

children on the diet developed a carnitine deficiency. However, only 1 child

developed symptomatic carnitine insufficiency (acyl/free ration > 0.4) with

increased seizures and lack of energy. Two of the 20 children experienced

improved energy and alertness after carnitine supplementation, although free

carnitine levels had improved in all of them. Children who received the diet

orally appeared to have more abnormalities than those who were fed enterally,

perhaps because the formula was fortified. Others who have looked at total

carnitine levels find that they stabilize or return to baseline over time and

that most children on the diet do not need supplementation. This remains an area

in need of further prospective clarification with clinically relevant

observations.

A report on nephrolithiasis in the setting of topiramate, zonisamide, and the

ketogenic diet in various combinations was presented by Jonas and

colleagues,[11] from UCLA School of Medicine. Of 309 patients, only 3 (1%), 1 of

whom was receiving the ketogenic diet, developed kidney stones; this appeared

related to dehydration. This is considerably lower than the 6% to 7% reported by

Kossoff and associates[12] from s Hopkins, and confirms that adequate fluid

intake on the diet, with or without other medications, is extremely important.

The Science of the Diet

Pan and colleagues[13] from Albert Einstein College of Medicine, Bronx, New

York, and Yale University School of Medicine, New Haven, Connecticut, have

addressed monitoring the diet from another important point of view. They have

asked how the brain uses ketones, recognizing that a simple measurement of

plasma ketones may not reflect the critical biological parameter. They used in

vivo MR spectroscopy to evaluate how beta-hydroxybutyrate (BHB) is used in the

brains of healthy adults who become ketotic. They found that the rise in plasma

BHB is rapid and accompanied by a near simultaneous rise in brain BHB. Perhaps

their most interesting finding is that the BHB consumption appears to be

preferred by the neuronal compartment, bypassing the astrocytic compartment that

had been suggested by others.

Five poster presentations discussed various aspects of basic science relating

to the ketogenic diet. Sullivan and associates[14] from University of California

at Irvine examined synaptosomal mitochondria from the cortex of mice fed either

normally or with the ketogenic diet for 10 days, with BHB levels reaching twice

the normal level in the ketogenic-diet-fed rats. They found increased

mitochondrial uncoupling activity and reduced reactive oxygen species (ROS)

production in the animals on the diet, suggesting a possible neuroprotective as

well as anticonvulsant effect.

Bough and coworkers[15] from University of Washington, Seattle, University of

California at Irvine, and University of California at , reported on in vivo

recordings from Kcna1-null mice with recurrent seizures, a possible model of

developmental epilepsy. The ketogenic diet did not further augment the

inhibition shown by Kcna1 -/- mice to paired-pulse stimulation within the

dentate gyrus, resulting in an elevated threshold to electrographic seizures at

5-6 weeks of age.

Two other presentations dealt with seizure susceptibility using 2 different

models. In a multicenter Korean study, Dong-Wook Kim and colleagues[16] examined

flurothyl-induced seizure susceptibility in 3- to 12-week old rats that were

treated with a ketogenic diet. Levels of ketosis were lower and seizure

latencies were shorter in older animals, suggesting that the diet was more

efficacious in younger animals. The efficacy of the diet is generally assumed to

be better in younger patients, but substantive evidence to confirm this is not

available. In a second, multicenter Korean study, Jae-Moon Kim and

colleagues[17] examined the effect of the diet on continuing seizures in rats

with PTZ-induced seizures. The diet was effective in reducing the length of

seizures, again more so in the younger animals.

Finally, Eagles' group[18] at town University, Washington, DC, presented

information about the effects of gamma-butyrolactone (GBL) -- which induces

absence seizures -- and the ketogenic diet on the behaviors of male and female

rats. Absence seizures were induced in rats, and several functions (posture,

gait, and performance on a roto-rod) were scored. Ketogenic animals,

particularly females, did less well behaviorally than standard-fed animals. In

general, sex differences on the ketogenic diet have not been observed

clinically. This preliminary finding in animals is obviously of interest as we

explore the neuroendocrine effects of the diet.

Ketogenic Diet Special Interest Group

During the evening meeting of the Ketogenic Diet Special Interest Group, a

lively discussion revolved around whether caloric restriction or ketosis is at

the heart of the efficacy of the diet. We know that caloric restriction reduces

synaptic excitability, increases fast inhibition in the dentate gyrus, and

raises the electroconvulsive threshold. However, ketosis may be more important

in maximal dentate afterdischarge. Participants queried whether we could

possibly use blood glucose levels as a surrogate for BHB, and specifically

whether lower blood glucose levels may be directly related to seizure control.

One of the suggestions that also evolved from this discussion was whether a

protocol should be devised that would look at calorie restriction vs

nonrestriction in an otherwise classical ketogenic diet. Certainly in diabetic

patients who are both ketotic and hyperglycemic, there is no protection against

seizures. It might also be possible to retrospectively look at glucose levels in

children who have been on the diet and establish whether there is a relationship

to seizure control.

Conclusion

Although fewer presentations about the ketogenic diet were made at this

meeting than in recent years, it remains clear that a number of centers remain

committed to understanding and maximizing the clinical utility of the diet, and

growing numbers of basic scientists are using new tools to discern the mechanism

of action of the diet. It is hoped that elucidating the mechanism of action will

lead to an even more specific and effective therapy.

References

1.. Snively CG, McClernan CS, Maze MF, et al. Efficacy and tolerability of

the ketogenic diet in the very young: one center's experience. Program and

abstracts of the American Epilepsy Society 56th Annual Meeting; December 6-11,

2002; Seattle, Washington. Abstract 2.281.

2.. Sotero de Menezes MA, Saneto RP. Onset of epileptic spasms after age 2

years: a report of four cases. Program and abstracts of the American Epilepsy

Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington. Abstract

2.127.

3.. Wirrell EC, Darwish HZ, -Dyjur C, et al. Is a fast necessary

when initiating the ketogenic diet? Program and abstracts of the American

Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington.

Abstract 2.252.

4.. Wirrell EC, Darwish HZ, -Dyjur C, et al. Is a fast necessary

when initiating the ketogenic diet? J Child Neurol. 2002;17:179-182.

5.. Schultz LM, Berquist WE, Olson DM. Calorie requirement at ketogenic diet

initiation. Program and abstracts of the American Epilepsy Society 56th Annual

Meeting; December 6-11, 2002; Seattle, Washington. Abstract 2.247.

6.. Frantz CL, Chee CM, Bergqvist C. Monitoring the ketogenic diet - is

there a standard? Program and abstracts of the American Epilepsy Society 56th

Annual Meeting; December 6-11, 2002; Seattle, Washington. Abstract 2.245.

7.. Bergqvist CAG, Peruto CM, Frantz C, et al. A cross sectional study of

bone density in children treated with the ketogenic diet. Program and abstracts

of the American Epilepsy Society 56th Annual Meeting; December 6-11, 2002;

Seattle, Washington. Abstract 2.244.

8.. Hahn TJ, Halstead LR. Anticonvulsant drug-induced osteomalacia:

alterations in mineral metabolism and response to vitamin D3 administration.

Calcif Tissue Int. 1979;27:13-18.

9.. Kang HC, Chung DE, Kim HD. Early and late onset complications of

ketogenic diet in intractable epilepsy. Program and abstracts of the American

Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington.

Abstract 2.246.

10.. Werner RR, Zupec-Kania B, Zupanc ML, et al. The incidence and

management of carnitine deficiency in children on the ketogenic diet. Program

and abstracts of the American Epilepsy Society 56th Annual Meeting; December

6-11, 2002; Seattle, Washington. Abstract 2.251.

11.. Jonas R, Desai SS, Wu JY, et al. Topiramate, zonisamide, and the

ketogenic diet: incidence of nephrolithiasis. Program and abstracts of the

American Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle,

Washington. Abstract 1.161.

12.. Kossoff EH, Pyzik PL, Furth SL, et al. Kidney stones, carbonic

anhydrase inhibitors, and the ketogenic diet. Epilepsia. 2002;43:1168-1171.

13.. Pan JW, deGraaf RA, Rothman DL, et al. Oxidative metabolism of 13C

labeled ketones in human brain. Program and abstracts of the American Epilepsy

Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington. Abstract

2.248.

14.. Sullivan PG, Rippy NA, Dorenbos KA, et al. A ketogenic diet enhances

respiratory uncoupling and decreases reactive oxygen species production in

mitochondria isolated from mouse cortex. Program and abstracts of the American

Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle, Washington.

Abstract 3.029.

15.. Bough KJ, Robbins CA, Tempel BL, et al. In vivo recordings from

ketogenic diet-fed Kcna1-null mice, lacking the KVL.L channel subunit. Program

and abstracts of the American Epilepsy Society 56th Annual Meeting; December

6-11, 2002; Seattle, Washington. Abstract 3.062.

16.. Kim DW, Moon JS, Chae SA, et al. Ketogenic diet: age-related effects on

ketosis and flurothyl-induced seizure susceptibility in rats. Program and

abstracts of the American Epilepsy Society 56th Annual Meeting; December 6-11,

2002; Seattle, Washington. Abstract 1.022.

17.. Kim JM, Jung KY, Kim DW. Effect of ketogenic diet on the continuing

seizures of Ptz-induced seizure models in rats. Program and abstracts of the

American Epilepsy Society 56th Annual Meeting; December 6-11, 2002; Seattle,

Washington. Abstract 1.053.

18.. Eagles DA, Lee MK, Yang HF. The effects of gamma-butyrolactone (GBL)

and the ketogenic diet on the behavior of male and female rats. Program and

abstracts of the American Epilepsy Society 56th Annual Meeting; December 6-11,

2002; Seattle, Washington. Abstract 1.018.