The Ketogenic Diet in the Treatment of Childhood Epilepsy
randomised 145 children between two and 16 years of age who had at least daily seizures and failed to respond to at least two anti- epileptic drugs (AEDs). Children were randomly assigned to receive a KD either after a four-week baseline period of seizure documentation or after a further three-month delay when there was no change in treatment; the latter was the ‘control’ group. The primary end-point of this study was reduction in seizures; tolerability of the diet was also assessed. Of the 145 children, 73 were assigned to the KD and 72 to the control group. At three months, data from 103 children were available for analysis (54 on the KD and 49 controls). The percentage of baseline seizures was significantly lower in the diet group than among the controls (62 versus 136%) and, with regard to responder rates (>50% reduction in seizures), 28 children in the KD group achieved this compared with four (6%) controls. This result reached significance. Further analysis was performed as the KD group was randomised to either the classic KD or the MCT diet. At no time-point – namely three, six or 12 months – was there a significant difference in efficacy, either in percentage of baseline seizures or in responder rates.10
One further randomised controlled study has been published: a double-blind study assessing children with Lennox-Gastaut syndrome.11
High serum cholesterol is of concern; this is seen with both the classic and the MCT diet. The long-term implications of this in terms of heart disease are unclear, due to the poor performance of prognostic indicators in childhood for future development of heart problems. This aside, triglycerides, although they may increase on the classic diet, do not increase on the MCT diet, and in the presence of family history the latter diet may be more appropriate. In the long term, a risk of renal calculi has been reported. On further evaluation, children who may be at particular risk are those who are young, have a poor fluid intake and are non-ambulant. Furthermore, children with a high calcium excretion are also at risk.14
Although children need to be monitored for the occurrence of such, if they do occur they rarely require dietary discontinuation and may be alleviated with administration of citrates. The latter may be routinely given alongside the diet in some centres.
Children were initially fasted and subsequently clinical and electroencephalogram (EEG) events were documented. Children were randomised to receive a KD with either a glucose drink or a saccharin drink. Children and parents were unaware which of the diets they were on. After six days they then crossed over to receive the alternative drink. Seizure count and EEG data were recorded at this point and again after a further six days. No significant difference in electrical or clinical events were noted between the KD and the non-KD (glucose drink) period. However, the methodology may have precluded ultimate significance in view of the fact that the baseline seizure frequency was documented after a 36-hour period of fasting and subsequently children receiving the glucose drink did not come out of ketosis.
How Well Tolerated Is the Ketogenic Diet – Is It Palatable?
There has been a wide belief that side effects are problematic on the KD. These can be divided into two categories: those that can be seen in the short term, most of which can be alleviated with alterations to the diet; and those that may be seen to be a concern over a prolonged duration of the use of the diet. The diet cannot be seen to be a natural treatment, although parents often interpret it as such.
In the short term, in the randomised controlled trial reported9,10 as in data from open-label studies,8,12,13
as well vomiting, diarrhoea,
constipation and hunger are the most commonly reported side effects; however, there were very few withdrawals at three months in the randomised controlled trial due to these side effects, which on the whole resolved with manipulation of the diet. Furthermore, no significant difference was seen between the classic and the MCT diet with regard to these side effects at either three or 12 months.10 Constipation is a common problem seen with both diets, seen in up to 45% of the population at any one time. Manipulation of the diet as well as use of non-absorbable laxatives is a common way forward. Hunger should be alleviated as with the appropriate calorie intake this should not be an issue. Parents are often concerned about the volume of food as smaller portions are seen on a high-fat diet, and such concern needs to be alleviated.
EUROPEAN NEUROLOGICAL REVIEW
In the longer term children appear to bruise more easily while on the KD, and this has to be carefully monitored in view of the inaccurate conclusions that may be drawn from the occurrence of unexplained bruising. Children studied in detail with regard to this symptom have been found to have prolonged bleeding times with abnormalities in platelet aggregation,15 safety during surgical procedures.16
but these do not preclude Of greater concern has been the
growth of children on the KD. Growth appears to be restricted with a negative change in z-score – that is, a deviation of height velocity away from the expected with increasing duration on the diet; this is particularly noticeable in the very young.17
Although originally it
was thought that this might be due to the low protein in the diet (although this is kept to recommended daily intake), a further study has demonstrated this not to be the case with similar changes seen on an MCT and classic diet.18
With administration of the diet supplementation is required to ensure appropriate mineral and vitamin intake. Mineral and vitamin deficiencies have been reported, with clinical consequences.19,20 Despite appropriate supplementation using standardised vitamin preparations, changes in vitamin A and vitamin E were seen in children in the randomised controlled trial over time, of uncertain significance.21
No change in plasma zinc was seen, but plasma selenium decreased slightly in the group as a whole. However, more notably there was a marked decrease in mean plasma magnesium within the classic diet group. There has also been increasing concern about vitamin D deficiency.22
Further data suggest that these children
are at risk prior to initiating the diet and therefore this needs to be carefully monitored. In the longer term a possible increased risk of fractures has been suggested, although this needs verification.23 Monitoring therefore needs to be undertaken on at least a six- monthly basis of mineral and vitamin values to determine whether additional supplementation is required.
Specific Indications or Contraindications to the Use of the Diet
The premise of the KD is that an individual will be able to switch from carbohydrate to fat as the primary fuel for energy. Absolute contraindications therefore include metabolic defects that lead to decompensation should glucose/carbohydrate not be readily available. This would include such defects as pyruvate carboxylase deficiency and fatty acid oxidation defects.24
There are of course also
specific defects where ketones provide a ‘bypass’ to a fuel that is not otherwise available, such as glucose transporter defects (GLUT1
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