Keywords
infantile spasms - Lennox–Gastaut syndrome - drug-resistant epilepsy - ketogenic diet
Introduction
Dietary therapy has been an established therapy for the management of drug-resistant
epilepsy. Dietary therapy is indicated among those with drug-resistant epilepsy where
two appropriately chosen antiseizure medications have failed.[1] Various dietary options include the classic ketogenic diet (KD), modified Atkins
diet (mAD), low glycemic index treatment (LGIT), and medium chain triglyceride diet.
The traditional KD is a medically supervised high-fat, low-carbohydrate, and restricted
protein diet that maintains a chronic state of ketosis.[2] The classic KD is high in fat, appropriate protein (1 g/kg), and low in carbohydrates.[3] The fat-to-protein plus carbohydrate ratio (by weight) is often 1:1 initially and
then increased to 4:1 or 3:1.[1] The mAD restricts the carbohydrate to 10 g daily, and the fat is encouraged.[4] The mAD allows meals containing 60% fat, 30% proteins, and 10% carbohydrates, thus
being a nearly balanced diet compared with KD.[5] LGIT, in contrast, focuses on the glycemic index of the food rather than strict
ratios of fats to carbohydrates and protein.[6]
The mAD has demonstrated an efficacy of 60% seizure reduction, and 50% of children
on LGIT achieve > 50% seizure reduction.[7] LGIT is a less restrictive diet, with patients showing better compliance when compared
with mAD. Considering poor compliance with mAD, authors stipulate that those of mAD
can be shifted to LGIT without loss of efficacy. Despite data on the effectiveness
and safety of the mAD and LGIT, there is no evidence to assess the efficacy of combined
or sequential dietary therapy when we switch from one dietary therapy (mAD) to a less
restrictive diet (LGIT). With this background, the present study was conducted to
study the efficacy and safety of combined dietary treatment using the mAD in the first
month, followed by LGIT.
Methods
This study was conducted in a tertiary care referral center's department of pediatrics
and neurology. The data was collected from February 2021 to March 2022. We obtained
ethical approval from the Institutional Ethics Committee [BREC/Th/20/Peds011]. The
patient information sheet was provided to the parents or legal guardians before obtaining
the written informed consent.
Children aged 6 months to 5 years with drug-resistant epilepsy were consecutively
enrolled in the study. Drug-resistant epilepsy was defined as a failure (seizure persisting
daily or > 7/week) of adequate trials of two well-tolerated and appropriately chosen
antiseizure medication schedules (whether as monotherapies or in combination) to achieve
sustained seizure freedom.[8] Children with known or suspected inborn errors of metabolism,[1] systemic illness, severe acute malnutrition, and those having motivational and psychosocial
issues in the family were excluded from the study. Children with surgically remedial
lesions like tumors, cortical dysplasia, and mesial temporal sclerosis were also excluded
from the study.
The baseline demographic and clinical details were recorded, including the frequency
of seizures, the nature of antiseizure medications, and their doses. Medications were
changed to carbohydrate-free preparations. A baseline electroencephalogram (video
EEG whenever possible) was performed during enrolment. Eligible participants were
administered mAD for the first month and subsequently shifted to LGIT for the next
2 months. The LGIT was introduced gradually 1 week before the schedule of 1 month
so that the transition could be gradual and not sudden and the parents and the children
could adjust to the new diet.
In the mAD, carbohydrate was restricted to 10 g/day (18–60 months of age) and 5 g/day
(9–18 months of age).[9] The carbohydrate content of daily food was explained to parents, and the exchange
list was provided. Fats (cream/oil/butter/ghee) were encouraged. Clear carbohydrate-free
fluids were not restricted. A list of recipes from locally available food was provided.
A list of dietary options with a glycemic index of less than 50 was provided in the
LGIT group. The LGIT diet consisted of an increased intake of carbohydrates with a
specific goal of 40 to 60 g per day.[10] Calcium and multivitamin supplementation were prescribed in the form of tablets.
The parents of enrolled participants were encouraged to maintain a daily seizure log
in the seizure diary for a 1-week observation period. Medications were changed to
carbohydrate-free preparations, wherever available. Steroid/ hormonal therapy, if
any, was tapered. All children were reviewed as outpatients every 2 weeks. At each
follow-up visit, a 24-hour dietary intake chart was reviewed, and compliance with
the prescribed diet was reinforced. Weight was checked at each visit. Parents were
asked to measure urine ketones at least twice weekly.
The tolerability of the diet was evaluated using parental interviews at each visit.
Parents were questioned for the presence and frequency of the following symptoms:
vomiting, lethargy, poor appetite, refusal to feed, and constipation. Any other parental
concerns were also recorded. A 2-mL fasting venous blood sample was drawn for liver
and renal function tests and lipid profile at baseline and repeated at the end of
12 weeks. A 30-minute EEG record (video EEG whenever possible), including at least
one sleep-wake cycle, was performed at baseline and repeated at 12 weeks.
The primary outcome measure was the proportion of patients who were “good responders”
at the end of 12 weeks. Good responders were considered as those patients with > 50%
seizure reduction (seizure frequency measured as average seizure per week in the preceding
4-week period) from the baseline.[11] Secondary outcome measures included the proportion of children who achieved seizure
freedom at 12 weeks and the description and proportion of parent-reported adverse
effects.
All data collected were entered in Microsoft Excel. Data were analyzed using the SPSS
21.0 version. All categorical variables were expressed in numbers (percentage), and
all continuous variables were expressed as median (interquartile range). The laboratory
parameters were compared between the baseline and 12 weeks using paired t-tests, and a p-value of < 0.05 was considered significant.
Results
Seventy-five children with drug-resistant epilepsy visited the center between February
2021 and February 2022. Out of these 75 patients, 53 agreed to participate in the
study. Of these 53 willing participants, 45 children were enrolled (excluded [n = 8]: a suspected inborn error of metabolism [n = 1], hepatic dysfunction [n = 1], severe acute malnutrition [n = 3], surgically remedial causes of epilepsy [n = 1], and motivational issues in family [n = 1]). Six children were lost to follow-up, of whom 4 were lost within the first
month of mAD, and the remaining 39 children completed the 12-week follow-up. All six
children were diagnosed with West syndrome, and their demographic and clinical characteristics
were comparable to those who continued follow-up till 12 weeks.
The baseline characteristics of enrolled participants are enumerated in [Table 1]. Most of the enrolled children had West syndrome (n = 35 [77.7%]), and the rest had possible evolution to Lennox–Gastaut syndrome (n = 10 [22.2%]). Etiology was secondary to perinatal insult in all enrolled children,
with perinatal asphyxia (26 [57.7%]) being the most common cause.
Table 1
Baseline characteristics of enrolled participants (n = 45)
|
Characteristic
|
Observation
|
|
Age in months, median (IQR)
|
18 (12.50, 24.0)
|
|
Age at onset of epilepsy, median (IQR)
|
5.0 (3,7)
|
|
Male gender
|
28 (62.2%)
|
|
Perinatal and postnatal history, n (%)
|
|
Asphyxia
|
26 (57.7)
|
|
Meningitis
|
11 (24.4)
|
|
Hyperbilirubinemia
|
2 (4.4)
|
|
Hypoglycemia
|
6 (13.3)
|
|
Microcephaly
|
38 (84.4)
|
|
Type of seizure
|
|
Epileptic spasms, n (%)
|
28 (62.2)
|
|
Other seizure types, n (%)
|
17( 37.8)
|
|
Antiseizure medication
|
|
Valproate
|
45 (100)
|
|
Clonazepam
|
44 (97.8)
|
|
Vigabatrin
|
25 (55.6)
|
|
Levetiracetam
|
29 (64.4)
|
|
Lamotrigine
|
4 (8.8)
|
|
Zonisamide
|
1 (2.2)
|
|
Topiramate
|
13 (28.9)
|
|
EEG
|
|
Hypsarrhythmia
|
20 (44.4)
|
|
Multifocal
|
22 (48.7)
|
|
Generalized
|
1 (2.2)
|
|
Normal
|
2 (4.4)
|
Abbreviations: EEG, electroencephalogram; IQR, interquartile range.
At the end of 4 weeks, 17 of 45 (37.7%) children were good responders. At 12 weeks,
30 of 39 (76.9%) children were good responders with more than 50% seizure reduction.
Seizure frequency at baseline and at 12 weeks are shown in [Fig. 1]. Of these 30 children, 11 (24.4%) had more than 90% seizure reduction, with 9 (20%)
achieving complete spasm freedom. Constipation was the most common side effect of
the diet among the enrolled subjects. Lethargy was the second most common adverse
effect ([Table 2]).
Table 2
Outcome measures of enrolled participants
|
Outcome measure
|
Observation
|
|
> 50% seizure reduction (good responders)
|
30 (66.7%)
|
|
Seizure freedom
|
9 (20%)
|
|
> 90% seizure reduction
|
11 (24.4%)
|
|
Adverse effects
|
N = 45
|
|
Constipation, n (%)
|
28 (62.2)
|
|
Lethargy, n (%)
|
3 (6.7)
|
|
Vomiting, n (%)
|
9 (20.0)
|
|
Severe adverse effects, n (%)
|
1 (2.2)
|
Ketosis achieved by the enrolled participants at the end of 12 weeks was classified
as trace (3 [6.7%]), mild (5 [11.1%]), moderate (17 [37.8%]), and large (14 [31.1%]).
There was a statistically significant fall in hemoglobin level with an increase in
serum glutamic pyruvic transaminase, serum glutamic-oxaloacetic transaminase, and
serum cholesterol levels on laboratory parameter monitoring. Still, all the values
were within the standard, acceptable range ([Table 3]).
Table 3
Comparison of laboratory parameters from baseline to 12 weeks
|
Parameter
|
Baseline
|
At 12 weeks
|
p-Value
|
|
Hemoglobin (g/dL)
|
9.75 (1.6)
|
9.25 (1.27)
|
0.02
|
|
Blood sugar (mg/dL)
|
98.97 (17.90)
|
94.33 (15.77)
|
0.12
|
|
Serum sodium (meq/L)
|
140.46 (3.75)
|
141.56 (4.204)
|
0.27
|
|
Serum potassium (meq/L)
|
4.27 (0.45)
|
4.34 (0.379)
|
0.39
|
|
Serum calcium (mg/dL)
|
9.436 (0.76)
|
9.63 (0.714)
|
0.26
|
|
Aspartate aminotransferase (IU/L)
|
30.36 (13.30)
|
37.13 (11.37)
|
< 0.01
|
|
Alanine aminotransferase (IU/L)
|
27.69 (13.26)
|
35.67 (11.28)
|
< 0.01
|
|
Blood urea (mg/dL)
|
20.74 (5.36)
|
20.82 (5.69)
|
0.93
|
|
Serum cholesterol (mg/dL)
|
40.51 (29.51)
|
151.72 (25.51)
|
< 0.01
|
|
High-density lipoprotein (mg/dL)
|
47.08 (10.08)
|
47.72 (7.59)
|
0.72
|
|
Low-density lipoprotein (mg/dL)
|
78.15 (22.31)
|
82.51 (21.37)
|
0.16
|
Discussion
The present study assessed the efficacy of sequential mAD followed by LGIT among children
under 5 years with drug-resistant epilepsy. This noncomparative study revealed that
76.9% of children achieved > 50% reduction in seizures with sequential dietary therapy
at the end of 12 weeks. The diet was well tolerated, with the majority having constipation.
In the present study, most enrolled children were diagnosed with West syndrome with
a median age of 21 months at the time of enrolment. The predominant etiology was perinatal
asphyxia. Previous studies have also demonstrated the predominance of perinatal insult
in the etiology of West syndrome.[12] Most of them had failed to respond to prednisolone or adrenocorticotropic hormone
and vigabatrin. Hence, the results of the present study cannot be extrapolated beyond
this relatively homogenous population of drug-resistant epilepsy. Moreover, many authors
have used various definitions for drug-resistant epilepsy. Reports range from failure
of three antiepileptic drugs by Tonekaboni et al,[13] occurrence of more than four spasm clusters per month despite treatment with two
or more than two antiepileptic drugs by Sondhi et al,[9] or daily infantile spasms persisting more than 6 weeks with at least one cluster
per day and EEG evidence of hypsarrhythmia and failure of hormonal treatment and vigabatrin
by Sharma et al.[2]
Most studies, however, have shown an efficacy of 50 to 60% with mAD.[10] The primary outcome measure for the present study was considered good responders
per the parental reports at 12 weeks. In the present study, 30 out of 39 children
who completed the 12-week follow-up had achieved > 50% seizure reduction, accounting
for nearly three-fourths of children being good responders with this sequential treatment.
These findings are consistent with previous studies quoting 70 to 77.8% efficacy of
LGIT on seizure reduction of more than 50%.[11]
[14]
[15]
[16]
[17]
[18]
In a study by Sondhi et al,[9] the median change with KD was 60%, mAD was 45%, and LGIT was 54%. In a study by
Tonekaboni et al,[13] 67% of children on mAD had > 50% seizure reduction, like the present study. Hence,
the comparable results of the sequential dietary therapy with isolated LGIT revealed
that the sequential dietary treatment does not improve the efficacy of the dietary
therapy.
Although the diet was well tolerated, nearly two-thirds of the children complained
of constipation. Other reported adverse effects included vomiting in almost 20% and
lethargy. This was similar to the study conducted by other authors, in which constipation
was the most common adverse effect in children on mAD.[1]
[6]
[14] However, severe adverse effects have not been reported with LGIT.[18]
The present study was a descriptive study providing a novel insight into the combined
sequential dietary therapy with mAD in the first month, followed by LGIT in the subsequent
2 months. The present study shows that shifting from mAD to LGIT is safe after 1 month
of mAD. This might be useful for those facing mAD compliance issues. The present study
has limitations of not having a comparative group, a small sample size, and a 3-month
follow-up period. Attrition rates in the present study (6 out of 45 children) need
to be kept in mind while interpreting the results of the present study. The majority
(4 out of 6) of dropouts was in the first month of mAD, and their clinical characteristics
were like those who continued in the study. Attrition rates with LGIT are minimal,
forming the basis for the present study to shift from mAD to LGIT.
Further research is needed to study the long-term outcome of the diet on seizure control,
growth, and biochemical parameters. In addition, a comparative trial of sequential
treatment with mAD alone could provide more meaningful results.
Fig. 1 Box and whisker plots of seizure frequency at baseline and at 12 weeks.
