Abstract
Objective
Ketogenic diets like the modified Atkins diet (MAD) are increasingly used in patients with refractory epilepsy. For epilepsy patients, stress is a well‐known seizure‐precipitating factor. New possibilities for measuring biomarkers of stress are now available. The purpose of this study was to investigate the impact of MAD on endocrine stress biomarkers.
Methods
Forty‐nine patients with drug‐resistant epilepsy were investigated at baseline and after 12 weeks on MAD. Cortisol and cortisol‐binding globulin (CBG) were measured and free cortisol index (FCI) calculated. We also measured metanephrine, normetanephrine, and methoxytyramine, all markers of epinephrine, norepinephrine, and dopamine, respectively. Changes were analyzed according to sex and antiseizure medications. The different markers at baseline and after 12 weeks of MAD treatment were correlated with seizure frequency and weight loss, respectively.
Results
The change in total cortisol was modest after 12 weeks on the diet (from 432.9 nmol/L (403.1–462.7)) to 422.6 nmol/L (384.6–461.0), P = 0.6). FCI was reduced (from 0.39 (0.36–0.42) to 0.34 (0.31–0.36), P = 0.001). CBG increased during the study (from 1126.4 nmol/L (1074.5–1178.3) to 1272.5 nmol/L (1206.3–1338.7), P < 0.001). There were no changes in the metanephrines after 12 weeks on the diet. The decrease in FCI was significant only in women, and only observed in patients using nonenzyme‐inducing ASMs. We did not find any correlation between cortisol, CBG, or FCI levels and seizure frequency.
Significance
After being on MAD for 12 weeks, FCI decreased significantly. The reduction in FCI may reflect reduced stress, but it may also be an effect of increased CBG. The reasons behind these alterations are unknown. Possibly, the changes may be a result of a reduction in insulin resistance and thyroid hormone levels. Treatment with MAD does not seem to influence “fight or flight” hormones.
Keywords: adrenal hormones, cortisol, cortisol binding globulin, free cortisol index, metanephrines
Key points.
Free cortisol index (FCI) was significantly reduced after 12 weeks on MAD.
Reduction in FCI may be an effect of increased CBG but could also reflect reduced stress.
Metanephrines as markers of the “fight or flight” reaction did not change during the study.
No association between FCI and seizure frequency was observed.
There were no major differences in effect between EIASMs and NEIASMs on the studied stress biomarkers.
1. INTRODUCTION
Epilepsy is one of the most common neurological diseases with a prevalence of about 0.7% in the adult population in Western countries. 1 Almost one‐third of the patients have drug‐resistant epilepsy and may be candidates for nonpharmacological treatments like epilepsy surgery or ketogenic dietary treatment. 1 Over the past decades, ketogenic diets, including the modified Atkins diet (MAD), have been used increasingly as an alternative or as a supplement to antiseizure medications (ASMs). 2 These high‐fat low‐carbohydrate diets induce a switch of metabolism from glucose to fatty acids and ketones as the main sources of energy. The mechanisms behind the diets' seizure‐reducing effect are still unclear, and multiple factors are probably involved. 3 An updated review reported a 35% seizure reduction, on average, for adult patients treated with ketogenic diets. 4
Concerns have been raised about difficulties adhering to the diet, especially for adult patients. The diet demands strong commitment to the treatment and requires calculating nutritional contents and preparing meals over time. In addition, a radical change in eating habits may have challenging consequences for both family and social life. Moreover, starting with such a strict diet may introduce mental stress, a well‐known and often reported seizure precipitator by patients with epilepsy. 1 , 2 , 5 , 6
When humans experience stress, this triggers a hormonal response that involves activation of the sympathetic nervous system. Epinephrine (85%), norepinephrine (15%), and small amounts of dopamine are produced and released from the adrenal medulla, 7 , 8 and there is an increased release of norepinephrine from the nerve terminals. These amines are metabolized to metanephrines, which can be measured in blood as possible markers of the “fight or flight” reaction. During acute stress, the hypothalamic–pituitary–adrenal (HPA) axis is also activated. Corticotrophin‐releasing hormone is released from the hypothalamus and stimulates the secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland into the circulation. 9 Consequently, the adrenal cortex synthesizes cortisol, which targets many organs including the brain. It is assumed that raised cortisol levels are associated with lowered seizure threshold. 10
Little has been published regarding the effect of ketogenic diets on stress markers in humans. In a study by Fraser et al 11 13 patients with rheumatoid arthritis had an increase in cortisol levels following treatment with a ketogenic diet for 7 days. In a review article from 2019, including 38 studies, cortisol levels among patients with epilepsy showed divergent results, indicating the need for further studies. 10
The aim of this study was to investigate whether treatment with MAD for 12 weeks in adult patients with drug‐resistant epilepsy had an impact on stress biomarkers measured in blood.
2. MATERIALS AND METHODS
2.1. Patients
All patients were recruited at a tertiary referral epilepsy center to two prospective studies by Kverneland et al. 12 , 13 The current study is based on data and material collected and described in detail in these previous studies. A study period of 12 weeks was considered sufficient for changes in endocrine stress biomarkers to develop, in line with our previous findings in thyroid hormones and bone parameters.
In short, 49 adults with drug‐resistant focal or generalized epilepsy were included. Two senior neurologists and a clinical dietician performed the screening and inclusion. The MAD allowed an intake of maximum 16 grams of carbohydrates daily, that is, 5% carbohydrates, 70% fat, and 25% protein. 12
The inclusion criteria were (i) age >16 years, (ii) having tried at least three ASMs, including current treatment, (iii) having a body mass index >18.5 kg/m2, and (iv) having at least three countable seizures per month. The seizures had to be countable by either the patients or their relatives/caregivers. The patients (and/or their caregivers) had to be motivated to adhere to the diet, and they were trained to be confident in preparing meals. No change in the drug treatment was allowed during the study period.
Exclusion criteria were pregnancy, use of a ketogenic diet the previous year, change of ASMs during the last 6 months, psychogenic nonepileptic seizures, status epilepticus the previous 6 months, surgery or implantation of a vagus nerve stimulator the last 12 months. Patients having psychosocial or physical comorbidities were also excluded after an individual assessment. In addition, patients who used selective serotonin reuptake inhibitors (SSRI), selective noradrenaline reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), or other medication that could affect the production of epinephrine or norepinephrine from the adrenal medulla were excluded. In addition, we excluded patients that used hormone treatments like antiestrogen (tamoxifen), medications that contained estrogen or progesterone, or for unknown reasons had a high serum concentration of cortisol binding globulin (CBG). None of the patients had abnormal thyroid hormone levels at baseline.
Adherence to the diet was confirmed by measuring ketosis in urine and blood. At home, the patients recorded urine ketosis twice daily (morning and evening) during the 12 weeks of dietary treatment. During the hospital stays after 4 and 12 weeks on the diet, the extent of blood ketosis was measured between eight and 10 a.m. after an overnight fast by the concentration of ß‐hydroxybutyrate based on a finger‐prick blood sample in the morning. Urine ketosis was measured using urine dipsticks. These results were all reported previously by Kverneland et al and indicated satisfactory adherence to the dietary treatment. 12 , 13 , 14 We measured body weight in the morning after an overnight fast during hospital stays.
As reference measurements, we used the data from 19 of the 53 patients from 3 months before starting on the MAD. In addition, nine patients ate their habitual diet for 3 months without starting on the MAD afterward. The reference group of 28 patients had a habitual diet in line with a typical Norwegian diet with average energy distribution of 43%–44% from carbohydrates, 34% from fat, and 18% from protein. 15 Venous blood samples were collected at start and after 3 months on the habitual diet from the patients in the reference group.
The study was approved by the Regional Committee for Medical and Health Research Ethics in South East Norway (number 2010/2326). Written informed consent was obtained from all patients.
2.2. Laboratory tests and other analyses
Venous blood was collected between eight and 10 a.m. after an overnight fast for both the diet group and the reference group at baseline and after 12 weeks, that is, 12 weeks on the MAD and 12 weeks on a habitual diet, respectively. Serum was separated from the blood samples and stored at −80°C until analyzed. We analyzed all samples in one batch, and all stress biomarkers were measured in serum.
We measured cortisol as an indicator of the stress response from the adrenal cortex 16 with an in‐house liquid chromatography‐tandem mass spectrometry (LC‐MSMS) method (CV% 8 at 146 nmol/L).
CBG was determined using radioimmunoassay (DIAsource ImmunoAssays, CV% 15 at 529 nmol/L). FCI was calculated as a surrogate marker for free cortisol, dividing cortisol by CBG. 17 We analyzed metanephrine and normetanephrine as metabolites from epinephrine and norepinephrine, respectively, and as markers of the stress response from the adrenal medulla and sympathetic nervous system. We also analyzed methoxytyramine as a marker of dopamine secretion. 18 All these metabolites were determined with an in‐house LC‐MSMS method (CV% 12 at 0.29 nmol/l, CV% 10 at 0.68 nmol/L, and CV%13 at 0.20 nmol/L, respectively). All samples were measured at the Hormone Laboratory at Oslo University Hospital. All methods were accredited according to NS‐EN ISO/IEC 17025:2017, except for the CBG measurements. Thyroid hormone levels including TSH were analyzed in a prior publication. 21
The antiseizure medications (ASMs) were categorized and analyzed according to category, that is, enzyme‐inducing ASMs (EIASMs) or nonenzyme‐inducing ASMs (NEIASMs), see Table 1.
TABLE 1.
Antiseizure medication (ASM) used by the patients.
| Enzyme‐inducing ASMs | n = 11 | Nonenzyme‐inducing ASMs | n = 38 |
|---|---|---|---|
| Phenytoin | n = 4 | Zonisamide | n = 4 |
| Phenobarbital | n = 2 | Levetiracetam | n = 13 |
| Carbamazepine | n = 6 | Valproate | n = 14 |
| Topiramate a | n = 8 | ||
| Oxcarbazepine a | n = 11 | ||
| Clobazam | n = 8 | ||
| Lamotrigine | n = 16 | ||
| Lacosamide | n = 6 | ||
| Pregabalin | n = 2 | ||
| Clonazepam | n = 1 |
Note: Patients using one or more of the EIASMs were included in the EIASM group.
Abbreviation: N, number of patients that used different ASMs.
Partly enzyme‐inducing ASMs. Topiramate doses: mean (range) 365.2 (200–550) mg/day. Oxcarbazepine doses: mean (range) 1622.7 (900–3000) mg/day.
2.3. Statistics
Normality checks included Shapiro–Wilk tests for significant deviation from the normal distribution as well as visual inspections of histograms and Q–Q plots.
All samples were analyzed at baseline and after 12 weeks on the MAD, and results compared using a paired samples Student's test for the normally distributed data, and a Wilcoxon signed‐rank test for the not normally distributed data. Subgroup analyses were performed for sex and type of ASMs. Seizure frequency was recorded at baseline and during the 12‐week study period. Weekly seizure frequency was the mean weekly value from week 5 to 12.
We performed a linear regression analysis to examine possible associations between seizure frequency and stress biomarker levels (i.e., FCI, metanephrine, and normetanephrine) at baseline and at week 12 (i.e., the mean weekly seizure frequency from week 5 to 12). A linear regression analysis was also used to explore possible associations between weight loss and changes in FCI and CBG, and possible associations between changes in thyroid stimulation hormone (TSH) and changes in FCI.
Statistical significance was assumed at P < 0.05. All analyses were performed using SPSS Statistics v28.
3. RESULTS
3.1. Patient characteristics
The characteristics of the diet group and the reference group at baseline are given in Table 2. The study groups were comparable regarding sex, age, body mass index, weight, duration of epilepsy, and the mean number of ASMs used at baseline and tried previously. There was no significant difference in mean seizure frequency between the reference group and the diet group (P = 0.63). The number of patients with intellectual disability was higher in the reference group than in the MAD group. None of the patients in the reference group had generalized epilepsy Table 2.
TABLE 2.
Patient characteristics for 49 patients on MAD and 28 patients on a habitual diet (reference group).
| MAD n = 49 | Reference group n = 28 | |
|---|---|---|
| Women/men (n) | 30/19 | 13/15 |
| Intellectual disability n (%) | 14 (28.6) | 12 (42.9) |
| Mean age, years (range) | 37.8 (16–65) | 36.0 (22–65) |
| Mean BMI, kg/m2 (range) | 26.9 (18.5–41.7) | 25.5 (18.7–35.1) a |
| Mean weight, kg (range) | 79.0 (51.6–138.8) | 78.8 (51.6–128.0) |
| Epilepsy etiology | ||
| Structural n (%) | 12 (24.5) | 9 (32.1) |
| Infectious n (%) | 3 (6.1) | 1 (3.6) |
| Unknown n (%) | 28 (57.1) | 18 (64.3) |
| Years with epilepsy, mean (range) | 25.0 (5–58) | 25.1 (3–58) |
| Seizure frequency per week, mean (range) | 16.3 (0.08–268.0) | 22.8 (0.0–196.0) |
| Mean no of ASMs used, currently (range)/earlier (range) | 2.1 (1.0–3.0)/8.4 (3.0–18.0) b | 2.0 (1.0–3.0)/8.6 (2.0–18.0) c |
| Focal/generalized epilepsy | 43/6 | 28/0 |
n = 18. Height was available for 18 patients in the reference group.
n = 42.
n = 26.
3.2. Stress biomarkers
Tables 3 and 4 show the changes in the stress biomarkers (cortisol, CBG, FCI, metanephrine, normetanephrine, and methoxytyramine) from baseline to 12 weeks on MAD. There was a significant increase in CBG and a decrease in FCI for the diet group. There were no significant changes in cortisol, metanephrine, or normetanephrine levels. There was no significant association between the difference in FCI and TSH (r 0.155, P 0.288). As for the reference group, the changes were not significant for any of the stress biomarkers.
TABLE 3.
Cortisol markers at baseline and after 12 weeks on MAD or a habitual diet (reference group).
| Baseline | 12 weeks | % change | P‐value | |
|---|---|---|---|---|
| Cortisol (ref ≥16 years 130–600 nmol/L) All n 49 | ||||
| Mean (95%CI) | 432.9 (403.1–462.7) | 422.6 (384.6–461.0) | −2.4 | 0.6 |
| Women n 30 | ||||
| Mean (95%CI) | 442.5 (403.8–481.1) | 423.4 (368.8–478.0) | −4.4 | 0.5 |
| Men n 19 | ||||
| Mean (95%CI) | 417.8 (367.2–468.5) | 421.4 (368.2–474.6) | 0.9 | 0.9 |
| Reference group n 28 | ||||
| Mean (95%CI) | 474.5 (417.7–531.4) | 446.0 (372.1–520.0) | −6.1 | 0.5 |
| CBG (ref ≥18 years 750–1600 nmol/L) All n 49 | ||||
| Mean (95%CI) | 1126.4 (1074.5–1178.3) | 1272.5 (1206.3–1338.7) | 13.0 | <0.001 |
| Women n 30 | ||||
| Mean (95%CI) | 1149.6 (1076.5–1222.7) | 1271.7 (1175.1–1368.3) | 10.6 | <0.01 |
| Men n 19 | ||||
| Mean (95%CI) | 1089.7 (1016.9–1162.6) | 1273.8 (1185.4–1362.3) | 16.9 | <0.001 |
| Reference group n 28 | ||||
| Mean (95%CI) | 1149.6 (1080.8–1218.3) | 1183.5 (1093.3–1273.6) | 2.9 | 0.3 |
| FCI (ref <0,54) All n 49 | ||||
| Mean (95%CI) | 0.39 (0.36–0.42) | 0.34 (0.31–0.36) | −13.0 | 0.001 |
| Women n 30 | ||||
| Mean (95%CI) | 0.39 (0.35–0.44) | 0.34 (0.29–0.38) | −13.0 | <0.01 |
| Men n 19 | ||||
| Mean (95%CI) | 0.39 (0.34–0.43) | 0.33 (0.29–0.37) | −15.4 | 0.05 |
| Reference group n 28 | ||||
| Mean (95%CI) | 0.42 (0.37–0.46) | 0.38 (0.33–0.42) | −9.6 | 0.2 |
TABLE 4.
Markers of the adrenal medulla stress hormones at baseline and after 12 weeks on MAD or a habitual diet (reference group).
| Baseline | 12 weeks | % change | P‐value | |
|---|---|---|---|---|
| Metanephrine (ref <0.34 nmol/L) | ||||
| All n 45 | ||||
| Mean (95%CI) | 0.19 (0.17–0.22) | 0.18 (0.16–0.21) | −5.3 | 0.4 |
| Women n 28 | ||||
| Mean (95%CI) | 0.19 (0.15–0.22) | 0.18 (0.15–0.22) | −5.3 | 0.8 |
| Men n 17 | ||||
| Mean (95%CI) | 0.20 (0.16–0.24) | 0.18 (0.15–0.22) | −10.0 | 0.1 |
| Reference group n 27 | ||||
| Mean (95%CI) | 0.18 (0.15–0.22) | 0.19 (0.15–0.22) | 5.5 | 0.6 |
| Normetanephrine (ref <1.2 nmol/L) | ||||
| All n 45 | ||||
| Mean (95%CI) | 0.48 (0.42–0.54) | 0.47 (0.41–0.54) | −2.1 | 0.8 |
| Women n 28 | ||||
| Mean (95%CI) | 0.48 (0.40–0.57) | 0.48 (0.38–0.57) | 0 | 0.7 |
| Men n 17 | ||||
| Mean (95%CI) | 0.48 (0.38–0.57) | 0.47 (0.38–0.55) | −2.1 | 0.9 |
| Reference group n 28 | ||||
| Mean (95%CI) | 0.46 (0.38–0.55) | 0.50 (0.39–0.61) | 8.7 | 0.8 |
| Metoksytyramine (ref <0.11 nmol/L) | ||||
| All n 45 | ||||
| Mean (95%CI) | <0.08 | <0.08 | 0 | – |
| Reference group n 28 | 28 | 28 | ||
| Mean (95%CI) | <0.08 | <0.08 | 0 | – |
3.3. Seizure frequency
We used a linear regression model and found no significant association between FCI, metanephrine, or normetanephrine levels and seizure frequency at baseline or after 12 weeks on the diet. See Table 5.
TABLE 5.
Associations between FCI, metanephrine, and normetanephrine levels and seizure frequency at baseline and after 12 weeks.
| Seizure frequency baseline | Seizure frequency 12 weeks | |||
|---|---|---|---|---|
| Pearson, r | P‐value | Pearson, r | P‐value | |
| FCI (ref <0.54) | 0.14 | 0.4 | 0.07 | 0.6 |
| Metanephrine (ref <0.34 nmol/L) | 0.05 | 0.8 | 0.07 | 0.7 |
| Normetanephrine (ref <1.2 nmol/L) | 0.13 | 0.4 | 0.16 | 0.3 |
Abbreviation: FCI, free cortisol index.
3.4. Enzyme‐inducing ASMs versus nonenzyme‐inducing ASMs
All patients used ASMs, and the majority used combinations of ASMs. Some patients used both EIASMs and NEIASMs. Table 6 shows the changes in stress markers from start of the MAD to the end of the study period for the patients that used EIASMs and NEIASMs. We found no major differences between the groups. See Table 6.
TABLE 6.
Mean values of stress biomarkers at baseline and after 12 weeks on MAD according to type of ASM in use (enzyme‐inducing ASMs (EIASMs), and nonenzyme‐inducing ASMs (NEIASMs)).
| Baseline | 12 weeks | % change | P‐value | |
|---|---|---|---|---|
| Cortisol (ref ≥16 years 130–600 nmol/L) | ||||
| EIASMs n 11 | ||||
| Mean (95% CI) | 415.1 (384.4–445.8) | 504.6 (408.8–600.4) | 21.6 | 0.06 |
| NEIASMs n 38 | ||||
| Mean (95% CI) | 438.1 (400.2–475.9) | 398.9 (359.2–438.6) | −8.9 | 0.08 |
| CBG (ref ≥18 years 750–1600 nmol/L) | ||||
| EIASM n 11 | ||||
| Mean (95% CI) | 1269.0 (1135.4–1402.6) | 1557.5 (1385.3–1729.6) | 22.7 | <0.01 |
| NEIASM n 38 | ||||
| Mean (95% CI) | 1085.1 (1034.4–1135.8) | 1190.0 (1143.6–1236.5) | 9.7 | <0.001 |
| FCI (ref <0,54) | ||||
| EIASM n 11 | ||||
| Mean (95% CI) | 0.33 (0.30–0.37) | 0.33 (0.27–0.38) | 0 | 0.7 |
| NEIASM n 38 | ||||
| Mean (95% CI) | 0.41 (0.37–0.44) | 0.34 (0.30–0.37) | −17.0 | <0.01 |
| Metanephrine (ref <0.34 nmol/L) | ||||
| EIASM n 11 | ||||
| Mean (95% CI) | 0.16 (0.12–0.20) | 0.18 (0.13–0.22) | 12.5 | 0.2 |
| NEIASM n 37 | ||||
| Mean (95% CI) | 0.19 (0.16–0.22) | 0.18 (0.15–0.20) | −5.3 | 0.2 |
| Normetanephrine (ref <1.2 nmol/L) | ||||
| EIASM n 11 | ||||
| Mean (95% CI) | 0.48 (0.29–0.68) | 0.43 (0.32–0.54) | −10.5 | 0.8 |
| NEIASM n 37 | ||||
| Mean (95% CI) | 0.52 (0.44–0.60) | 0.49 (0.41–0.56) | −5.8 | 0.3 |
| Metoksythyramine (ref ≥3 år < 0.11 nmol/L) | ||||
| EIASM n 11 | ||||
| Mean (95% CI) | <0.08 | <0.08 | 0 | a |
| NEIASM n 37 | ||||
| Mean (95% CI) | <0.08 | <0.08 | 0 | a |
Measurements at both time points were below limit of detection.
We also analyzed the stress markers in the NEIASMs group without the partly enzyme‐inducing drugs topiramate and oxcarbazepine but it did not alter the main results (data not shown).
3.5. Body weight
At baseline, the mean body weight was (range) 79.0 (51.6‐138.8) kg for the patients that used MAD. After 12 weeks on MAD, the weight was significantly reduced to 74.6 (46.7‐126.3) kg (P < 0.001). For unknown reasons, two patients were not weighed at 12 weeks. We found no significant association between weight loss and FCI (r 0.024, P 0.870), or weight loss and CBG (r 0.286, P 0.051).
4. DISCUSSION
In this study of stress biomarkers investigated in 49 patients with drug‐resistant epilepsy treated with MAD for 12 weeks, we found a significant decrease in FCI and a significant increase in CBG. The reduction in FCI was probably due to the increase in CBG as total cortisol was unchanged during the study period. To our knowledge, this is the first study to evaluate FCI in patients with drug‐resistant epilepsy on a MAD.
FCI is considered to reflect the active cortisol effect in humans, and an increase of FCI is regarded to be a stress signal. Cortisol acts on several organs and activates stored energy mostly by hepatic glycogenolysis and lipolysis, as are known from other situations with an increased demand for energy, like fasting. 10 Cortisol is known to increase brain excitability, and seizures have been related to an increase in cortisol levels. 10 Free cortisol also conducts an effect in the cell nucleus modifying gene expression, which may secondarily lead to alterations in seizure threshold. 19 However, in this study, the FCI was significantly reduced.
The reason for the reduction in FCI and increase in CBG may be due to reduced insulin resistance after 12 weeks on MAD. In support of such a claim is the body weight reduction we previously found. 20 However, weight loss was not significantly correlated with CBG, nor with FCI.
Also, a modest fall in thyroid hormone levels in the same patients 21 may have influenced the CBG levels. It is known that the CBG level is closely tied to thyroid hormone levels with an increase in hypothyroid and a decrease in hyperthyroid patients. 22 Thus, both reduced insulin resistance and reduced thyroid hormone levels may possibly have contributed to the increase in CBG levels.
The reduction in FCI was significant only in women, but the magnitude of change was the same in both sexes (13% in women, 15% in men). This finding may, therefore, be due to the small sample size. An interesting observation is the lower FCI in patients taking NEIASMs only. So far, we have no explanation for this, but this should be confirmed in further studies as it may have clinical implications.
Altogether, in patients with severe epilepsy being on MAD for 12 weeks, we found a significantly lower free cortisol level compared with the reference group that used a habitual diet. Thus, assumed that free cortisol is a valid stress marker, using MAD may reduce stress in these patients. Whether the lowered FCI is due to the increase in CBG or as a genuine reduction of cortisol production, is unclear.
Cortisol is generally considered to increase brain excitability, 10 but no correlation between free cortisol and seizure frequency could be found in our study. It can, therefore, be speculated if reduced FCI is involved in the antiseizure effect of MAD. Opposite, corticosteroids are used in drug‐resistant epilepsy in children. Especially ACTH and prednisolone are established as treatments for infantile spasms. 23 Altogether, treatments that affect the HPA axis may be of value for patients with epilepsy. 3 , 24 Further studies are needed in this field.
We found no significant differences in the metabolites of epinephrine (metanephrine), norepinephrine (normetanephrine), or dopamine (methoxytyramine) during the study period, which indicates no activation of the adrenal medulla. To our knowledge, this has not been shown before. 25
The strength of the present study is the very strict monitored diet with frequent measurement of ketosis and the sophisticated measurement of stress biomarkers. Our study is possibly underpowered to look at correlations between seizure frequency and stress biomarkers. Subanalyses regarding age, different types of seizures, epilepsy type, etiology, and the effects of individual ASMs or ASM combinations are of interest, but again a higher number of subjects would be needed. ACTH was not measured, consequently we have no information of possible effects on the HPA‐induced stress involving the pituitary. Finally, the biomarkers in this study were analyzed in venous blood. This should be taken into account, as the levels of biomarkers in blood not automatically reflect the levels of biomarkers in the brain.
5. CONCLUSION
We conclude that FCI was significantly lower after 12 weeks on MAD compared to before the diet. No difference was observed in a reference patient group. This reduction may be due to diet‐induced metabolic changes leading to increased CBG levels after treatment with MAD for 12 weeks. Whether it reflects reduced stress or merely metabolic changes in these patients, is unknown.
AUTHOR CONTRIBUTIONS
E.M., P.M.T., and E.T. designed the study. E.M., M.K., and K.O.N collected the data. E.M. and D.H. executed the statistical analysis. E.M., P.M.T., and E.T. interpreted the data. K.K.S., P.O.I., K.O.N., and M.K. provided study supervision. All authors edited the manuscript.
CONFLICT OF INTEREST STATEMENT
K.K.S received speakers and consultant honoraria from Roche and Orion Pharma. K.O.N received lecture fees from Eisai and Desitin. M.K. received two honoraria from Nutricia. E.M. received lecture fees from Nutricia. The other authors have no conflicts of interest to disclose.
ETHICAL APPROVAL
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGMENTS
We are grateful for the economic support from the Norwegian Epilepsy Association's Research Fund and the Norwegian Epilepsy Federation.
Molteberg E, Thorsby PM, Kverneland M, Iversen PO, Selmer KK, Hofoss D, et al. Stress biomarkers in adult patients with drug‐resistant epilepsy on a modified Atkins diet: A prospective study. Epilepsia Open. 2023;8:1331–1339. 10.1002/epi4.12808
Ellen Molteberg and Per M Thorsby shared first authorship.
Ellen Molteberg and Per M Thorsby contributed equally to this work.
REFERENCES
- 1. Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet. 2019;393(10172):689–701. [DOI] [PubMed] [Google Scholar]
- 2. Höhn S, Dozières‐Puyravel B, Auvin S. History of dietary treatment: Guelpa & Marie first report of intermittent fasting for epilepsy in 1911. Epilepsy Behav. 2019;94:277–280. [DOI] [PubMed] [Google Scholar]
- 3. Sorbron J, Thevissen K, Lagae L. The ketogenic diet revisited: beyond ketones. Front Neurol. 2021;12:720073. 10.3389/fneur.2021.720073 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Martin‐McGill KJ, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug‐resistant epilepsy. Cochrane Database Syst Rev. 2020;6(6):Cd001903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Nakken KO, Solaas MH, Kjeldsen MJ, Friis ML, Pellock JM, Corey LA. Which seizure‐precipitating factors do patients with epilepsy most frequently report? Epilepsy Behav. 2005;6(1):85–89. 10.1016/j.yebeh.2004.11.003 [DOI] [PubMed] [Google Scholar]
- 6. Haut SR, Hall CB, Masur J, Lipton RB. Seizure occurrence: precipitants and prediction. Neurology. 2007;69(20):1905–1910. [DOI] [PubMed] [Google Scholar]
- 7. Wong DL, Tai TC, Wong‐Faull DC, Claycomb R, Meloni EG, Myers KM, et al. Epinephrine: a short‐ and long‐term regulator of stress and development of illness: a potential new role for epinephrine in stress. Cell Mol Neurobiol. 2012;32(5):737–748. 10.1007/s10571-011-9768-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Carmichael SW. Molecular and cellular endocrinology, principles of medical biology. In: Bittar E, Bittar N, editors. The adrenal medulla. London: JAI Press, Elsevier; 1997. p. 207–225. [Google Scholar]
- 9. Herman JP, McKlveen JM, Ghosal S, Kopp B, Wulsin A, Makinson R, et al. Regulation of the hypothalamic‐pituitary‐adrenocortical stress response. Compr Physiol. 2016;6(2):603–621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Cano‐López I, González‐Bono E. Cortisol levels and seizures in adults with epilepsy: a systematic review. Neurosci Biobehav Rev. 2019;103:216–229. [DOI] [PubMed] [Google Scholar]
- 11. Fraser DA, Thoen J, Bondhus S, Haugen M, Reseland JE, Djøseland O, et al. Reduction in serum leptin and IGF‐1 but preserved T‐lymphocyte numbers and activation after a ketogenic diet in rheumatoid arthritis patients. Clin Exp Rheumatol. 2000;18(2):209–214. [PubMed] [Google Scholar]
- 12. Kverneland M, Selmer KK, Nakken KO, Iversen PO, Taubøll E. A prospective study of the modified Atkins diet for adults with idiopathic generalized epilepsy. Epilepsy Behav. 2015;53:197–201. [DOI] [PubMed] [Google Scholar]
- 13. Kverneland M, Molteberg E, Iversen PO, Veierod MB, Tauboll E, Selmer KK, et al. Effect of modified Atkins diet in adults with drug‐resistant focal epilepsy: a randomized clinical trial. Epilepsia. 2018;59(8):1567–1576. [DOI] [PubMed] [Google Scholar]
- 14. Kverneland M, Taubøll E, Molteberg E, Veierød MB, Selmer KK, Nakken KO, et al. Pharmacokinetic interaction between modified Atkins diet and antiepileptic drugs in adults with drug‐resistant epilepsy. Epilepsia. 2019;60(11):2235–2244. [DOI] [PubMed] [Google Scholar]
- 15. Health H‐TNDo . Norkost 3, a nationwide dietary survey among men and women in Norway aged 18–70, 2010–11. 2012.
- 16. Angela Clow NS, Salpekar JA, Basu T, Thangaraj S, Maguire J. Chapter eight – the intersections of stress, anxiety and epilepsy. Int Rev Neurobiol. 2020;152:195–219. [DOI] [PubMed] [Google Scholar]
- 17. Panton KK, Mikkelsen G, Irgens W, Hovde AK, Killingmo MW, Øien MA, et al. New reference intervals for cortisol, cortisol binding globulin and free cortisol index in women using ethinyl estradiol. Scand J Clin Lab Invest. 2019;79(5):314–319. [DOI] [PubMed] [Google Scholar]
- 18. Peitzsch M, Novos T, Kaden D, Kurlbaum M, van Herwaarden AE, Müller D, et al. Harmonization of LC‐MS/MS measurements of plasma free normetanephrine, Metanephrine, and 3‐Methoxytyramine. Clin Chem. 2021;67(8):1098–1112. [DOI] [PubMed] [Google Scholar]
- 19. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids — new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–1723. [DOI] [PubMed] [Google Scholar]
- 20. Molteberg E, Taubøll E, Kverneland M, Iversen PO, Selmer KK, Nakken KO, et al. Substantial early changes in bone and calcium metabolism among adult pharmacoresistant epilepsy patients on a modified Atkins diet. Epilepsia. 2022;63(4):880–891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Molteberg E, Thorsby PM, Kverneland M, Iversen PO, Selmer KK, Nakken KO, et al. Effects of modified Atkins diet on thyroid function in adult patients with pharmacoresistant epilepsy. Epilepsy Behav. 2020;111:107285. [DOI] [PubMed] [Google Scholar]
- 22. Dumoulin SC, Perret BP, Bennet AP, Caron PJ. Opposite effects of thyroid hormones on binding proteins for steroid hormones (sex hormone‐binding globulin and corticosteroid‐binding globulin) in humans. Eur J Endocrinol. 1995;132(5):594–598. [DOI] [PubMed] [Google Scholar]
- 23. Jain P, Sahu JK, Horn PS, Chau V, Go C, Mahood Q, et al. Treatment of children with infantile spasms: a network meta‐analysis. Dev Med Child Neurol. 2022;64(11):1330–1343. 10.1111/dmcn.15330 [DOI] [PubMed] [Google Scholar]
- 24. Basu T, Maguire J, Salpekar JA. Hypothalamic‐pituitary‐adrenal axis targets for the treatment of epilepsy. Neurosci Lett. 2021. Feb 16;746:135618. 10.1016/j.neulet.2020.135618 [DOI] [PubMed] [Google Scholar]
- 25. Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004;56(3):331–349. [DOI] [PubMed] [Google Scholar]