E-mail management of the Modified Atkins Diet for adults with epilepsy is feasible and effective

Authors


Address correspondence to Mackenzie C. Cervenka, Johns Hopkins Epilepsy Center, 600 North Wolfe Street, Meyer 2-147, Baltimore, MD 21287, U.S.A. E-mail: mcerven1@jhmi.edu

Summary

Purpose:  The modified Atkins Diet (MAD) is an effective dietary treatment for children with epilepsy. However, adults may have limited access to this therapy because of lack of availability of dietitian or nutrition support or familiarity with the diet by their treating neurologist. This study was designed to investigate the tolerability and efficacy of the MAD administered solely via e-mail to adults with pharmacoresistant epilepsy.

Methods:  A prospective, open-label, proof-of-principle 3-month study design was employed. Adults were enrolled, instructed on how to self-administer a 20 g carbohydrate per day MAD, and followed by the investigators only via e-mail. There were no clinic visits or dietitian contacts during the study period.

Key Findings:  Twenty-five participants (median age 30 years [range 18–66 years], 68% female) consented and 22 started the MAD. The median prior anticonvulsants was 5 (range 2–10) and seizure frequency was 5 per week (range 1–140). Urinary ketosis was achieved in 21 participants (95%), of which 16 (76%) reported at least 40 mg/dl (moderate). Twenty-one participants (95%) remained on the MAD at 1 month and 14 (64%) at 3 months. After 1 month, 9 (41%) had >50% seizure reduction including one (5%) with >90% seizure reduction using intent-to-treat analysis. After 3 months, 6 (27%) had >50% seizure reduction including 3 (14%) with >90% seizure reduction. The mean ketogenic ratio was 1.1:1 (fat:carbohydrates and protein) for those who provided a MAD food record at follow-up. Over the study period, the median number of e-mails sent by the participants was 6 (range 1–19). The most frequent side effect was weight loss.

Significance:  E-mail administration of the MAD to adults with refractory epilepsy appears to be feasible and effective. Therefore, when dietitian or physician support is limited for adult patients with epilepsy, remote access via telemedicine could provide an alternative.

Dietary therapies for treating patients with epilepsy are designed to utilize high fat and low carbohydrate foods with the goal of achieving urinary ketosis and seizure control. The ketogenic diet (KD) was first used nearly a century ago to control seizures (Weeks et al., 1923; Barborka, 1930). However, administration of the diet to adults with medically refractory epilepsy has only been reintroduced within the last decade due to the restrictive nature of the KD and concerns regarding compliance (Sirven et al., 1999; Klein et al., 2010). New, less restrictive dietary therapies such as the modified Atkins Diet (MAD) and low glycemic index treatment (LGIT) have been shown to have comparable efficacy rates and may be well-tolerated in adults (Carrette et al., 2008; Kossoff et al., 2008a; Muzykewicz et al., 2009; Smith et al., 2011).

In contrast to the KD, the MAD does not require hospital admission for fasting to initiate the diet, weighing foods on a gram scale, or calorie or fluid restriction (Kossoff et al., 2008a). For these reasons, it is easier to self-administer and more practical for adults who may be working and responsible for the activities of daily living for themselves and others. Many adults with medically or surgically refractory seizures may find this option appealing, but they discover that there are no centers within a reasonable distance offering this treatment.

A major barrier to delivery of dietary therapies to adults has been a lack of neurologist and dietitian training and availability. Recent studies have demonstrated the feasibility and efficacy of telemedicine in the field of neurology, also referred to as “teleneurology,” including in the care of patients with epilepsy (Patterson, 2003; Ahmed et al., 2009). Similarly, providing written materials and dietary guidance via e-mail has been demonstrated to be possible for children with the MAD, even in the case of a child with Lennox-Gastaut syndrome living in Honduras (Kossoff et al., 2008b). We hypothesized that the MAD could be successfully started, implemented, and managed in adults solely via e-mail without direct dietitian involvement. Doing so could allow adults with medically refractory seizures to take advantage of this treatment option.

Methods

The study was approved by the Johns Hopkins Institutional Review Board. All participants signed and faxed written informed consent forms sent via e-mail. The study was listed at http://www.clinicaltrials.gov (NCT00436631) with instructions for potential participants to e-mail study team physicians (MC, EK, and PM) directly. The study period was from 2007 to 2010.

A prospective, open-label, proof-of-principle 3-month cohort study design was employed. Twenty-five participants were chosen to approximate the study size of a previous in-person study (Kossoff et al., 2008a). Participants were 18 years of age or older and had at least weekly seizures despite therapeutic trials of at least two anticonvulsants. They were all living in the United States, with access and personal ability to e-mail. Adults who tried the Atkins Diet for more than 7 days or the ketogenic diet within the past year, those who had status epilepticus within 6 months prior to enrollment, with nonepileptic seizures, renal, or coronary artery disease, or were underweight (body mass index <18.5) were excluded.

Once participants made initial e-mail contact with study team physicians via the Johns Hopkins e-mail server, every e-mail sent by the study team contained the following disclaimer: “WARNING: E-mail sent over the Internet is not secure. Information sent by e-mail may not remain confidential. This e-mail is intended only for the individual to whom it is addressed. It may be used only in accordance with applicable laws. If you received this e-mail by mistake, notify the sender and destroy the e-mail.” as per the Johns Hopkins policy with regard to exchanging e-mail correspondence with patients. E-mail access was password protected.

Verification of qualification to participate was confirmed by requiring participants to fax or e-mail the last 6 months of their medical records from their treating neurologist; records were then thoroughly reviewed by the study team physicians (MC, EK, and PM) for any discrepancies. Participants were also required to obtain written permission from their physician to participate that included the following text: “I am an English-speaking physician who has been involved in the care of this patient. I have no concerns of kidney, atherosclerotic, or heart disease in this patient, and am comfortable with his/her nutritional status at this time. I have no concerns about the planned initiation of the modified Atkins Diet for epilepsy and see no major contraindications. I understand that Dr. Kossoff, Morrison, and/or Cervenka will handle all aspects of the diet from afar (Baltimore, MD) for the next 3 months and I will be available locally for any emergencies and will contact them by telephone should any occur.” This permission was obtained to verify absence of comorbid conditions that would prevent enrollment and to confirm that patients had immediate access to a physician if any potential side effects needed to be addressed.

All participants were provided with a prescription to obtain a screening complete blood count with differential, comprehensive metabolic panel, fasting lipid panel, urine calcium, creatinine, and human chorionic gonadotropin level (if a woman). Laboratory results were faxed directly to the study physicians for review, and if abnormal leading to exclusion, the results were discussed. Participants were excluded if they had hyperlipidemia on initial screening labs (total cholesterol >200 mg/dl), given the potential increased risk of underlying cardiac or atherosclerotic disease, or were pregnant. Participants provided a baseline 3-day food record.

Adults were then e-mailed a detailed manual of instructions (Appendix S1) on how to self-administer a 20 g carbohydrate per day MAD. High fat foods were encouraged and total daily caloric and fluid intake were ad lib. All participants had unlimited e-mail access to corresponding neurologists trained in administering dietary treatments for epilepsy (MC, EK, and PM) to ask questions regarding the diet, and report any problems or side effects. Questions and/or concerns were thoroughly addressed to participant’s satisfaction and understanding within 24 h of e-mail receipt. There were no clinic visits or dietitian contacts.

Participants were evaluated at baseline and at 1 and 3 months. They were provided a prescription to purchase urine ketone reagent strips and to check urine ketones biweekly (see Appendix S1). Participants were instructed to record daily seizure frequency, biweekly urine ketones, and weekly weights on a provided calendar and fax or e-mail the scanned document monthly. They were provided with monthly feedback from study investigators regarding completeness of these calendars and to verify accuracy of recorded information (whether or not all information was documented correctly). They were asked not to change anticonvulsants during the study period. After 3 months, participants were instructed to obtain repeat laboratory studies, complete another 3-day food record, and decide if they planned to continue the MAD. They were instructed to report any and all potential side effects that they experienced during the duration of the diet.

An intent-to-treat analysis was employed for outcomes and a two-tailed t-test (p < 0.05) was used for examining differences between means.

Results

Twenty-five participants (median age 30 years [range 18–66 years]) underwent initial screening and completed consent to participate in the study. Of these, 22 participants actually started the MAD. Baseline participant demographics are provided in Table 1.

Table 1.   Participant demographics
  1. Values are expressed as median (range) or number (percentage of 25 participants enrolled).

Age of first seizure (years)13 (0–64)
Age at start of diet (years)30 (18–66)
Anticonvulsants tried5 (2–10)
Anticonvulsants at start of diet2 (1–6)
Seizure frequency per week5 (1–140)
Female gender17 (68%)
Generalized or multifocal epilepsy9 (36%)
Prior resective epilepsy surgery6 (24%)
Prior vagus nerve stimulator implantation7 (28%)

An additional 42 individuals e-mailed requesting to participate in the study but were not included. Twenty were disqualified immediately on the basis of too infrequent seizures, documented nonepileptic seizures, recent treatment with dietary therapies, or inability to respond themselves to e-mails (a family member had inquired on behalf of a cognitively impaired individual). Twelve individuals initially qualified but did not follow-up with obtaining screening labs, previous records, or completing the permission form and/or the consent form. Finally, 10 individuals were excluded due to fasting total cholesterol >200 mg/dl at baseline.

Of the participants who started the MAD, urinary ketosis was achieved in 21 (95%), of which 16 (76%) reported at least 40 mg/dl (moderate) urine ketosis. Twenty-one (95%) remained on the MAD at 1 month; 14 (64%) at 3 months. Nine (41%) had >50% seizure reduction at 1 month, including 1 (5%) that had >90% seizure reduction using intent-to-treat analysis. After 3 months, 6 (27%) had >50% reduction in seizure frequency, including 3 (14%) who had >90% reduction, and 1 (5%) who was seizure-free. Participants who had a 1–50% reduction in seizure frequency occasionally still reported a decrease in intensity and duration of seizures. Of the participants who reported improvement in seizure frequency, the median time to improvement was 7 days (range 1–21 days). Six (27%) participants chose to remain on the MAD following the study conclusion.

Over the study period, the median number of e-mails sent by the participants was 6 (range 1–19). Of the participants who decided to continue the diet after the study, median number of e-mails sent during the study period was 5.5 (range 4–9). Estimated physician time spent reading and responding to e-mails was approximately 1–5 min per inquiry and a total of 161 e-mails were sent. Therefore, the total estimated clinician time spent supporting all participants was in the range of 5–13 h, or between 1 and 95 min per participant over the study period.

Eleven participants provided a 3-day MAD food record at 3 months, and the mean ketogenic (fat:carbohydrate and protein grams) ratio was 1.1:1. The mean available carbohydrate intake (carbohydrates grams minus fiber grams, also referred to as “net carbs”) was 17.8 g/day. The mean total carbohydrate intake was 25.0 g/day (8% of daily kcal), protein 75.9 g/day (26% kcal), and fat 96.1 g/day (66% kcal).

Thirteen participants provided 3-month weights; the mean weight loss was 3.1 kg (range 0–8.2 kg), with none reporting a weight gain. Nine participants obtained baseline as well as 3-month laboratory results (Table 2). A significant increase in total and low-density lipoprotein (LDL) cholesterol was seen in 6 and they were notified and encouraged to discuss these results with their primary care physician or local neurologist who consented to continuation of participant care during and after completion of the study. If they elected to remain on the MAD after 3 months, they were counseled extensively via e-mail to substitute saturated fats for polyunsaturated fats and offered follow-up in outpatient clinic.

Table 2.   Mean (standard deviation) laboratory values (mg/dl) at baseline and 3 months, and mean (standard deviation) changes between baseline and 3 months after starting the modified Atkins Diet (n = 13), with p-values using a two-tailed t-test
Laboratory valueBaseline3 monthsChange from baselinep-Value
  1. Bold indicates statistically significant results. HDL, high density lipoprotein.

Glucose87 (8)89 (8)4 (10)0.31
Blood urea nitrogen (BUN)14 (4)16 (6)2 (6.7)0.42
Creatinine0.9 (0.3)0.8 (0.2)−0.2 (0.4)0.17
Total protein6.8 (1.0)7.2 (0.3)0.06 (0.4)0.67
Aspartate aminotransferase (AST)23 (11)20 (4)−6.7 (18)0.30
Urine calcium:creatinine ratio0.10 (0.07)0.30 (0.3)0.21 (0.2)0.19
Total cholesterol170 (22)228 (51)62 (47) 0.01
HDL cholesterol54 (13)62 (23)8 (16)0.19
LDL cholesterol95 (21)136 (48)45 (47) 0.03
Triglycerides105 (52)130 (93)22 (56)0.29

Side effects reported during the study period included weight loss (13 participants), diarrhea (2), gastroesophageal reflux (1), flatulence (1), abdominal pain (1), weakness (1), menstrual irregularities (1), and increased seizure frequency (1). These as well as lack of efficacy and restrictiveness were the reported reasons for stopping the MAD.

Discussion

This study was designed to evaluate the feasibility, safety, and effectiveness of a novel, e-mail–administered dietary therapy for refractory epilepsy in adults. Of the 22 participants who started the MAD, more than 60% completed the 3-month study. Overall, 41% of participants had >50% reduction in seizure frequency at 1 month and 27% at 3 months. These percentages are similar to a previous study by our center of 30 adult patients treated with the MAD in an office setting with direct dietitian assistance (Kossoff et al., 2008a). In that study, 47% had >50% reduction in seizure frequency at 1 month and 33% at 3 months. Side effects reported during e-mail MAD administration were also similar to those reported in prior studies and no serious or irreversible side effects were reported (Carrette et al., 2008; Kossoff et al., 2008a; Smith et al., 2011).

One significant side effect that was noted at the conclusion of the study was an increase in total as well as LDL cholesterol. If participants with elevated cholesterol levels elected to remain on the diet following completion of the study, they were counseled to avoid saturated fats and increase intake of polyunsaturated fats. One participant’s LDL doubled between baseline and at 3-months. Once these results were shared with the participant, he elected to remain on the MAD because he felt that the benefits in controlling his seizures outweighed the risks. He was seen in outpatient clinic following completion of the study, counseled extensively on the substitution of polyunsaturated fats for saturated fats, and started on carnitine supplements, but remained on a 20 g of carbohydrates per day MAD. Within 3 months, his LDL and total cholesterol returned to normal and he is currently seizure-free and has reduced his number of daily anticonvulsants since starting the MAD. He also reports improved energy and concentration since starting the MAD.

This study provides evidence that adults are able to tolerate the MAD as a treatment for intractable seizures. E-mail administration of dietary therapies could lead to more universal access to these treatments. Areas where this could be of particular benefit include developing countries (Kossoff et al., 2008b), regions with limited (or no) dietitian availability, and busy neurology practices. Future directions could include e-mail contact with ketogenic dietitians, teaching through digital media or through video-teleconference (Patterson, 2003; Ahmed et al., 2009). This study excluded participants who were not able to use e-mail themselves (e.g., cognitively impaired), but we suspect many might benefit through administration by a caregiver.

This study also demonstrated that e-mail can be a useful method of communicating with patients regarding their health care in general. Participants in the study did not abuse the privilege of e-mail communication (median number of e-mails sent was 6 during the entire study period). Total time spent responding to e-mail inquiries was between 5 and 13 h for all 25 participants. These findings may encourage health care practitioners to consider using e-mail communication more liberally in treating patients.

Although this novel method of providing dietary treatment was successful, there may be additional benefit of in-person interaction with a neurologist and dietitian to provide encouragement and address questions in detail. Office visits also provide the opportunity for group teaching sessions on administration of the MAD and provide patients with a potential support group with which to share recipes and their experiences with the diet. Of course, if a patient remains on the MAD long-term after initial e-mail administration, an opportunity for later in-person clinic consultation can be offered.

Studies are warranted to determine feasibility of other dietary approaches to epilepsy treatment, such as the ketogenic diet or the low glycemic index treatment, and to determine the relative feasibility and efficacy of these diets compared to the MAD in adults. This was beyond the scope of the current study. Other potential areas of investigation could also include a comparison of the relative financial savings and improvements in quality of life with the various dietary therapies, especially if done via e-mail. The participants in this study likely represent a biased sample based on the recruitment techniques (given that participants responded to a study advertisement posted on http://www.clinicaltrials.gov). Participants were, therefore, self-selected and were likely in a higher than usual socioeconomic status for patients with medically refractory epilepsy given their access to technology and foods required to follow the diet. A randomized trial comparing seizure outcomes in participants who contacted the study team and were subsequently not placed on the diet or compared to those who were started on the diet in a clinic setting would provide a more rigorous evaluation of the feasibility of the diet in adults. Nonetheless, e-mail administration of the MAD was shown to be efficacious in this motivated population.

Conclusions

E-mail administration of the modified Atkins Diet to adults with intractable epilepsy without dietitian support was feasible, safe, and effective. This novel approach to providing epilepsy care is worthy of future study.

Acknowledgments

This study was supported by the Carson Harris Foundation.

Disclosures

Dr. Kossoff has received support from Nutricia, Inc., for research and is a consultant for Atkins Nutritionals, Inc.; neither was involved in this study. None of the other authors have any conflicts of interest. 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.

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