Considering Alternative Treatments for Epilepsy: Ketogenic Diets, Marijuana, and Progesterone

Michael R. Page, PharmD, RPh

Kristen Park, MD, assistant professor of pediatrics and neurology at the University of Colorado, discussed the potential risks and benefits of alternative therapies for epilepsy, including medical marijuana.



At the 68th annual meeting of the American Epilepsy Society in Seattle, Washington, Kristen Park, MD, assistant professor of pediatrics and neurology at the University of Colorado, discussed an important topic regarding epilepsy: the use of alternative therapies.



Emerging and alternative treatments for epilepsy include a wide variety of interventions, including ketogenic diets, herbal preparations, and cannabinoids. For many of these therapies, the clinical efficacy is not well established, and the side effects are poorly understood or unknown. Understanding these treatments, putting them in clinical context, and making a decision on whether to use these alternative therapies is often a challenge for health care professionals.



One of the most well-established and widely used nondrug therapies for epilepsy is the use of very-low-carbohydrate diets that force the body to generate ketones. These ketones may have an antiepileptic effect.



One of Dr. Park's patients, a 3-year-old boy named Ethan, had experienced episodes of myoclonic and atonic seizures suggestive of Doose syndrome. After failing to achieve adequate control of Ethan's seizures with levetiracetam, topiramate, and valproate, Ethan's parents expressed an interest in trying a ketogenic diet.



Ketogenic diets can be initiated with varying levels of carbohydrate restriction, but the most restrictive diet is still generally the standard therapy that is used in patients with epilepsy. Unfortunately, as with any intervention, ketogenic diets are not free of side effects, and are associated with short- and long-term adverse events.



Patients with epilepsy beginning a ketogenic diet are admitted to the hospital to manage the short-term side effects of ketosis, such as hypoglycemia, vomiting, and dehydration. These adverse events must be managed with antiemetic drugs and intravenous fluids. Treatment with a ketogenic diet requires strict avoidance of all carbohydrates, and it is advised to add to the diet certain vitamins and minerals, notably selenium, which is not included in most multivitamins, and carnitine, which can aid in processing fat in mitochondria.



As the diet is maintained, ketosis may lead to the long-term effect of causing osteopenia. Although some evidence suggests that ketosis-associated osteopenia is related to bone mineral loss, newer evidence suggests that impaired conversion of vitamin D to its active form may also be involved.1,2 To counteract osteopenia, patients may take calcium and vitamin D supplements, and may undergo mechanical stimulation of bone to counteract bone wasting.



In addition to potentially compromising bone strength, ketogenic diets carry the risk of limiting growth. Ketosis is associated with lower levels of the growth hormone insulin-like growth factor 1, and some small, older studies show that 85% of children adhering to a ketogenic diet experienced growth restriction. A larger, more recent, study out of Johns Hopkins University shows that younger children are more affected than older children.



Ketosis can also increase the risk of developing kidney stones due to the high levels of urine calcium that develop as a result of bone mineral wasting. Approximately 3% to 7% of children treated for epilepsy with ketogenic diets will develop kidney stones. The risk for this potential adverse event can be reduced by acidifying urine with potassium citrate, and ensuring that patients are receiving adequate hydration.



Ketogenic diets can also lead to hyperlipidemia in 13% to 49% of children, which may increase the risk of later cardiac events. Typically, niacin, lipid-lowering agents, and bile acid sequestrants are typically used to treat the hyperlipidemia. Cases of long QT syndrome and cardiomyopathy have also been reported, although the true incidence of these adverse events is unclear.



For Ethan, a ketogenic diet was associated with some reductions in the incidence of seizures. Unfortunately, Park noted, “that benefit did not last long.” Over time, Ethan developed significant osteopenia and experienced 2 pathologic fractures, despite having normal levels of calcium and vitamin D throughout treatment.



Another of Dr. Park's patients, Sarah, developed intractable generalized epilepsy at 15 years of age. Sarah's seizure episodes occurred predictably during menstrual cycles. After attempting to treat the seizures with benzodiazepines, Dr. Park decided to treat Sarah with progesterone.



Data from randomized controlled trials suggests that, for the treatment of seizures, progesterone had inconclusive effects. However, in a post hoc analysis of the trial, patients with seizures that only occurred during menses experienced a meaningful reduction in seizure frequency.3 Another open-label study with an intramuscular formulation of progesterone documented a 39% reduction in seizure frequency.4



Intramuscular progesterone, a commonly used form of long-term birth control, is associated with some side effects, including irregular menstrual bleeding, weight gain, and reduced bone mineral density. However, for some patients, it can be a helpful option. In Sarah's case, progesterone has successfully prevented all seizures for 6 months.



Another popular alternative treatment for epilepsy is marijuana, which contains cannabinoids.



The side-effect profile of cannabinoids is primarily gleaned from information gathered among long-term recreational users of marijuana. However, some animal studies have also been conducted. Cannabinoids have been associated with pregnancy complications in animals when administered in the third trimester of gestation, and led to permanently altered behavior in the resulting offspring. Similar effects have been observed in humans, as the mothers of children who were exposed to cannabinoids during pregnancy have a higher incidence of psychiatric issues than the general population. Other side effects of cannabinoids include squamous metaplasia, cancers of the lung, abnormal inflammation of the large and small airways, and pneumonia.



Central nervous system toxicities have also been documented with marijuana use, including a higher incidence of schizophrenia and depression in exposed adolescents, disturbed sleep quality, and impairment of learning, memory, and cognition with concurrent reductions in the volume of the hippocampus, as well as gray and white matter.5 A powerful synthetic cannabinoid known by the street name Spice, has also been implicated in strokes.6



A former patient of Dr. Park who is currently using marijuana is Asha, a 5-year-old child with epilepsy and a medical history of intrauterine growth restriction and facial dysmorphia. Asha’s parents were very concerned about using pharmacotherapy, and Park noted that the parents were convinced that, “a natural alternative would be better.” After refusing treatment with conventional therapies, Asha’s parents unsuccessfully attempted to treat their daughter with marijuana, and refused to attempt treatment with conventional pharmacotherapy. According to Park, with medical marijuana, as with other herbal remedies, “there is a lot of unknown risk, unknown benefit, and a lot of toxicity.”



In a survey of an expert audience on whether medical marijuana would be an appropriate alternative therapy for Lennox-Gastaut syndrome, the majority (53%) agreed that it is an appropriate option, but only when used in a clinical trial setting.



For patients with epilepsy, alternative therapies are commonly used. More than half of children with epilepsy have received some form of complementary treatment, often without the advice of the child’s neurologist. Openly discussing all treatments is an important component of care that may help patients and caregivers make a more informed decision about unapproved alternative treatments.



References

1. Hahn TJ, Halstead LR, DeVivo DC. Disordered mineral metabolism produced by ketogenic diet therapy. Calcif Tissue Int. 1979;28(1):17-22.

2. Williams S, Basualdo-Hammond C, Curtis R, Schuller R. Growth retardation in children with epilepsy on the ketogenic diet: a retrospective chart review. J Am Diet Assoc. 2002;102(3):405-407.

3. Herzog AG, Fowler KM, Smithson SD, et al. Progesterone vs placebo therapy for women with epilepsy: a randomized clinical trial. Neurology. 2012;78(24):1959-1966.

4. Mattson RH, Cramer JA, Caldwell BV, Siconolfi BC. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology.1984;34(9):1255-1258.

5. Lorenzetti V, Solowij N, Whittle S, et al. Gross morphological brain changes with chronic, heavy cannabis use [published online November 27, 2014]. Br J Psychiatry.

6. McSherry JW. Spice, pot, and stroke. Neurology. 2014;82(23):2147.

