Bastyr University San Diego Clinic:
Student Case Report:

Late Post-Traumatic Epilepsy in An Elderly Male


by Fernanda Gallo Moreno 
edited by Baljit Khamba, ND, MPH

Fourth-year interns at Bastyr University are actively developing their clinical skills through treating patients at the school's clinic. They engage their didactic skills in rigorous case taking, examinations, evaluation, and a naturopathic-focused treatment plan under the supervision of their attending doctor. The interns are able to gain experience in areas such as mental health, mind-body medicine, oncology, hydrotherapy, physical medicine, out-reach community care, IV treatment, biofeedback, and so on. Each one of these opportunities presents a prime opportunity for the students to enrich their knowledge about conditions and approaches to care. In efforts to salient their understanding, the students write case reports under the supervision of Dr. Baljit Khamba in their course "Advanced Case Studies." By completing these reports, future practitioners gain a valuable skill that they can then utilize once they graduate.

Abstract
The purpose of this case report is to investigate the prognosis, outcome, and naturopathic treatment available for the elderly population experiencing post-traumatic epilepsy. The case discussed in this paper is of an 85-year-old male diagnosed with late post-traumatic epilepsy, which began in 2013 after a single trauma to the top of his head. The elderly population is the most vulnerable to post-traumatic epilepsy, though only about 4% of epilepsy is due to trauma.(1) The initial treatment for epilepsy due to trauma is immediate anti-seizure medication, which has been shown to improve seizure remission rate; this medication is often prescribed prophylactically when trauma occurs to an elderly person to prevent the onset of an initial seizure.(1) Anti-seizure medication, unfortunately, has been known to cause extensive and persistent side effects; therefore, research has investigated a natural alternative for children with epilepsy. The effects of cannabidiol (CBD) oil in epilepsy has been shown to improve remission rates and symptomology associated with seizures in children, though the mechanism of action is not yet fully understood.(2) The ketogenic diet has been shown to improve neuro-degeneration, epileptiform activity, and side effects from anti-epileptic medication by optimizing energy output by the mitochondria in all cells.(3) It is still unclear if CBD oil is effective in seizure remission in adults. Further research is highly suggested to address the lack of knowledge in natural alternatives for epilepsy treatment in the elderly population.

Introduction
When treating seizures in the elderly, many factors should be considered: predisposition to epilepsy and trauma, the natural aging process, the increased risk of polypharmacy, drug-to-drug interactions, increased susceptibility to side effects, and multiple comorbidities. Older patients experience a loss of independence and have an increased risk of falls and physical injuries. A seizure diagnosis may further exacerbate their already declining quality of life. The standard of care for post-traumatic epilepsy, particularly in the elderly, is to prescribe anti-epileptic medication to prevent future incidences of seizures. Epilepsy is a condition where recurrence of unprovoked seizures are expected in the absence of treatment; therefore, treatment is highly indicated.(4) Natural therapies have not been studied in the elderly population and are not considered alternative or adjunctive treatment for epilepsy.(1) There is a clear need for alternative treatment to pharmaceuticals for elderly experiencing epilepsy in order to avoid drug interactions, drug side effects, and to increase quality of life.

There is currently no drug cure that exists for epilepsy. Symptomatic relief has been achieved through antiepileptic drugs (AEDs) for up to 70% of patients; however, only two-thirds of patients with epilepsy are successfully treated by the AEDs. The remaining 30% of epileptic patients, both adult and children, with intractable seizures not controlled by AEDs seek treatment available to them in the medical system that is often invasive, requires surgical resection, or neuro-stimulation.(4)

Current Research of Treatment

Recent research suggests that cannabis may be a potential alternative treatment for refractory epilepsy. There are two chief cannabinoids present in marijuana, or cannabis: D-9-tetrahydrocannabidinol (THC), the main psychoactive component, and cannabidiol (CBD), the main non-psychoactive component. CBD has been shown to be an antiepileptic, though the exact mechanism is not yet understood. CBD has a low affinity for CB1 and CB2 receptors found in the body; both receptors are linked to Gi protein-coupled receptors and inhibit adenylyl cyclase activity. Activation of CB1 receptors inhibits glutamate release. The presence of CB1 receptors in the basal ganglia, cerebellum, neocortex, spinal cord, hippocampus, and amygdala may explain why CBD has shown improvements in children with epilepsy; the direct effect on the nervous system is being investigated. CB2 receptors are found mainly in peripheral tissues of the immune system, such as monocytes, B-cells, T-cells, and macrophages, which may explain their role in cytokine release.(5)
      
A 2016 study investigated the effects of CBC oil (CBD:THC at a 20:1 ratio dissolved in olive oil with a dose ranging from 1 to 20 mg/ kg/d) in 74 children with retractable epilepsy, who failed treatment with ketogenic diet and vagal nerve stimulation implantation. Of the 74 children, 89% reported reduction in seizure occurrence with 18% reporting 100% reduction; 7% reported aggravations, which led to CBD withdrawal. Other symptoms that were observed were improvements in behavior, alertness, language, communication, motor skills and sleep.(2)  Larger double-blind clinical trials are indicated. Despite positive findings, a survey conducted by Epilepsia showed that fewer practitioners specializing in epilepsy support prescribing CBD products and medical marijuana to patients compared to other medical doctors, due to a lack of conclusive data on its effects.(6)

It is known that traumatic brain injuries (TBIs) have many repercussions, including what is known as mitochondrial disease, which is caused by mitochondrial dysfunction. One of the most common presentations of mitochondrial disease is epileptic seizures and encephalomyopathy; whether one is the cause or effect is still debatable.(6)  It is clear that lipid peroxidation during seizure activity could be responsible for neuronal damage in the hippocampus, as seen in a rat model.(7)  For this reason, it is critical to aim for complete seizure remission in all vulnerable patients. To date, the only proven treatment to aid in recovery are anticonvulsant medication, vitamins, nutritional supplements, and the ketogenic diet; there is no known cure.(6)

This case report will investigate the prognosis of a person with late-onset post-traumatic epilepsy and the impact that CBC oil and a ketogenic diet may have on prognosis and quality of life.

Case Description
The patient is an 85-year-old male who experienced a head injury to the top of his head while swimming laps in a swimming pool on June 2013. Twenty-four hours after the impact, the patient experienced his first seizure. He was taken to his medical doctor that day where he was diagnosed with adult epilepsy. He is currently seeing a neurologist, a cardiologist, an endocrinologist, a doctor of oriental medicine and now, a naturopathic doctor, to address all aspects of his health. His wife, who has been his primary caretaker since the start of his health concerns, accompanied him at every visit.

In the span of two and a half years, from the initial impact in 2013 through December 2015, the patient had a total of five seizures. After the first seizure, the patient began taking gabapentin; after the second seizure on December 2013, he was prescribed a different AED; after the third seizure on July 2014, he was prescribed another AED. Finally, on December 2015, he experienced two seizures back-to-back, 45 minutes apart. He was instructed to begin taking levetiracitam 250 mg, four times per day, and has not had a seizure since. Every seizure, excluding the first, had occurred between 1 to 3 am and was preceded by stomach upset, extreme fatigue, decreased appetite and choking on heavy, viscous, yellow phlegm. His wife reports that during the seizures, he was gasping, coughing, and experienced full body convulsions for less than five minutes. After the event, the patient had difficulty breathing, erratic snoring and had no recollection of the event after a 25-minute postictal phase.

Naturopathic Doctor Prescribing Rights

The patient and his wife presented to clinic with the goal of seeking help to completely wean off of levetiracetam, which he believed was causing him extreme fatigue, and to seek guidance in obtaining and dosing CBD oil as alternative treatment. The laws in California do not permit licensed naturopathic doctors to alter or prescribe Schedule I or II drugs; naturopathic doctors are allowed to prescribe legend or Schedule IV and V drugs only under the supervision of an MD/DO, and schedule III drugs under patient-specific protocol checked by a supervising MD or DO.(8)  The Federal Drug Agency (FDA) and the Drug Enforcement Agency (DEA), work together to categorize drugs that are then put on the market for use. If the FDA has labeled a drug a 'controlled substance', due to potential for abuse, the drug is sent to the Drug Enforcement Agency (DEA) to be put into a "schedule" before it is available for use. Some drugs used for epilepsy, like phenobarbital, are considered controlled substance, though most anti-epileptic medications have not been shown to be abused or have addictive properties. Forms of cannabis, including CBD oil, is currently considered a schedule I substance, is illegal under federal law, and is considered by the FDA and DEA to have no therapeutic benefit.(9)  For this reason, our naturopathic team, researched a medical doctor in the area who is not only qualified to wean this patient off of levetiracetam, but also willing and experienced in prescribing CBD oil for epilepsy.

History of Present Illness
The patient presented with an initial chief complaint of excessive mucus, which began the day after the initial impact. The mucus was thick, ropy, yellow, began in the chest, and took great force to expel. Patient wakes at night to expel ¼ to ½ cup of mucus every night. He has attempted therapies such as prednisone, Flonase, and hydrogen peroxide mouth rinse, with no avail. Eliminating sugar, corn, and dairy has helped improve the mucus. His second chief complaint is extreme fatigue, which he believes, is a side effect to the medications he has been taking. He rates his fatigue an 8 out of 10. He experiences depression, which he describes as constant "melancholy." He states that he did not experience fatigue or depression prior to the head trauma. The biggest detriment to his overall wellness has been his inability to swim, jog, or do Pilates, like he used to.

Past Medical History and Review of Systems

The patient was taking the following medications and supplements managed by his medical doctor: levetiracetam (Keppra) 1000 mg daily (250 mg 4x/day); levothyroxine (Synthroid) 125 mg tablets daily; tamsulosin HCl 40 mg daily; cholecalciferol (vitamin D3) 50,000/week; fluoxetine (Prozac) 20 mg daily; glucosamine chondroitin (Osteo Bi-Flex) 1200 mg daily. Though the mechanism of action of levetiracetam is not entirely understood, scientists speculate that it may inhibit sodium channels, inhibit calcium channels, cause GABA-ergic inhibition, reduce the potassium current, and modulate neurotransmitters. Some of the many side effects from levetiracetam alone include impaired coordination, abnormal gait, fatigue, dizziness, somnolence, toxic epidermal necrolysis and Steven-Johnson syndrome, decrease in red blood cells, in hemoglobin and in hematocrit, hypersensitivity reaction, hypertension, and psychiatric conditions including suicidal ideation.(10)  The former of these symptoms pertain to this case.

The patient has a past medical history of hypothyroidism, squamous cell carcinoma, arthritis, and has had monoclonal gammopathy detected—Waldenstrom's macroglobulinemia will be ruled out by bone marrow biopsy. He is a retired pilot and has four healthy children. His lifestyle includes a pescatarian diet, lowered hydration status, about 30 minutes of slow walking per day, and one normal bowel movement per day. The patient takes up to two hours to fall asleep every night, wakes up two to three times per night, and sleeps two to three hours during the day. Review of systems is positive for weakness, fatigue, decrease appetite, changes in sleeping habits. He experiences heavy eyelids, pressure behind his eyes, hearing impairment, frequent tinnitus, and decreased sense of smell. He experiences shortness of breath much sooner and more often with exercise, as well as cough, sputum production, bilateral tremors, memory loss, and depression.

Physical Examinations

Physical examinations presented as follows: vitals within normal limits; blood pressure: 110/70; pulse: 66 bpm; temperature: 97.5 ° Fahrenheit; weight: 189 lbs; height: 5'11"; and BMI: 26.30 kg/m2. Previous workup with medical doctor showed high MCV, low vitamin D, high LDH, and high beta-2-microglobulin. Physical exams revealed multiple crowns on all wisdom teeth and canines, multiple mercury fillings; tongue displayed involuntary shaking and difficulty with voluntary movement; tongue with thick yellow white layer; bilateral tonsils at a +3, posterior oropharynx with some erythema, and left pharyngeal arch unable to rise. Cardiovascular exam with normal heart sounds with diminished sounds. Respiratory exam revealed no wheezing, rales, or tenderness; diminished breath sounds, and restricted chest movement. Neurological exam revealed that the patient was alert and oriented of place and timing; abnormal coordination, postural tremors, slight shuffling gait, hunched over posture, and minimal arm swing, all of which are reflective of parkinsonism.


Diagnosis

The differential diagnosis includes mitochondrial dysfunction, psychogenic non-epileptic seizures, drug-induced symptomology, drug-induced parkinsonism, vasovagal response and syncope, and systemic infection secondary to oral microbial toxins. The working diagnosis being late post-traumatic seizures, considering there was an initial head trauma involved and no pertinent family history, as well as, diagnoses of fatigue due to old head trauma, and chronic mucus hyper-secretion.

Treatment and Future Plan

On the initial visit, the take home plan involved a three-day diet diary including bowel movements, water intake, physical activity, and mood. Patient was instructed to increase his water intake. The patient, his wife, and the naturopathic team agreed to research medical doctors in the area qualified and experienced in safely weaning off anti-seizure medication and prescribing and dosing with CBD oil. 
      
Three weeks later the patient reports that him and his wife and the naturopathic team had both coincidentally decided on the same medical doctor in the area. Patient had begun to decrease his anti-seizure medication and had started taking 15 mg of CBD oil twice per day the night before the second visit. Patient reported that his morning walk went noticeably better than usual. After reviewing his diet diary, we strongly suggested he completely eliminate inflammatory foods such a gluten and dairy. The patient was asked to begin the ketogenic food plan in order to encourage healthy energy production and removal of offending foods. A handout and complete instructions by Institute for Functional Medicine on a mitochondria-supporting diet were provided. The patient was asked to carefully observe the changes he experiences for the next two weeks with the new diet changes and with daily doses of CBD oil.
      
Six weeks after beginning treatment with CBC oil and discontinuing levetiracetam, we recommended alternating 'smooth move' tea, initially used to aid in producing daily bowel movements, with organic psyllium fiber. Patient had eliminated dairy from his diet, with only occasional goat cheese, and increased his daily proportion of vegetable intake. An internal referral was made for intravenous therapy (IV) infusion therapy for nutrient and glutathione antioxidant support for the purpose of preventing further neuro-degeneration due to TBI and medication, and to provide powerful antioxidant protection to his central nervous system.(11)

Future treatment may involve the consideration of acetylated glutathione, if IV therapy is less preferred by patient. Future treatment may also involve CoQ10 supplementation and respiratory chain cofactors, such as, riboflavin, tocopherol (vitamin E), succinate, ascorbate (vitamin C), menadione, and nicotinamide. It is also highly indicated to address sleep, immune modulation, dental hygiene, past and current environmental exposures, and the consideration of homeopathy as adjunctive treatment.

Outcomes

Subjective patient recall after only one day of CBD oil and discontinuation of levetiracetam shows he is slightly more physically able. Upon six-week follow up, patient reported improved mucus production and change in color of mucus from yellow to clear. Patient continues to wake at night from excess mucus production, which he manages with mouthwash; otherwise, he reports improved sleep with recent negative sleep study results. Patient reports a decrease in resting and postural tremors, which he attributes to the change in medication. Patient's chief complaint of fatigue remains the same despite these changes, though patient has once again began to do physical exercise twice per day, including Pilates and weight lifting. Patient continues to be seizure free without the help of AEDs. The patient seems very hopeful about this treatment and plans to continue to return to Bastyr University for follow-up treatment.

Discussion

Research has shown that when CBD is taken orally, it has a bioavailability as low as 6% after it has undergone first-pass metabolism, with a half-life of only one-to-two days. CBD is a powerful inhibitor of cytochrome P450 isozymes; therefore, caution should be taken when paired with medications.(5)  For this reason, it was of great importance to find a medical professional who is trained and experienced in not only pharmaceuticals, but also in CBD. 
      
The patient may likely experience benefits from a consistent ketogenic diet, which includes high-fat, low-carbohydrate diet, and high antioxidant content. The ketogenic diet not only aids in neuroprotection and seizure control, it is now understood that it may also improve mitochondrial redox status. A 2008 study in rats, showed an increase in hippocampal mitochondrial glutathione (GSH) production, increase enzymatic activity of glutamate cysteine ligase, increased hippocampal reduced CoA, and lipoic acid, as well as a decrease in H2O2 production and mtDNA damage. There are indicators that the ketogenic diet aids in GSH biosynthesis, enhances mitochondrial antioxidant status, and protects mDNA from oxidative damage.(3)  It is important in this case to also consider the long-standing side effects of not only the initial TBI, but also the effects of the anti-seizure medications taken for several years. Though the patient is 85 years old, the Parkinson-like symptoms he is now experiencing are a drastic change from the physical and mental ability that he had just prior to taking medications. In the Substancia Nigra – the area in the brain impacted in Parkinson's disease – the antioxidant defenses are more vulnerable to low levels of GSH than other areas of the brain.(13)  It is possible that the neuro-damage from the TBI and from the AEDs has lowered the intrinsic oxidant defenses in his brain making him susceptible to potential drug-induced parkinsonism.

Diagnostic Process and Outcomes of Disease

Post-traumatic epilepsy (PTE) is considered 'late' when seizures occur more than one week after head injury and 'early' if they occur within the first week of injury. Late post-traumatic seizures often present with more permanent structural and physiological changes to the brain typical of a TBI. Of those suffering from PTE, up to 80% will experience a seizure within two years. Those with more severe TBIs are at risk for late-PTE for a longer span of time; a mild TBI leaves a patient at risk for five years versus a severe TBI with a 20-year risk. Risk of recurrent seizures without treatment is up to 86% in the first two years. For this reason, long-term anticonvulsant medication is recommended for patients with an initial seizure and used prophylactically for patients at risk of seizures who experience a TBI. Over 13% of patients with prophylactic anti-seizure drug trials had seizures even with aggressive pharmaceutical treatment. The remission rate for PTE is about 25 to 40% with initial anti-seizure treatment.(12)

Limitations and Biases

This particular case is still in progress and may require time in order to investigate the impact that both anti-seizure medication and CBD oil may have on symptoms. It is still unclear how severe and how long-lasting the side effects of the medications are, and whether these changes are permanent. Future studies investigating the impact of CBD oil as initial treatment or as initial adjunctive treatment have yet to be studied. Most medical doctors in California do not advocate the use of any cannabis products and do not offer this as an option to patients as part of the treatment regimen for epilepsy. Many people suffering from seizure disorders and epilepsy are not made aware of the potential benefits of CBD through the medical system. Most studies on human trials have focused on children and have not demonstrated the effects on adults and seniors. Further research on the impact that CBC oil may have on seniors with epilepsy, as well as a comparison of effects between anti-seizure pharmaceuticals and CBC oil is indicated.

Conclusion

It is still unclear whether this patient will experience complete remission from seizures from the transition from leveteracitam to daily doses of CBD oil capsules. There are many variables to consider that may have contributed to the patient's symptoms of fatigue, seizures and excess mucus production; therefore, it may take months to assess complete effects of the given treatment. Potential modifications of treatment based on individual need may be necessary. The patient demonstrates a great desire to recover from the side effects of the various anti-epileptic medications he has taken in the span of four years; his persistence and the support from his wife is not to be under-estimated as a significant factor in his recovery. The patient has received careful guidance on weaning off of anti-epileptic medication and dosing with CBD oil by his medical doctor, in conjunction with guidance by a naturopathic team, who is addressing the side effects from the TBI and pharmaceuticals through a ketogenic diet and antioxidant support. This may provide a good foundation for neuro-regeneration and complete seizure remission. Future research on the impact of these therapies on the elderly population are in great need.

References
1.  Choi H, Mendiratta A. Treatment of seizures and epilepsy in older adults. UpToDate.com [Internet]. [Updated: 2016 July 15; Cited:2017 August 11]. 
2.  Tzadok M. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure.   2016 Feb;35:41-4. 
3.   Jarrett S, et al. Ketogenic diet increases mitochondrial glutathione levels. J Neurochem.   2008 Aug;106(3):1044-51. 
4.    Schachter SC. Evaluation and management of the first seizure in adults. UpToDate.com [Internet]. [Updated: 2017 February 21; Cited:2017 August 11]. 
5.    Reddy D, Golub, V. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016; 357:45–55; Senchi G, et al. Intravenous Glutathione in the Treatment of Early Parkinson's Disease. Prog Neuropsychopharmacol Biol Psychiatry, 19(7), 1159-70
6.    Kang H, Lee Y, Kim H. Mitochondrial disease and epilepsy. Brain and Development, 2013; 35(8): 757-761. 
7.    Bellissima M, et al. Superoxide dismutase, glutathione peroxidase activities and the hydroperoxide concentration are modified in the hippocampus of epileptic rats. Epilepsy Research 46 (2001), 121–128. 
8.    California Naturopathic Doctors Association. Scope of Practice of California Naturopathic Doctors. [Updated: 2013; Cited 2017 August 17]. www.calnd.org 
9.     Fountain N. The Relevance of the DEA for Epilepsy. [Updated: 2015 March 18; Cited:2017 August 17]. Available from: http://www.epilepsy.com/article/2015/3/new-role-dea-epilepsy 
10.    Surges R, et al. Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited. Ther Adv in Neuro Disor. 2008;1(1): 13-34.
11.    Senchi G, et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry. 1996;20(7): 1159-70.
12.    Evans RW, Schachter SC. Post-traumatic seizures and epilepsy. UpToDate.com. [Updated: 2017 April 04; Cited:2017 August 11]. 
13.    Smeyne M, Smeyne RJ. Glutathione metabolism and Parkinson's disease. Free Radic Biol Med. 2013;62:13-25.

Dr. Fernanda Moreno

Dr. Fernanda Moreno

Dr. Fernanda Moreno is a naturopathic doctor. She graduated with honors from Chapman University, where she competed in NCAA diving and water polo, in 2012 with a bachelor's degree in health sciences with an emphasis in complementary and alternative medicine. Dr. Moreno received her doctorate in naturopathic medicine in 2018 from Bastyr University California where she focused her studies in physical medicine, mental health, and women's health. Dr. Moreno has received extensive training in craniosacral therapy, environmental medicine, and homeopathy. Dr. Moreno is a certified yoga instructor and certified swimming instructor and is passionate about teaching communities of all ages. She will continue expanding her education as she pursues a Master's in Public Health.