Tag Archives: medical

Epilepsy

Vagal nerve stimulation device: its role in medically refractory partial epilepsy and reports of weight loss

 

Virginia Thornley, Neurologist, Epileptologist

@VThornleyMD

April 15, 2018

Introduction

The vagal nerve stimulation device is an implanted device that exerts its effort by pulses of electrical activity that stimulates the vagal nerve or cranial nerve X. It had initially been found to work in animal studies in the 1990’s then later applied in clinical studies.

Mechanism of action 

For years, the mechanism was unknown and was used rather effectively in the clinical realm. The elucidated mechanisms were thought to be that the vagal nerve stimulator modifies the highly synchronized electrical activity that occurs in epilepsy through desynchronization via the vagal nerve. In addition, there is increased regional cerebral perfusion, and there is increased GABA neurotransmitters which are inhibitory towards electrical activity causing seizures and a decrease in glutamate which is known to increase excitation with the brain. There are GABA-A receptor increases, an increase in locus ceruleus produced noradrenergic substances which are released through the vagal nerve and an increase in serotonin transmissions through the raphe nucleus.

Role in controlling seizures

In the original open-label trial in 5 clinical trials, the vagal nerve stimulation device was found to be effective in reducing seizures by 50%. 454 patients had the implanted device and clinical information was obtained from 440. A cardiac stimulation device was implanted along with a coil in the ipsilateral vagal nerve. At 1 year of implantation, more than 50% of reduction of seizures occurred in 36.8% of patients at year 1, 43.2% year 2, and 42.7% at year 3.  The most common side effect at year 2 was hoarseness of about 9.8% and headache in 4.5% and at 3 years there was shortness of breath in 3% (4).

In one retrospective study from 1997 to 2008, 436 patients were found with implanted vagal nerve stimulation devices from ages 1-76, 220 were women and 216 were men. 33 had poor follow-up and 3 had removal due to infection. The mean frequency of seizures was better at 50% reduction.  There was 90% better control on 90 patients, >75% control in 162 patients and 50% control in 255 patients, <50% control in 145 patients. Permanent damage to the vagal nerve happened in 2.8% or 11 patients out of the 400 patients (after the removal of the ones lost to follow-up and infected) (5).

Long-term value of vagal nerve stimulating device, effectiveness after 5 years

There have been many studies reported that it may be effective short-term. But there was one pediatric study that reported success in seizure control in longer than 5 years. In a study of 56 pediatric patients ages 4-17, >9.8% were seizure free after 9 months, 24% after 2 years, 46.4% after 3 years and 54% after 5 years.11 out of the 56 patients became seizure free. After 5 years 62% of the patients had fewer seizures after 5 years.

What happens from diagnosis to implantation to use

A patient is identified as medically refractory, meaning a patient who has already failed 2 or more agents. Once control is failed after 2 anti-epileptic drugs after an adequate dosage and trial,  the likelihood of being seizure free becomes significantly less.  It is usually applied to patients with partial seizures, the most common being temporal lobe epilepsy. After appropriate identification is done, the patient undergoes a procedure where a cardiac device is implanted under the skin which generates an electrical impulse. A wire or coil is attached to the vagal nerve which reacts to this signal and emits an electrical pulse which inhibits the seizure which is electrical activity in the brain by disrupting this through various mechanisms. The device can be programmed to have a set frequency, amount of power and can be set to automatic with features where the patient can apply a magnet to inhibit the seizure when it is about to occur. The magnet is typically swiped over the cardiac device which was implanted over the left side of the chest. The settings can be changed in the doctor’s office adjusting according to the number and frequency of seizures.

Common side effects

Some of the most common side effects reported include hoarseness, cough, throat irritation, dyspnea, insomnia, dyspepsia, and vomiting. The symptoms are related to the location of the device near the nerve causing local irritation and likely due to the functions subserved by the vagal nerve.

Incidental weight loss effect

Vagal nerve stimulation device was applied to treatment-resistant patients with depression where an incidental effect on weight loss was found. One study in 33 patients showed that the vagal nerve stimulator implanted in patients seemed to alter cravings for sweet food which may play a part in weight loss (2). There have been some conflicting studies proving that there is no weight loss in vagal nerve stimulating device at the settings recommended in epilepsy in 21 patients (3). In a large study of 503 patients from 15 study centers, vagal nerve blockade was applied intrabdominally. 294 patients were randomized to treated (192) and to control groups (102). Therapy involved electrical stimulation through an external power source to the vagal nerves in the subdiaphragm which inhibits afferent and efferent vagal transmission. At 12 months, the excess weight loss in the treated group was 17% and in the control group, it was 16%. There was no statistic difference between the two groups, however, the post-study analysis demonstrated a possible result in weight loss related to the system check of the devices using low charges which may have caused weight loss in the control group (6).

In conclusion

There is strong evidence that the vagal nerve stimulation device is effective at reducing seizures of >50% of the medication-resistant epilepsy patient. It is effective even after 5 years of implantation. There are very little side effects which are mild to moderate. In addition, it can cause weight loss.

References:

  1. Serdaroglu, et al, “Long-term effect of vagus nerve stimulation in pediatric intractable epilepsy: an extended follow-up,” Child’s Nervous System, 2016, 32 (4):641-646.
  2. Bodenlos, “Vagus nerve stimulation acutely alters food craving in adults with depression,” Appetite, 2007, 48: 145-153.
  3. Koren, et al, “Vagus nerve stimulation does not lead to significant changes in body weight in patients with epilepsy,” Epilepsy Behav. 2006;8:246–249.
  4. Morris, et al, “Long-term treatment with vagus nerve stimulation with refractory epilepsy,” Neurology, 1999, 53 (8):1731-1735.
  5. Elliot, et al, “Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response,” Epilepsy Behavior, 2011, Jan., 20(1):57-83.
  6. Sarr, et al, “The EMPOWER study:randomized, prospective, double-blind, multicenter trial of vagal blockade to induce weight loss in morbid obesity,” Obes. Surg., 2012, Nov., 22 (11):1771-82.

 

Standard
medical marijuana

Cannabinoids: the other side of the coin, side effects, drug-drug interaction and possible problems of cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D., Board-Certified Neurologist, Epileptologist

@VThornleyMD

April 6, 2018

 

Introduction

Medical marijuana seems like the shining breakthrough drug the shining pill in armor, the magic pill that seems to cure everything. However, there are always two sides to every coin. One must still proceed with caution. The phytocannabinoids, cannabidiol, and tetrahydrocannabinol exert their effects through the endocannabinoid pathway, the CB1 receptor is most abundantly found in the nervous system. Cannabidiol which has no euphoria acts weakly with the CB1 receptor almost as a reverse agonist blocking the THC from exerting its effect offsetting potent side effects of tetrahydrocannabinol.

The medical benefits are overwhelmingly numerous including ameliorating seizures, spasms from multiple sclerosis, peripheral neuropathy in HIV patients, chronic debilitating pain, post-traumatic stress disorder symptoms and other associated diseases. Despite the stigma of using it, the delay in clinical trials and marked hesitation of the medical community, medical marijuana has landed and there is no going back. Yet even with its numerous health benefits, it is always prudent to take a step back and examine any flaws as with any other new kid on the block or any new agent that comes along even though it’s been around for thousands of years.

Is marijuana safe for medical use? The take on medical marijuana by the FDA

So far from the FDA official website, the FDA does not recognize medical marijuana coming from the botanical plant with any medical indication. The FDA does not recognize it to be safe or beneficial for any type of disease or condition. The FDA will facilitate any companies interested in bringing quality products including science-based research. The full take of the FDA on marijuana can be found here https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#use

Long-term effects on the brain

Perusing the scientific literature, it is difficult to find any long-term damage to the brain. There was a report in a heavy marijuana user where there was damage to the corpus callosum, possibly worse with young users (1). This is a small study of 11 heavy marijuana users with 11 age-matched cohorts. Diffusion tensor imaging was used. Previous reports alluded towards poor cognition with heavy marijuana use. This study is aligned with that. It was suggested that there may be increased diffusibility within the white matter tracts of the corpus callosum. Young age is thought to make the corpus more susceptible to white matter damage. The only caveat is this is with heavy use and the substance found in recreational marijuana is going to be a different form compared to medical marijuana extracted from the marijuana plant used for medicinal purposes. It is not clear if this report would carry over to medical marijuana users where the preparation of the product is much different(1).

IMG_7828_preview

Effect on schizophrenia spectrum diseases

In a large study of 171 patients, it was found that with heavy use of cannabis, the age of onset of schizophrenia spectrum disorders seems to occur earlier (6). This is one of the reasons why in some dispensaries, it is not sold to patients with a history of schizophrenia. There are some anecdotal reports of some patients having a paranoia with medical marijuana that is reversible once taken off.

Effect on the heart, reports of myocardial infarcts and ST elevations

While the literature suggests low toxicity and most side effects are related to cognition and gastrointestinal problems, there are several cannabis-associated myocardial infarcts in the literature. The dispensaries in the state of Florida use a previous history of a previous myocardial infarct as a contraindication in using medical marijuana. These were synthetic drugs used recreationally. There was one case report where a heavy user suffered from an ST elevation and subsequent myocardial infarct after becoming toxic to marijuana used recreationally.  In one study, synthetic cannabis was used, the myocardial happened to a young patient where an atheromatous plaque was excluded as the source. Etiology and mechanism are unclear why infarcts should occur. It is quite possible that because it works on the 5HT receptor for anxiety which can cause vasoconstriction, this may be one mechanism. Other studies are needed to elucidate the mechanism of action.

Drug-drug interactions

Because medical marijuana is used as an adjunctive agent for epilepsy, perhaps off-label since it has not been approved through FDA as an anti-epileptic agent yet, it was found that medical marijuana used in conjunction with Clobazam (Onfi) tended to elevate Onfi at higher levels.

In one small clinical study, in 13 patients, 9 had an increase of about 60 in the Clobazam level and by 300 in Norclobazam level. There was, however, a tremendous reduction of seizures by >50% but Onfi (Clobazam and Norclobazam levels) should be monitored (3) on a routine basis to avoid any untoward toxicity.

Other milder symptoms

In one large study on Lennox-Gastaut syndrome where cannabidiol was titrated to a 20mg/kg over a course of 14 weeks, mild to moderate symptoms were noted including pyrexia, sedation, dizziness, and diarrhea. However, the titration rate was very rapid and the patents who were 50kg were quickly at 1000mg within 14 weeks which does not usually happen in the real world. Medications are usually increased over a longer period of time in slower increments.

IMG_7857_preview

In summary

While everybody is touting the horn of medical marijuana it is always prudent to stand back and ensure there are no possible risk factors for adverse side effects. The most serious and common seen in the literature appear to be related to schizophrenia spectrum disorders and cannabis associated myocardial infarct. The only caveat is that the literature is peppered with these reports, however, the quality of the recreational drugs are vastly different from medical marijuana which tends to be organic and all natural extracted from the plant in licensed medical dispensaries. The extraction of the medical components is vastly different from the smoked synthetic version of tetrahydrocannabinol. So, is difficult to know if these reports would actually corroborate with use in medical marijuana. The ones with side effects were heavy users of recreational smoked types of marijuana, it is unclear if it was synthetic or organic. As the popularity of medical marijuana progresses, more information will be available regarding the side effect profile.

References

  1. Arnone, et al, “Corpus callosum damage in heavy use: preliminary evidence from diffusion tensor tractography and tract-based spatial statistics,” Neuroimage, 2008, Jul., 1, 41 (3): 1067-74.  “J Addict Med. 2017 Sep/Oct;11(5):405-407. doi: 10.1097/ADM.0000000000000326.
  2. Volpon, et al, “Multiple cerebral infarcts in a young patient associated with marijuana use, ” Journ. Addic. Med, 2017, Sep./Oct., 11(5):405-407.
  3. Geffrey, Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy,” Epilepsia, 2015, Aug., 58 (8):1246-1251.
  4. Stewart, et al, “Obstructive sleep apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones,” Epilepsia, 2017, Jun., 58(6): e87-90
  5. https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm#use
  6. Shahzade, et al, “Patterns in adolescent cannabis use predict the onset and symptom structure of schizophrenia-spectrum disorder,” Schizophrenia Research, 2018, Feb., 2 pii S090-9964 doi:10. 1016/j. schres. 2018.01.008 (Epub ahead of print)
  7. Orsini, et al, “Prolonged cardiac arrest complicating massive ST-segment elevation myocardial infarct associated with myocardial consumption,” J. Community Hosp. Intern. Med. Perspect, 2016, Sep., 7. 6 (4):31695
  8. Thiele, et al, “Cannabidiol in patients with seizures from Lennox-Gastaut Syndrome (GWPCARE4): a randomized, double-blind placebo-controlled phase 3 trial,” Lancet, 2018, Jan., 390 (10125):1085-1096

    About

 Introduction/Disclaimer
Standard