- Hughes, B., Herron, C.E., Cannabidiol reverses deficits in hippocampal LTP in a model of Alzheimer’s disease. Neurochem. Res. 2019, Mar. 44(3):703-713
This is medical information not medical advice. Please consult with your physician.
This is medical information not medical advice. Please consult with your physician.
Virginia Thornley, M.D., Neurologist, Epileptologist
June 9, 2018
Back pain is one of the most common pain disorders encountered by neurologists, neurosurgeons, orthopedic surgeons and pain specialists in the out-patient setting. It is not uncommon for patients to go through an extensive list of medications, steroid injections, physical therapy and even surgery and still remain in unrelenting pain. There is a growing interest in alternative treatments especially with the opioid crisis looming and restriction of strong pain medications. This seeks to review scientific mechanisms behind the success in stem cell treatment. It recaps clinical data. Despite a scarcity of published huge randomized clinical trials, there is a growing and clamoring need for alternative treatments such as stem cell therapy for patients desperately trying to find alleviation from their pain. Trailblazing physicians are using this treatment option in real life practice with growing results.
Back pain is a very common disorder which is especially prevalent in the elderly after wear and tear of long-term activity in conjunction with the natural degenerative changes that come with the aging process. Normally the intervertebral disc complex can withstand compression and shear forces because of the proteoglycans that bind water molecules. This becomes lost with aging. In degenerative disc disease, there are pro-inflammatory molecules.
Pathogenesis of degenerative disc disease
Within the nucleus pulposus, there is no vascular supply except at the end neural plate, has no nerves and is prone to damage. The nucleus pulposus relies on glycolysis for effective disposal of waste products through the endplates. After decades, the nucleus pulposus no longer has notochordal features and is replaced by small chondrocyte like cells. There is replacement of the collagen type 1 and collagen type 2 loss eventually replaced with fibrocartilaginous material. Eventually with time, the endplates have calcification of the small pores where molecules diffuse (1).
There are anabolic processes involved as well as catabolic processes including involvement of enzymes, inflammatory mediators, proteinases, aggrecanases. Examples include IL-1 and TNF-alpha. because the disc is avascular this creates an environement of poor regenerative responses with harsh conditions (3).
Some patients may have a genetic predisposition to have flawed extracellular matrix where degenerative disc disease may occur more severely than in other people. Cleavage of proteoglycan can occur with enzymes resulting in loss of height and less ability to reduce compressive and shearing forces. In addition, environmental factors including occupational activities, excessive physical activity impacting the spine may contribute towards degenerative disc disease (1).
Alternative treatment: stem cell therapy
In order to address these issues, various treatments have arisen to try to try to halt the cascade leading to degenerative disc disease. This includes implantation of biomolecules to reduce the catabolic process.
Stem cell research is gaining more traction as a viable alternative for treatment of this debilitating condition. One study looked at the potential of nucleus pulposus-like cells derived from mesenchymal cells in the rabbit model. From these cells, SOX9, ACAN, COL2, FOXF1, and KRT19 genes were expressed(2). Transplanted nucleus pulposus cells were integrated into the intervertebral disc complex. Improved water content, glycosaminoglycan, and cellularity within the complex was noted. There was a suggestion of biosynthesis with the gene expression of SOX9, ACAn, COL4 (2). This animal study demonstrates that there may be value in nucleus pulposus cells derived from mesenchymal cells may lead to clinical studies where stem cells can be used for back pain.
Injection of mesenchymal stem cells
Injections of mesenchymal stems cells into the disc may reduce the clinical pain and restore disc tissue loss. It may be able to reduce the catabolic microenvirnment (3)
Clinical studies of stem cell use in humans
It appears that stems cells of mesenchymal type derived from adipose or the umbilicus may have the most promise (4).
In one small study of 10 patients, autologous bone marrow mesenchymal cells were were injected in the nucleosus pulposus and followed for a year. After 3 months, there was improvement of pain and disability of 85% of the maximum. After 12 months, there was still high water content within the nucleosus pulposus (5).
Stem cell effects were studied in 2 patients with back pain and leg numbness. Marrow fluid was obtained autologously from the ilium from each patient. Mesenchymal stem cells were cultured in autogenous serum. Fenestration was performed and collagen sponge was applied percutaneously to the affected intervertebral disc complex. After 2 years, the T2 signal was high showing increased disc content in the grafted discs. Clinical symptoms were ameliorated (6).
In an open label trial of 26 patients, using the VAS and Oswestbry disability scale, there was reduced pain after percutaneous injection of bone marrow cell concentrate showing autologous mesenchymal stem cells are a viable alternative treatment for back pain (7). They studied the patients through 12 months. Those who received >2000 colony forming fibroblast units/ml had faster and greater pain reduction.
There is one small randomized controlled clinical trial in 24 patients using the Pfirrmann grading scale for degeneration, allogeneic mesenchymal cells were transferred to the clinical cohort. Significant relief of pain was noted compared to the sham group demonstrating that allogeneic transfer may be logistically better than autogenous transfer (8).
Possible adverse effects
Concerns include transformation into neoplastic process. This seems to be true with embryonic stem cells which are much earlier seen in the cell lineage. Mesenchymal cells are further down the line as a committed cell type to obviate this. With in vitro culturing, there is concern for cell mutations, but this is less of a concern if it is a same day procedure, autologous and exist as when they were in the body previously. There is concern for extravasation beyond the limit of the disc and if combined with other treatments such as PRP it may promote osteogenesis. In addition, animal models may not replicate the harsh microenvironments of disc pathology where continual torsion and pressure is involved and effects and outcomes might be different (3).
There is much scientific and animal model data that stem cells remain a viable option for treatment of back pain which is one of the most common problem encountered by neurologists, neurosurgeons, orthopedic surgeons and pain management specialists. While there is much demonstrated in animal studies, clinical trials are still very sparse. This treatment, however, shows promise and despite paucity of clinical trial data, this treatment is gaining traction in practicing clinicians who treat back pain.
Given the failure with medications and even with surgery there is increased interest in alternative treatments including stem cell therapy.
1. Rosenberg, et al, “Bedside to bench and back to bedside: translational implications of targeted intervertebral disc therapeutics,” J. Orthop. Translat., 2017, Apr., 10:18-27.
2. Perez-Cruet, et al, “Potential of human nucleus pulposus-like cells derived from umbilical cord to treat degenerative disc disease,” Neurosurgery, 2018, Feb., doi:10.1093/neuros/nyy012
3. Zeckser, et al, “Multipotent stem cell treatment for discogenic low back pain and disc degeneration,” Stem Cell Int., 2016, doi: 10.1155/2016/3908389
4. Knezevic, et al, “Treatment of chronic low back pain – new approaches on the horizon,” J. Pain Res., 2017, May 10, 10:1111-1123
5. Orozco, et al, “Intervertebral dis repair by autologous mesenchymal bone marrow cells: a pilot study,” Transplantation, 2011, Oct., 15, 92 (7):822-8
6. Yoshikawa, et al, “Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of 2 cases,” Spine, 2010, May 15, 35 (11):E475-80
7. Pettiness, et al, “Percutaneous bone cell concentrate reduces discigenic lumbar pain through 12 months,” Stem Cell, 2015, 33(1):146-156
8. Noriega, et al, “Intervertebral disc repair by allogeneic mesenchymal bone marrow cells,” Transplantation, Aug., 2017, 101(8):1945-1951.
Virginia Thornley, M.D., Neurologist, Epileptologist
May 8, 2018
Cannabinoids are being more and more widely used in a variety of neurological conditions. This always leads to the questions of side effects and will it interacts with other medications? Because this is wholly unchartered territory, in order to answer these questions, it is necessary to understand the underlying mechanisms.
Cannabinoids can cause tachycardia
Phytocannabinoids, when ingested, can induce tachycardia. The metabolism of cannabinoids by cardiomyocytes likely impacts the side effects elicited in cardiac cells. CYP2J2 is the most significant cytochrome p450 which metabolizes endocannabinoid anandamide (AE) into the cardioprotective epoxides. 6 phytocannabinoids were studied in one paper including delta-9-tetrahydrocannabinol, cannabinol, cannabidiol, cannabigerol, and cannabichromene. These were found to be metabolized more quickly compared to anandamide. The cannabinoids may potentially inhibit the metabolism of anandamide by CYPJ2 such that its effects are still circulating in the system. The most significant inhibition was from delta-9-tetrahydrocannabinol. It follows a non-competitive inhibition model such that the cardioprotective epoxides are not formed as abundantly as they should by the cytochrome p450 CYP2J2 (1).
The cytochrome P450 system has a significant impact on the metabolism of cannabinoids. Tetrahydrocannabinol is metabolized by CYP2C19 and CYP3A4. cannabinol is metabolized by CYP2C9 and CYP3A4. Synthetic cannabinoids include JWH-018 which is metabolized by CYP1A2 and CYP2C9 and AMC2201 which is metabolized by CYP1A2 and CYP2C9.
The cytochrome P450 enzymes are also thought to be involved in the metabolism of tetrahydrocannabinol. CYP2C9 greatly influences the metabolism of tetrahydrocannabinol. Cytochrome P450 3A4 is important in the metabolism of THC and CBD (2).
Cannabinoids in relation to hyperemesis syndrome
Once abdominal pain has been explored regarding medical etiologies, and there is a presence of 1-year history of cannabis use usually weekly, this diagnosis comes to mind. It usually involves cyclical vomiting associated with nausea. The mechanism is thought to be related to dysregulation by the endocannabinoid pathway in relation to the gastrointestinal tract. The CB1 receptor by which THC or tetrahydrocannabinol exerts it actions is also present in the GI tract. Exogenous cannabinoids may dysregulate the normal endocannabinoid pathway thereby affecting the GI tract through the down-regulation of the normal CB1 receptors so that it is no longer sensitive to endocannabinoids which regulate the system. This results in a dysfunction of the GI tract clinically manifested as cyclical nausea and vomiting. A disruption of the cannabinoid receptors may occur resulting in slowed motility of the gut. Relief can occur with use of hot water which influences the TRPV receptor a G-related coupled protein
Virginia Thornley, M.D., Neurologist, Epileptologist
May 6, 2018
There is a well-known correlation of use of cannabis whether it is medical or recreational to the onset of schizophrenia. It unclear if this could be to a direct correlation and disinhibition of the genetic component or the behavior of using it is a prodrome leading up to schizophrenia. This review seeks to elucidate the mechanisms in the correlation of the use of cannabis and onset of schizophrenia.
Mechanisms related to the underlying genetic composition
Schizophrenia may be linked when some of the normal pathways become disrupted with an introduction of THC. There are 4 genes that were described after a lifetime use of cannabis including KCNT2 which were THC responsive, NCAM1 and CADM2 are significant in functioning in post-synapse. With THC in the system, there are more post-synaptic density genes (1).
Mechanisms related to other neurotransmitter pathways influenced by cannabinoids
In one study, because of the alarming rate of potent synthetic cannabis used recreationally which was found to leave long-lasting schizophrenia disorder in recreational users, this has accelerated research into the pathophysiology. Because cannabinoids work on the CB1 receptor, it is likely that it plays a modulatory role on the other neurotransmitters that can give rise to schizophrenia including dopaminergic, glutamatergic and serotonergic pathways. These pathways are well-established as playing a role in a pro-psychotic state. High efficacy synthetic cannabinoids which are manufactured for recreational purposes are highly more potent compared to natural organic cannabinoids and there is an alarming increase in the correlation of schizophrenia in these users (2).
In one study it is thought to be due to the hypofunctioning of the glutamate system which is directly affected by THC. Exposure to tetrahydrocannabinol appears to reduce the activity at the level of the glutamate receptor as well as deregulate genes for synaptic function(1).
Susceptibility is related to the development of schizophrenia
In one animal model, the set-up tried to mimic a more real state seen where not all adolescents exposed to synthetic cannabinoids react by developing schizophrenia, there are some studies where all animals develop schizophrenia with exposure. In this animal model, they provided a model that resembles the human model more closely and found that exposure to synthetic cannabinoids in schizophrenia-prone animals caused hyperfunctioning of dopaminergic pathways compared to the control group who were not susceptible at the same dosages. There may be underlying genetic or environmental factors that cause certain individuals to become more prone (2).
THC can cause anxiety and behavioral disorders but can be prevented with CBD
In one animal study, it was found in a rat study that THC can induce anxiety and behavioral disorders. With THC administration object recognition was impaired in adolescent rates. The studies support effect on the developing brain in relation to cognitive impairment in the animal model. In addition, when rats were exposed to THC there was increased marble burying behavior which in scientific research is thought to signify anxiety or obsessive-compulsive type behavior usually ameliorated with serotonin reuptake inhibitors or benzodiazepines(4).
It was found, however, that a combination of CBD and THC or cannabidiol alone was administered, these behaviors were not produced or produced only minimally. The thought is that CBD is an allosteric competitive inhibitor at the CB1 receptor so that one sees less of the toxic undesirable effects of THC if administered alone (4).
Cannabinoids have a similar profile to atypical anti-psychotics and may be a possible adjunctive treatment in the treatment of psychotic events (5).
There is historical evidence that exposure to THC can give rise to schizophrenia in those individuals that are susceptible accounting for the fact that it does not happen to everybody exposed to it. This is related to its influence on serotonergic, dopaminergic and glutamate pathways. THC can induce anxiety, repetitive behaviors which are ameliorated by CBD. CBD may be a useful adjunctive treatment for psychotic disorders. However, the elucidated mechanisms are based on scientific research based on animal models which may not translate into humans.
Virginia Thornley, M.D., Neurologist, Epileptologist
May 6, 2018
Medical cannabis is being more and more commonly used in medical conditions specifically neurological. The CB1 receptor is found predominantly within the nervous system and in a few other organs on a lesser basis. The CB2 receptor is mainly in the immune system and found in other organs to a lesser extent.
Recent arguments have arisen promoting medical cannabis in children particularly in those with autism and attention deficit hyperactivity disorder. It has already been well-established in patients with epilepsy. However, the effects on the developing brains of children have not yet been well-documented as it is not yet widely used or studied in the pediatric population. There are many animal models but this does not always correspond to translate into similar human findings.
Effect in autism in animal models and clinical studies
A current topic of debate is not only using THC in pediatric patients but those with autism. Autism is part of the pervasive developmental disorder consisting of social inhibition and isolation including poor eye contact, delayed language skills, aggressive behavior and may be characterized as having stereotypies such as flapping of the arms. Self-injury, eating and sleep disorders may occur. The etiology may be related to genetic, neurobiochemical or environmental and the exact cause is unclear.
In one animal model study, mice with induced Dravet syndrome-like symptoms was noted to improve in autistic-like social interactions with the addition of low dose cannabidiol (2) of 10mg/kg. At low doses, the DS mice interacted more with stranger mice. At higher doses, this was not noted. Dravet syndrome is a type of epileptic syndrome affecting the SCN1A gene causing medically refractory seizures combined with autism. However, this was an animal model. Scientific studies do not necessarily translate into positive human clinical results.
There was one case report of a six-year-old boy with early autism. Dronabinol (delta-9-THC) was administered at 3.62mg a day and followed for 6 months. Using the ABC scale (aberrant behavior checklist), the patient improved in terms of stereotypies which were less, lethargy was reduced, hyperactivity improved, and inappropriate speech improved (4).
Endocannabinoid system and mechanisms in relation to autism
There are several lines of thinking regarding the role of the endocannabinoid and autism. It is thought that the endocannabinoid system plays a role in neurological development, but can also be modulated by outside cannabinoids. Another line of thinking is that autism spectrum disorders may be related to disrupted pathways that have been affected by the endocannabinoid pathway (5). In one animal study, it was found that the oxytocin peptide may be responsible for disrupting normal signaling pathways giving rise to autism spectrum disorders. Oxytocin appears to be crucial in mediating social reward which is impaired in autistic patients. Anandamide seems to play a role in the signaling pathways for oxytocin which is responsible for the social reward. Social reward is aberrant in those with autism and this pathway thought to play a key role in causing its pathogenesis. By increasing anandamide at the CB1 receptor, ASD and social impairment is improved (5).
Effect on a fetus
Tetrahydrocannabinol is lipophilic and crosses the blood-brain barrier. It can get stored in the fatty stores which are likely the reason it may have a long-lasting effect. Cannabinoids have been found to cross the placenta and affect the fetus. It may result in hyperactivity and impulsivity in babies with cannabinoid exposure in utero.
Effect on early cerebral development
It was found that in adolescents who used cannabis, there is a reduction in the IQ by the age of 38. It was found that cannabinoid receptors influence axonal migrations as well as subcortical projections within the cerebrum. This affects synaptic connections during childhood and adolescence(3).
The adolescent brain is still not fully matured and likely still subject to neuronal plasticity and changes. It may be affected by substances. One study showed that the frontal lobe is vulnerable to cannabis in adolescents who used it heavily and that cannabis use may impact working memory. (1)
During adolescence, when cannabis is initiated it may affect the neuronal circuitry developing in the immature brain. The richest regions in the brain with cannabinoid receptors are the prefrontal cortex, medial temporal lobes, striatum, white matter connections, and cerebellum. When cannabis is introduced during this neurocritically important time of development, these regions can become dysfunctional although some functional studies have shown altered, weakened, strengthened or combination of changes (6).
Some of the most common adverse effects
At high doses in chronic users, it was found to induce anxiety, panic attacks. It can increase blood pressure. However, clinically, it may control seizures
There is a small body of evidence from a scientific standpoint that cannabis may work to help alleviate autism-like symptoms based on the animal models. There is a not enough evidence from a clinical evidence standpoint in human studies to support its use in pediatric patients, with one case report that it helped with impulsivity, reduced lethargy, and inattention. Randomized placebo-controlled clinical trials are needed.
Research has found that cannabinoids may help oxytocin and disrupted signaling pathways that play a role in social reward which is impaired in autism. At present, there is evidence that cannabis may affect neurocognitive development but these are studies in pregnant mothers who used it heavily recreationally and adolescents who used it heavily. It is unclear if there may be a similar impact when used in the pediatric population at a medical dosage and administration as there are not enough studies to expound on this.
Virginia Thornley, M.D., Neurologist, Epileptologist
April 28, 2018
The Cannabis sativa plant has been known since the beginning of time. It can be traced back 5000 years ago when it was first known to man to alleviate common complaints. It came into the American pharmacopeia in the 19th century then abolished in the 1930’s, likely not coincidentally as the era of prohibition was lifted. It is known to treat ailments such as chronic pain and migraine. In the middle ages, it was used to treat headaches, vomiting, diarrhea, bacterial infections and pain from rheumatological conditions. It was previously known for its psychoactive properties. It is recently making a resurgence in popularity regarding its medical value. The issue is a topic of hot debate as state laws are at odds with federal laws. Currently, as of April 2018, it is still recognized as a category 1 drug, meaning it is not officially proclaimed to have any medical value despite the long rich history of treating medical symptoms. It is lumped in with other drugs of abuse such as heroin and cocaine.
Background on the Cannabis sativa plant and their metabolites
The Cannabis sativa plant is abundantly rich in phytocannabinoids, the most commonly known and used for its therapeutic value are cannabidiol and tetrahydrocannabinol. The endocannabinoid pathway is comprised of receptors that are coupled with G proteins and cannabinoids (1). In the Cannabis sativa plant, there are 80 phytocannabinoids that can bind to a cannabinoid receptor.
There are 8 major cannabinoids including cannabigerolic acid, delta-9-tetrahydrocannabolinic acid A, cannabidiolic acid A, delta-9-tetrahydrocannabinol, cannabigerol, cannabidiol, cannabichromene, and tetrahydrocannabivarin in the different strains of Cannabis sativa (1).
Ehlsoly, et al, classified it into 11 categories: cannabigerol, cannabichromene, cannabidiol, ∆9-trans-tetrahydrocannabinol, ∆8-trans-tetrahydrocannabinol, cannabicyclol, cannabielsoin, cannabinol, cannabinodiol, cannabitriol, and miscellaneous. ∆9 -trans-tetrahydrocannabinol , cannabinol, and cannabidiol are the most well-studied and well-known.
Cannabidiol is extracted from the hemp portion of the plant considered a male part of the plant, there are no psychoactive properties in cannabidiol. Psychoactivity is defined as anything above 0.3% of THC. Tetrahydrocannabinol is derived from the female portion of the plant, particularly the flowers. Conditions are such that in nurseries only a certain amount of sunlight is given to the plants so that specific strains can be grown. Some plants will be richer in cannabidiol, others will be more THC pure and other swill have an equal amount of CBD and THC but it depends on how the plants are grown and under what conditions.
It is through the endocannabinoid pathway that one gets the sense of well being after exercise or eating chocolate. It is not through endorphins, serotonin or noradrenergic neurotransmitters as they are too large to cross the blood-brain barrier. Tetrahydrocannabinol acts as a mimetic of Anandamide while cannabidiol acts as a mimetic of 2-Arachidinoylglyerol (or 2-AG). The endocannabinoid system works through cannabinoids, the receptors, transporters, and enzymes.
The phytocannabinoids work on cannabinoid receptors. The endocannabinoid system is mediated by 3 parts: the cannabinoids, the cannabinoid receptors, and the enzymes. The receptors are of 2 types, CB1 which is found primarily in the nervous system especially in the areas that subserve pain modulation, memory and movement. The CB2 receptor is more peripherally found specifically in the immune system. The CB2 receptor is found to a lesser extent in other organs including tissues of reproduction, pituitary, heart, lungs, adrenal and gastrointestinal systems. Cannabinoids also react with the TRPV receptor or the transient receptor cation channel subfamily V. They can also act on G receptors including GPR55 thought to be significant in controlling seizures. Other receptors include GPR12, GPR18, and GPR119 (2).
Tetrahydrocannabinol and cannabidiol and their effect on receptors
THC and CBD are the most well-known and well-studied. THC has psychoactive properties and works as a partial agonist on the CB1 receptor and the CB2 receptor. Cannabidiol which has no psychoactive properties works as an antagonist on CB1/CB2 receptor and an agonist on the CB1 and CB2 receptor. Rather than decreasing the effects of THC, it works in a synergistic manner in combination with THC. It potentiates the THC effects by increasing the CB1 densities. CBD increases vanilloid pain receptors, reduces metabolism and reduces re-uptake of anandamide, THC’s mimetic component. Other studies suggest CBD acts as an indirect agonist by interacting with the CB1 receptor so there are less psychoactive symptoms from THC when the two are combined.
Pharmacokinetics of tetrahydrocannabinol
Regardless of the way of taking it, the protein binding and the and volume of distribution are not affected by the route of taking it. Pharmacokinetics of creams and vaporizers are unclear. Smoking THC appears to exert an effect within minutes of intake and bioavailability is variable depending upon the extent of inhalation ranging between 2-69%. The effect is within minutes. Half-life increases with each inhalation at 2 puffs inhaled for THC it is 1.9 hours and 5.3 hours in CBD at 8 inhalations it is 5.2 hours in THC and 9.4 hours in CBD at a dosage of 5.4mgTHC/5.0mg CBD and 21.5mg THC/20 mg CBD respectively.
Oral routes may seem to be safer but have more adverse effects including GI symptoms such as nausea, vomiting, and diarrhea. Oral mucosal absorption is rapid within 15 minutes to 60 minutes. Oral tablets are lower in the rate of absorption at about 0.6 to 2.5 hours. The rate of elimination, when taken orally, is biphasic, initially occurring at 4 hours then 24-38 hours after ingestion.
There is much research ongoing on the mechanisms underlying the medical value of medical marijuana. It is now thought that cannabigerolic acid may have medicinal properties as well. So far, the most well-known and well studied are delta-9-tetrahydrocannabinol and cannabidiol. Most likely as research continues, greater value will likely be attributed towards the phytocannabinoids.
Virginia Thornley, Neurologist, Epileptologist
April 15, 2018
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).
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.