Tag Archives: Healthcare
Cannabidiol: a large study in the U.S., Netherlands, and Poland shows its efficacy in patients with the epileptic disorder Lennox-Gastaut Syndrome
Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD
March 31, 2018
Introduction
Lennox-Gastaut Syndrome is an epileptic syndrome starting in childhood characterized by a wide spectrum of seizures and slow spike and wave on EEG. The seizures are characterized by the classic mnemonic “a fall, a jerk and a stare” or atonic seizures, myoclonus and complex partial seizures, although there are many other different types. Slow spike and wave generalized epileptiform discharges of 2.5 Hertz or less on electroencephalogram clinch the diagnosis. Patients are often delayed in development. Controlling seizures, because of the sheer complexity, of the different types is often a medical challenge.
Methods of the study
A new study using cannabidiol, which is the non-psychoactive medical component of the cannabis sativa plant, was carried out with the results recently demonstrating value. It covered 24 sites from the U.S., the Netherlands and Poland and studied seizures in patients medically refractory to medications using cannabidiol as an adjunctive add-on agent. 171 patients were enrolled from April 28, 2015, to October 15, 2015, and were randomly assigned to either the placebo control or the group with cannabidiol. 86 received cannabidiol and 85 were in the placebo group. 14 discontinued treatment in the cannabidiol group and 1 in the placebo group. All patients had at least one dose of treatment. Eligible patients ranged from 2-55 years old. Cannabidiol was given at a dose of 20mg/kg.
Seizure reduction
The results were startling, there was a reduction of seizures by 43.9% in the cannabidiol group and 21% in the control group. 86% patients had side effects in the cannabidiol group and 69% in the control group on placebo. These included somnolence, pyrexia, diarrhea, reduced appetite, and vomiting. 12 stopped in the cannabidiol group due to adverse reactions considered mild to moderate while 1 withdrew from the placebo group. 1 died due to unrelated causes from the cannabidiol group.
Conclusion
Reviewing this study, perhaps one of my critiques of this study is that the dosage was 20mg/kg in a 14-week study which means that within 14 weeks a patient of 50 kg. would have been ramped up to about 1000mg. In real life practice, medications are titrated more gradually over a period of months before maximum efficacy may be seen and in such a gradual way in order to avoid side effects. Although a large percentage of patients had side effects which were mild to moderate, it is quite possible they may have needed a smaller dose and the dosages were increased more than it was necessary to achieve the beneficial effects seen in the study within a short period of time. Nevertheless, the bottom line is that cannabidiol, a product of the Cannabis sativa plant, shows a reduction in seizures in a patient with Lennox-Gastaut syndrome.
This study concluded that there is some efficacy of cannabidiol in Lennox-Gastaut syndrome, one of the most difficult epileptic syndromes to treat, and was found with only very mild to moderate side effects. An open-label study as an extension to this study is currently ongoing.
Neurologybuzz.com
Reference
- 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.
Ketogenic diet, modified Atkins diet and what is in them: used in seizure control, can these be a weight loss solution to morbid obesity, a risk factor for cerebrovascular and cardiovascular disease?
Virginia Thornley, M.D., Neurologist, Epileptologist
@VThornleyMD
March 29, 2018
Introduction
Ketogenic diet has been used for seizure control when physicians started to notice a reduction of seizures in patients with a high ketone laden diet. This fell out of favor in the 1920’s with the onset of newer agents. As a side note, weight loss has been noted in those on a ketogenic diet.
Previously, guidelines have recommended a reduction in saturated fat which was thought to be the cause of the growing morbid obesity epidemic. Currently, it has been found that carbohydrates which are rich and refined may contribute towards the obesity epidemic. Sugar-laden sodas, the white bread which has refined flour, pizza batter made out of refined flour, all these food which are popular in theIt is no Western culture contribute to the morbid obesity as it is looming today.
How current culture sets the perfect stage for morbid obesity
The current western diet is about 50% carbohydrates. In addition, physical activity is at an all-time low compared to other eras. The current culture is designed as a sedentary and carbohydrate-rich eating culture. Everything nowadays is rapid pace. There are drive-through banks, drive-through pharmacies. Rather than having to physically go to a shop or order things in person, many things can be done online or by phone reducing the daily need to exert physical activity. There is less time spent on physical activity compared to 100 years ago. If you go to neighborhoods, sidewalks no longer exist. Unless one lives in an urban environment where you are forced to walk to the bus station or live in cities amenable to walking or biking, the car is the mode of transport. Food is rich in carbohydrate, such hamburger buns, pizza dough, white bread or rolls. It is little wonder that morbid obesity abounds. Food rich in sugar is abundant in grocery store aisles including donuts, cookies, baking packets. The colorful rich in anti-oxidant fresh fruits and vegetables are usually on the sides of the grocery shops, the food that is actually good for you and you need to take time out of your schedule to cook.
Living a healthy diet is not just staying active but also eating the proper diet. Food that is closest to their original source are richest in nutrients. In short, the colorful vegetables you have to cook without any of the processing that takes place are the food richest in nutrients and have high anti-oxidant properties. Anti-oxidation is important in helping to combat a wide variety of diseases. Colorful fruits and vegetables are rich in fiber and more difficult to digest, hence, uses up more calories. Those which are high in refined carbohydrates are easily digested and contributes more towards obesity.
Components of the ketogenic diet and ketogenic diet variants
Ketogenic diet variants include modified Atkins diet, low glycemic index treatment, and medium chain diet. The ketogenic diet consists of 4:1 ratio of fat to carbohydrates shifting metabolism to the use of ketone bodies as a source of energy. A lower ratio is sometimes employed called the modified ketogenic diet with a 3:1 or 2:1 ratio of fat to carbohydrates. In the modified ketogenic diet, the palatability is improved and avoids the gastrointestinal symptoms associated with the ketogenic diet such as nausea. With the modified Atkins diet, carbohydrates are restricted to 10-20 grams a day, or a 1-2:1 ratio of protein to fat plus carbohydrates. In the low glycemic index treatment, carbohydrates are limited to 40-60 grams while 50-60% of the diet is fat and 20-30% is from protein. The medium-chain triglyceride diet employs oils as a supplement such as coconut oil. The palatability of these diets improve patient compliance and lessen the side effects of the ketogenic diet. Some patients also used the diets to incidentally lose weight in addition to treating seizures.
Ketogenic diet and evidence it works in losing weight
The ketogenic diet has a carbohydrate component of about 20-50 grams a day. It is not so much the restriction of the carbohydrates but the quality of carbohydrates that are ingested that causes people to shed pounds. High fiber, wheat, and whole grain carbohydrates portend a healthier diet as opposed to just restricting carbohydrates in general. In some clinical studies, it was found that weight loss was higher in those with a low carbohydrate diet compared to a low-fat diet (1).
Will the high fat cause me to have heart disease?
In one study where ketogenic diet was used in glucose transporter deficiency, a pediatric epileptic syndrome with encephalopathy, 10 patients were followed for 10 years. After 10 years on ketogenic therapies, there was no evidence of increased cardiovascular risk. While it is a small study, it shows evidence that eating a low carbohydrate diet did not appear to contribute towards heart disease. Larger clinical trials are needed (3).
How obesity relates to other diseases
It is not uncommon to see patients who come into the ER or the doctor’s office with a history of hypertension, diabetes mellitus type II, hypercholesterolemia and obesity all related to one common denominator-obesity. Take away the obesity, the bad cholesterol or the LDL values go down, glucose goes down and hypertension resolves. When these risk factors are reduced early enough in your life, the odds of cerebrovascular disease or strokes and cardiovascular diseases or heart attacks vastly diminish. If, however, obesity is long-standing, while it is definitely good to reduce risk factors, once atherosclerosis is present in the blood vessels, there is no magic pill to reverse that.
Early identification and reduction of obesity as a contributor towards many health problems is key. Ketogenic diet may play a role in weight reduction. A small case series did not show any risk of heart disease while on the ketogenic diet long-term, over a span of 10 years. Larger clinical trials are needed to support this.
Reference
- Giugliano, et al, “More sugar? No thank you! The elusive nature of low carbohydrate diets,” Endocrine, 2018, Mar, 19. doi: 10.1007/s12020-018-1580-X (Epub ahead of print)
- McDonald, et al, “Ketogenic diets for adults with highly refractory epilepsy,” Epilepsy Currents, 2017, Nov.-Dec., 17 (6):346-350.
- Heussinger, et al, “10 patients, 10 years-Long-term follow-up of cardiovascular risk factors in Glut1 deficiency treared with ketogenic diet therapies: a prospective , multicenter case series,” Clin. Nut., 2017, Nov, pil:S0261-5614 (17)31399-7.
Epilepsy surgery in temporal lobe epilepsy due to mesial temporal sclerosis: the timeline in investigative work-up from the neurologist’s office to the O.R.
Virginia Thornley, M.D. Neurologist, Epileptologist
March 27, 2018
Introduction
Temporal lobe epilepsy is one of the most common types of seizures. The most common cause and one of the most successfully treated causes of temporal lobe epilepsy treated through surgery is mesial temporal sclerosis. This article focuses on mesial temporal sclerosis and does not include discussions of other types of temporal lobe epilepsy due to other causes such as tumors, cystic lesions or head injury or non-lesional temporal lobe epilepsy. In order to identify a patient, the symptoms are generally stereotypical which suggest localizing towards one focus. An early age of identification may portend a better outcome since frequent temporal lobe seizures may cause the development of circuitry to the opposite side causing another focus to develop on the opposite temporal lobe. In addition, it is important to control temporal lobe epilepsy because of the location of the seizures are in the hippocampus which is important in memory. Many patients complain of poor memory which will continue to progress should seizures remain poorly controlled. Epilepsy surgery is the definitive treatment for temporal lobe epilepsy in mesial temporal sclerosis.
Identification
To identify an appropriate candidate for surgery, the patient should have stereotypical seizures which localize towards one focus. While the focus may cause contralateral clinical symptoms, automatisms of the limb are generally ipsilateral to the focus. Once a patient has been identified, further diagnostics tests are needed in order to confirm this focus including a routine electroencephalogram and an ambulatory 48-72 hour EEG which can be performed out-patient. The only downfall with an ambulatory EEG is that it is subject to the artifact, since the electrodes may be displaced causing poor adherence of the electrode to the scalp causing resistance manifested as artifact and a poor recording. However, it is still a good screening test to determine whether there may be a single focus versus multiple regions affected. Temporal lobe epilepsy may be seen with high voltage epileptiform spike and wave. It may be accompanied by focal delta slowing within the temporal lobe, suggesting temporal lobe dysfunction due to recurring seizures. If a patient is deemed an appropriate candidate, a referral may be made to an epilepsy center where more in-depth investigations are performed.
Admission to an epilepsy center
Expect to stay at least 1 week or more in order to allow the capture of typical seizures and to obtain an adequate sampling of ictal periods and pinter-ictal periods during wakefulness and sleep. A team of specialists is involved with the work-up including a clinical epileptologist who manages the medications and clinical aspect, a clinical neurophysiologist who interprets the video EEG monitoring and correlates it with the clinical symptoms, a neuropsychologist who performs the WADA testing and a slew of clinical EEG technicians who ensure that the electrodes are properly attached throughout the hospital stay. In-depth conferences are held to review the studies of the patients and evaluate which patients are suitable epilepsy candidates. Sometimes, multiple admissions are necessary before seizures can be captured.
Hospitalization
During admission, seizures are captured and correlated with the electroencephalographic recordings to determine the focus. More than one focus correlates with a poor outcome, a single focus is necessary. The clinician may provoke seizures by tapering medications safely in the hospital setting. Other techniques include sleep deprivation and encouraging any triggers. The full spectrum of clinical seizures must be captured in order to ensure adequate localization. Bitemporal foci portend a poor outcome.
Neuroimaging
A high-quality MRI of the brain using epilepsy protocol with thin cuts through the temporal lobes of 1.5mm to 2mm is essential. Coronal views are the best way to visualize the hippocampi to evaluate for hippocampal sclerosis which characterizes temporal lobe epilepsy. Usually, the hippocampus affected is much smaller than the contralateral one with hyperintensity on T2. As a result of excessive seizures, burning off of the cells in the hippocampus occurs so that is it is now atrophic. Although an MRI of the brain may have already been obtained pre-work-up, a higher resolution and exceptional quality brain MRI is likely to be repeated. This will serve as the visual point on which the neurosurgeon operates. Seeing a sclerotic hippocampus gives a high correlation with mesial temporal sclerosis.
Ictal SPECT
Spectroscopy is obtained in-house, where hexamethylpropylenamine oxime (HMPAO) injection is done 30 minutes before an ictus. When the patient has a seizure, the HMPAO perfuses to the area of interest showing where the seizure localizes. Images are obtained. This test has an added value of further localizing the focus. The drawbacks, however, include not being able to predict when a seizure is about to occur and missing the ictus. It is not unusual for this test to be repeated for it to be meaningful. In addition, it can only be done during office hours so that nocturnal seizure will be missed due to lack of adequate staff.
Magnetoencephalography
This is a costly examination which may not be available in some epilepsy centers. It uses a 3-dimensional modality for localizing the focus. The MEG dipoles are superimposed on the MRI images.
WADA testing
A neuropsychologist examines the patient’s memory and language by temporarily putting the opposite side of the brain to sleep through injection of amobarbital into the internal carotid artery. Short-term memory and language are examined. The neuropsychologist must determine that there is adequate memory on the contralateral temporal lobe for temporal lobe surgery to be successful. If both temporal lobes are impaired in terms of memory, the patient will suffer from poor memory following the surgery. Other tests are done by the neuropsychologist to check for cognition, any personality disorders and assess for evidence of mood disorders.
Electrocorticography
This is one of the final steps in the investigation where the cranium over the temporal lobe of interest is removed and electrodes are placed directly on top of the cerebrum. Depth electrodes are placed in order to capture epileptiform discharges buried deep inside the hippocampus which cannot be adequately detected by electrodes laying on top of the temporal lobe. The seizures are recorded and a more accurate mapping of the seizure focus is obtained.
Discussions
Once all the appropriate investigations are obtained, if all the data points towards a single focus then the patient is deemed an appropriate candidate. Epilepsy conferences are usually held and reviewed by all the specialists involved in the care. Some patients may proceed directly into surgery after mapping. Others may need to go home and return back for another admission to undergo epilepsy surgery. A patient who is still questionable may need to return for more in-depth recording, this may occur in non-lesional epilepsy where the information is not strong enough to justify surgery. The goal of epilepsy surgery is to resect the dysfunctional epileptogenic zone while preserving the functioning surrounding cortex.
After care
Once the surgery is performed, the patient will need to be on anti-epileptic agents for at least 2 years of seizure freedom. In appropriately investigated patients, a favorable outcome of seizure freedom may reach as high as 60%.
Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol
Virginia Thornley, M.D. Neurologist, Epileptologist
Introduction
The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010. Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.
How it works–the nitty gritty
Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly. Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated. CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.
Current legal state of affairs
Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law. In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store. Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.
In conclusion
In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.
Sativex (tetrahydrocannabinol and cannabidiol) and the European experience in medically refractory spasticity in multiple sclerosis
Introduction
Sativex has been available in Europe since 2010. It is a combination of tetrahydrocannabinol and cannabidiol at a ratio of 1:1 and has been found to be effective in spasticity resistant to medications in patients with multiple sclerosis. Spasticity is the increased tone seen in the muscles due to abnormalities in the central nervous system such as the white matter lesions seen in multiple sclerosis.
Sativex and medically refractory spasticity in multiple sclerosis
Sativex is a THC:CBD (tetrahydrocannabinol:cannabidiol) preparation taken oromucosally which was approved in European countries for the treatment of medically refractory spasticity in patients with multiple sclerosis. Sativex contains a 1:1 ratio of THC to CBD, where THC interacts with CBD receptors to reduce spasticity while CBD ameliorates the side effects often seen with THC. In one large clinical trial of 1615 patients, 42% showed improvement of spasticity in the first 4 weeks, defined as > or = to 20% reduction in spasticity. The responders were double-blinded and grouped under placebo or THC:CBD, a larger proportion of patients had significant response compared to placebo, > or = to 30% reduction of NRS score for spasticity. 47% had adverse effects including fatigue and dizziness. Reported side effects included psychiatric disturbances, 55 had cognitive (attention problems, cognitive worsening and memory problems) and psychiatric issues (confusion, panic attacks, hallucinations, depression and suicidal ideations). Fatigue, drowsiness, dizziness, gastrointestinal symptoms, mouth discomfort and allergic reactions were other reported side effects. There was no evidence of abuse or addiction in the patients. There were significant side effects deemed unrelated to Sativex including, myocardial infarct, hypertensive crisis (2).
In the original MOVE 2 trial in Italy, in the 322 patients studied, the NRS numerical rating scale decreased by -19.1% from baseline time to 3 months of treatment with Sativex. At visit 3 at 3 months, 24.6% were considered relevant responders to the medication with 30% or more reduction in spasticity. Side effects of >1% included somnolence, dizziness, and fatigue. 41 patients reported side effects 3 were serious side effects of which one was not related (3).
Sativex and studies in Germany, United Kingdom, Switzerland and Spain
Sativex was first approved in Spain and the United Kingdom in 2010 for use in spasticity related to multiple sclerosis. Data were collected to study continued efficacy and safety profiles. 941 patients (761 from the UK, 178 from Germany and 2 from Switzerland) were studied. Data was collected up until January of 2015. A patient registry was set up as per guidelines before new medications are approved. Patients from the UK were 22% of the patients registered in the UK using that medication since 2010. Continuation rates were 1 year for 68% of patients. Among those who stopped it, 30% cited lack of effectiveness and 25% described side effects. Some significant side effects include suicidality in 2% and depression in 6%. There was no evidence of abuse, addiction or misuse. The fatigue was within the known safety margins of the drug. The patients used on average 5.9 +/- 4.9 sprays per day
Sativex and timeline when it is found to be ineffective
In one large study in Italy involving 30 multiple sclerosis centers, the discontinuation profile was studied. Patient data from 30 MS centers were collected from a period of January 2014 to January 2015. 39.5% of patients disconnected treatment with Sativex. Spasticity was studied using the EDSS or expanded disability status scale and the patient NRS numerical rating scale 0-10 for spasticity. Information was collected at baseline (T0), 4 weeks (T1), 3 months (T2) and 6 months (T3).
Spasticity was noted in 1615 patients. 1597 (39.5%) discontinued treatment. Of those, 24.8% did not reach 20% effectiveness using the NRS scale. Reasons of discontinuing include lack of effectiveness 23%, side effects 16.3% and lack of compliance 0.8%, lost to follow-up 0.4%, patient choice 0.3% and unknown reasons 2%. Analysis showed that an increase in the NRS scale by 1 point at baseline time corresponded to a lower rate of discontinuation. While an increase in the NRS scale at timeline 2 or at 4 weeks corresponded with worsening spasticity and a higher non-responder rate. They concluded that Sativex is a good option for spasticity and by 4-6 weeks, patients can be reliably identified as responders or non-responders to avoid the cost burden on the healthcare system (1).
Reference
- Messina, et al, “Sativex in resistant multiple sclerosis spasticity: discontinuation study in a large population of Italian patients (SA.FE. study), Public Library of Science PLoS One, 2017, 12(8) e0180651
- Patti, et al, “Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity,” Journal of Neurology, Neurosurgery and Psychiatry, 2016, Sep., 87(9):944-951.
- Trojano, et al, “Effectiveness and tolerability of THC/CBD oromucosal spray for multiple sclerosis spasticity in Italy: first data from a large observational study,” European Neurology, 2015, 74:178-185,https://doi.org/10.1159/000441819
- Fernandez, et al, “THC:CBD in daily practice: available data from UK, Germany and Spain,”European Neurology, 2016, 75 (supp 1);1-3, https://doi.org/10.1159/000444234
Closed head injury: electroencephalographic changes in post-concussive syndrome
Virginia Thornley, M.D., Neurologist, Epileptologist
March 10, 2018
Introduction
A concussion occurs commonly as high-speed vehicular accidents become more common in today’s fast-paced world. In addition, it occurs frequently in sports-related activity such as football or boxing. The brain is composed of millions of connections and though a patient may complain of several neurological complaints, it is not often manifest in neuroimaging studies, except perhaps diffusion tensor imaging. More often than not, a good clinician can diagnose symptoms of post-concussion syndrome based on neurological symptoms and a preceding event. During injury, there is shearing of thousands of axons diffusely throughout the brain. The contrecoup effect of the injury occurring over the frontotemporal poles produces damage causing a myriad of neurological symptoms. On EEG, non-specific changes can be found corresponding with the degree of injury. There is slowing of the posterior dominant rhythm and excessive theta rhythms which eventually clears after weeks or months of recovery (1). Some patients, however, are left with recurrent symptoms such as post-concussion headaches, or dizziness or sensations of discomfort. On EEG, some studies show post-concussion symptoms correlating with bursts of theta rhythms.
EEG findings in a few minutes spanning more than 6 months
In animal studies, the EEG shows high voltage sharp waves followed by diffuse background suppression which can last a few minutes. This is followed by diffuse slowing that normalizes after 15 minutes in one study occurring between 10-60 minutes (2). Over a few hours to weeks, there are increased theta and delta rhythms and reduced ratio of theta to alpha frequencies. there was an increase in delta activity in the posterior regions. There are brief periods of reduced delta: alpha ratios. In one study called the “Belfast studies,” amnesia was evaluated in 73 patients at 24 hours and 6-week follow-up with EEG and brainstem auditory evoked potentials (BAEP). It was found that amnesia did not have EEG correlate but correlated with abnormal BAEPs suggesting amnesia was derived from brainstem dysfunction rather than cortical dysfunction. Over weeks to months, there are reduced alpha and increased delta rhythms are noted. In the Belfast studies, there was more persistent left temporal slowing, which seemed to correlate with chronic symptoms when it persisted beyond 6 months. After more than 6 months, there were increased delta activity and fewer alpha rhythms (2).
Other EEG findings in closed head injury and part-seizure like activity
In one retrospective study of 3 groups of veterans at a Veteran Affairs Medical Center, 30 comprised of normal subjects with normal EEGs, 30 had EEG’s with non-paroxysmal theta delta slowing and 38 patients had theta bursts. The patients with episodes of theta bursts seemed to have corresponding partial seizure-like clinical symptoms. Patients with head injury reported episodic symptoms across all 3 groups. These findings conclude that clinicians may want to evaluate patients for seizure-like activity in the context of closed head injury and presence of bursts of theta activity (3).
Reference
- Nuwer, et al, “Routine and quantitative EEG in mild traumatic brain injury,” Clinical Neurophysiology, 2005, Sep., 116(9):2001-2025
- Haneef, et al, “Electroencephalography and quantitative electroencephalography in mild traumatic brain injury,” Journal of Neurotrauma, 2013, Apr., 30(8):653-656.
- Roberts, et al, “Theta bursts, closed head injury, and partial seizure-like symptoms: a retrospective study,” Applied Neuropsychology, 2001, 8(3):140-7.
Peripheral neuropathy: chronic pain amelioration with cannabidiol and tetrahydrocannabidiol
Virginia Thornley, Neurologist, Epileptologist
March 8, 2018
Introduction
Chronic pain from neurological conditions such as neuropathic pain can become refractory to conventional medications. Interest is directed towards novel ways of treatment such as cannabidiol and THC which are known in animal models to be anti-inflammatory, analgesic and neuroprotective. Cannabinoids are being used more commonly in patients who have failed medical treatments and remain a viable option in the treatment of pain. Many animal models point towards mechanistic evidence that cannabidiol and THC reduce severity and frequency of pain syndromes. Cannabidiol is non-intoxicating and is an alternative form of management. With THC, the level of pain relief is higher but with that comes a higher risk of side effects at greater doses.
Cannabidiol and neuropathic pain in joints
Osteoarthritis involves inflammation, pain, and neuropathic pain. Cannabidiol was studied in rat models and its effect on pain from the joints and nerves. In end-stage osteoarthritis, cannabidiol reduced joint afferent pain. Transient joint inflammation was reduced using cannabidiol. CBD application used prophylactically demonstrated lack of development of pain and inflammation during later stages.
One study suggests that chronic neuropathic pain might be suppressed by cannabidiol through alpha 3 glycine receptors. In mice lacking these receptors, there is no cannabidiol analgesic effect. Cannabinoids are found to support glycine activity in the dorsal cell neurons in rats. This suggests that glycinergic cannabinoids may provide a potential therapeutic option in treating neuropathic pain. There is lack of psychoactive side effects or development of tolerance (1).
Cannabidiol and neuropathic pain studies
In one review of 15 randomized controlled trials against placebo with a total of 1619 patients, 13 studies consisting of 1565 patients reported a reduction of pain compared to placebo which was statistically significant. There was a frequency reduction in pain of 30%. 10 studies used nasal tetrahydrocannabinol /cannabidiol and 3 used synthetic cannabidiol while 2 used medical cannabis. They concluded that cannabidiols were marginally superior and had greater side effects than placebo. It is a treatment option for patients who have failed several lines of treatment. Some flaws that can be seen in this study is that with this study, some centers used synthetic forms of cannabinoids and others used a combination of THC and cannabidiol. Synthetic medical marijuana has a different quality compared to a product that is purely organic and made from natural materials. High doses of THC is known to cause side effects while with lower doses of THC pain relief may be obtained with fewer side effects. It is not clear how pure the products are which were being administered.
In one large study of 303 patients with peripheral neuropathy, 128 used CBD/THC spray and 118 randomized to placebo. End-point was a 30% responder rate using the PNP numerical scale 0-10. There was a substantially higher number of responders for CBD:THC but not statistically significant. Quality of life and sleep improved in those with CBD/THC nasal spray. They concluded that use of CBD/THC helped improve pain from peripheral neuropathy and there were no substantial adverse effects from the patients studied (3).
- Xiong, et al, “Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha 3 glycine receptors,” Journal of Experimental Medicine, 2012, Jun., 209(6):1121-1134.
- Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88
- Serpell, et al, “A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment,” European Journal of Pain, 2014, Aug., 18(7):999-1012.
Non-pharmacologic aspects of ALS: correlation of higher BMI with greater survival, beneficial use of cannabidiol, respiratory evaluation, exercise and anesthetic considerations
Virginia Thornley, M.D., Neurologist, Epileptologist
March 4, 2018
ALS is a progressive neurodegenerative illness which affects the lower motor neurons causing progressive weakness and eventually respiratory failure. There are currently only 2 prescription agents available for slowing the progression of the disease. Management is largely symptomatic treatment of debilitating symptoms. Much consideration is being directed towards alternative treatments such as dietary considerations and use of cannabidiol.
ALS and supplements and BMI
Based on one large review of studies, there was not enough evidence to support recommendations of Vitamin A, and C or Coenzyme Q10. For Vitamin B complex, Homocysteine, Vitamin D, there is limited data which is not enough to support or refute recommendation, more clinical trials are needed. Vitamin E may be beneficial in preclinical patients with a familial tendency. Omega-3 was found to accelerate disease progression with increased vacuolization of anterior horn cells and are deleterious in presymptomatic patients. L-Carnitine may increase survival time with a slower ALSFRS or ALS functional revised score and greater FVC volumes but more trials are needed (1). Body mass index of less than 18.5kg/m is found with less survival time, while those with a higher BMI have greater survival time. One small study suggested a high calorie, hypercaloric enteral diet was tolerable in patients but unclear if associated with better outcome in terms of survival time.
Cannabidiol as a novel therapeutic agent
Cannabidiol is known in animal models to be anti-inflammatory and anti-oxidant. In the G93A SOD-1 mouse model, it was found to slow progression of the disease and increase survival time. In a study of 13 patients, it reduced drooling, loss of appetite, pain, and spasticity.
In one study, cannabidiol was used in human gingiva-derived mesenchymal stromal cells. The transcriptomic sequence in the next generation shows a change in gene expression in ALS related genes. There was a change in the genes connected to ALS regarding oxidative stress, mitochondrial dysfunction and excitotoxicity in the human gingiva-derived mesenchymal stromal cells when treated with cannabidiol. This suggests that cannabidiol may serve as a modulatory role in the early pathogenesis of ALS (2).
Other aspects of ALS
Exercise
Studies regarding exercise showed flaws in methodology or were in small numbers. Therefore, based on available studies it is unclear if exercise benefits a patient’s long-term outcome.
Sialorrhea
Sialorrhea should be addressed. Aside from conventional medications, other options include botulinum toxin and small doses of radiation therapy delivered to the salivary glands.
Anesthesia
Anesthetic agents such as neuromuscular blockers are contraindicated in patients with ALS due to the risk of increased potassium release. In one study of 51 patients with ALS, general anesthesia was safely administered.
Pulmonary function
Pulmonary function tests are monitored every few months depending on the rapidity of the progression of the disease. Non-invasive positive pressure ventilation is used in patients with ALS with an oral or nasal mask. As force vital capacity (FVC) declines, it may be administered through a bi-level positive airway ventilation machine continuously at night(1).
References
1. Karam, et al, “Palliative care issues in amyotrophic lateral sclerosis: an evidence-based review,” American Journal of Palliative Care, 2016, Feb., 33(1):84-92.
2. Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
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