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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.

Epilepsy

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%.

Epilepsy

The deleterious effect of caffeine on epilepsy and anti-epileptic agents

Virginia Thornley, M.D., Neurologist, Epileptologist

March 25, 2019

Introduction

Caffeine (1,3,7-methylxantine) is one of the most commonly ingested stimulants in the world. It is not uncommon for someone to ingest a daily consumption of 200mg of caffeine a day. It is ubiquitously found in soda, coffee, tea, and chocolate. It is the bane of every neurologist who treats migraine and patients with insomnia. It acts as a stimulant and many people use it to counter fatigue induced by lack of sleep. Students consume it to stay up at night for late night studying in order to ace their tests the next day. Millions of people ingest caffeine on a regular basis to get through the full work day.

Caffeine worsen seizures

It has been found in animal models to lower the seizure threshold. At low doses, it reduces the efficacy of anti-epileptic agents. At more than 400mg of caffeine per day, in rodent models it is found to induce seizures. In experimental data, use of caffeine is found to lower the seizure threshold. In mouse models, at lower doses below the seizure-inducing effects, it is found to counter the protective beneficial effects of anti-epileptic agents such as carbamazepine, phenytoin, valproate, and phenobarbital as well as newer agents such as topiramate. There seems to be no effect of caffeine on newer agents such as tiagabine, oxcarbazepine or lamotrigine. There is clinical data confirming that ingesting high doses of caffeine correlates with greater number of seizures.

Dark cocoa and seizures

Dark chocolate is also found to be a proconvulsant, but little is known about the mechanism of action. Dark chocolate is rich in caffeine. In one mouse study, the effect of high intake of dark chocolate on the susceptibility of hippocampal cells to seizures was examined. Dark cocoa appeared not to affect mood behavior but improved motor coordination. However, electrophysiologic studies showed enhancement of bursts of epileptogenic potential within the dentate gyrus of the hippocampus. There was a reduction in GABA-alpha receptors suggesting that consumption of dark chocolate may alter the synaptic aspect of epileptogenesis in the temporal lobe.

These findings suggest that high consumption of caffeine especially dark cocoa can increase seizure frequency in animal models and in clinical studies. It seems to act as a proconvulsant and reduces receptors that are necessary for inhibiting seizures.

Reference

Chroscinska-Krawzyk, et al, “Caffeine and anticonvulsant potency of anti-epileptic drugs: experimental and clinical data,” Pharmacol. Rep., 2011, 63(1):12-18.
Cicvaric, et al, “Sustained consumption of cocoa-based dark chocolate enhances seizure-like events in the mouse hippocampus,” Food Funct., 2018, Mar., 1, 9(3):1532-1544.

Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

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.

Closed head injury

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.

Epilepsy

Ketogenic diet and its variants, modified Atkins diet and medium-chain triglyceride ketogenic diet and control of seizures

Virginia Thornley, M.D, Neurologist, Epileptologist

March 6, 2018

Introduction

In the past decade, different modifications of the ketogenic diet have evolved given the high intolerance to the side effects of the classic ketogenic diet and poor adherence to the strict regimen. Other variants have had similar effects in achieving control of seizures. The ketogenic diet remains a viable treatment option in patients medically refractory to conventional agents and should not be discounted as part of the armamentarium of the epileptologist or neurologist who treats patients with seizures.

Studies and classic ketogenic diet

In one small trial of febrile related seizures, 7 children with medically refractory febrile infection-related epilepsy syndrome (FIRES)were followed, 6 had less frequent and less severe seizures. On average, 4 antiepileptic agents were weaned (1). FIRES is a febrile related convulsion syndrome that starts during childhood where febrile seizures are thought to induce a cytokine reaction that occurs post-infectiously(2). In one remarkable study of 77 patients with refractory status epilepticus, only one patient had a shortened acute phase in response to ketogenic diet, 2 to anesthesia and 1 in response to IVIG, all other treatment modalities including conventional IV medications failed to shorten the acute phase (6).

In several case reports of pediatric patients in status epilepticus, the ketogenic diet was used to stop the continuous seizures. In 10 patients in one case series, all 10 pediatric patients were in continuous status epilepticus. 4 patients had focal partial status epilepticus while 6 had generalized status epilepticus. The patients had a mean duration of seizures of 18 days. The mean time for achievement of ketosis was 7 days of which 9/10 patients stopped having continuous seizures during that timeframe(4).

Modified Atkins diet and seizure control

In one study of 14 patients, the modified Atkins diet seemed to be better tolerated than the ketogenic diet. The diet was well-tolerated by 86%. 7 (50%)remained on the diet after 6 months and 36% had a 50% reduction in seizures 21% were seizure free. Strong ketosis appeared to be key in controlling the seizures (5).

Medium chain triglyceride ketogenic diet

In another variation, the medium-chain triglyceride ketogenic diet, ketones have been challenged as the substrate for control of seizures. It has been shown that medium-chain fatty acids can work through the AMPA receptors where the excitatory neurotransmitter glutamate binds, as the mechanism for controlling seizures and by changing the bioenergetics of the mitochondria (3).

https://www.epilepsy.com/

References:

Gofshteyn, et al, “Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome in acute and chronic phases,” Journal of Child Neurology, 2017, Jan.,32(1):35-40.
Gaspard, et al “New onset refractory epilepticus (NORSE) and febrile infection-related epilepsy syndromes (FIRES): state of the art and perspective,” Epilepsia, 2018, Feb., doi:10:1111/epi. 14022 (Epub ahead of print)
Augustin, et al, “mechanism of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorder,” Lancet Neurology, 2018, Jan., 17(1):84-93.
Appavu, et al, “Ketogenic diet treatment for pediatric super-refractory status epilepticus,” Seizure, 2016, Oct., 41:62-65.
Kang, et al, “Use of modified Atkins diet in intractable childhood epilepsy,” Epilepsia, 2007, Jan. 48(1):182-186.
Kramer, et al, “Febrile infection-related epilepsy syndrome(FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children,” Epilepsia, 2011, Nov., 52 (11):1956-1967.

By Virginia Thornley, M.D., Neurologist, Epileptologist
February 16, 2018

Introduction
Epilepsy is a condition involving 2 or more seizures. A seizure occurs when the electrical impulses in the brain do not cease and as a result, become recurrent resulting in excess cerebral activity. Typically, it occurs in the grey matter of the cortex, although seizures can be seen in white matter diseases such as in multiple sclerosis. Manifestations depend on the area involved. Etiologies are vast and are due to underlying structural abnormalities in the brain which may arise due to autoimmune processes, neoplastic causes (cancer), infectious diseases, traumatic etiologies or drug-induced causes. At times, there is no structural damage and may be genetic in predisposition. The seizures are similar in nature because the same underlying part of the brain is activated causing the same type of seizure. Different clinical manifestations signify a different or new area involved. If a seizure spreads to the entire brain it manifests as convulsions with clinical symptoms of loss of consciousness and whole body rhythmic jerking.

What to avoid if you have seizures

Sleep deprivation
Sleep deprivation causes seizures to occur. When the brain is well rested it performs at maximal capacity. When it performs at suboptimal conditions such as sleep deprivation or fatigue, neurological conditions become more manifest.

Missing meals
Missing meals can give rise to seizures. When you miss a meal your blood glucose or sugar is lower. This low level of sugar also known as hypoglycemia can cause seizures to occur.

Drugs
Certain medications can reduce the threshold of seizures including ciprofloxacine, certain cephalosporins and tramadol. Some psychotropic agents such as clozapine and chlorpromazine can lower the seizure threshold. It is best to avoid these agents and ensure your physicians know all your conditions. Amphetamines can also cause seizures and lower the seizure threshold.

Drugs of abuse
Some drugs are notorious for causing seizures such as cocaine. Cocaine can cause the blood vessels to constrict leading to strokes which can result in brain damage and seizures can result. Alcohol, if consumed by those with a genetic predisposition, can give rise to seizures. Excessive alcohol abuse can give rise to alcohol-induced seizures.

Other lifestyle changes

Because loss of consciousness may be involved, potential harm can occur. Avoiding heights such as ladders, cliffs, the edges of train platforms or subway platforms can help avert harm. Using the back burner while cooking help prevents burns. Avoiding driving for at least 1 year of seizure freedom can prevent accidents, some states require only 6 months. Avoiding the operation of heavy equipment such as forklifts, cranes can prevent accidents. Avoidance of swimming alone may prevent drowning, same is true with avoidance of taking baths alone.

It is an excellent idea to get a medics alert bracelet especially for young patients who may have a seizure late at night in public. After a seizure, patients may appear incoherent, disoriented and confused. It is also good to keep a list of medications.
Keeping everything clear around the patient can prevent injury.

An excellent resource for information and support is the Epilepsy Foundation. They provide a wealth of non-medical services including support and assistance in job-related issues. Some branches even have summer camps for children.