Kamil Detyniecki

Imaging synaptic density in the living human brain

Synaptic density in the living human brain was measured with positron emission tomography and a synaptic vesicle glycoprotein 2A tracer. Seeing synapses When synapses “fire,” information is transmitted from one neuron to another. Although many neurological and psychiatric diseases are characterized by misfiring synapses, there is currently no way to visualize healthy or aberrant neuronal connections in the living brain—tissues would need to be sampled, which is an invasive and often unwanted procedure. Finnema and colleagues developed a noninvasive approach to “see” human synapses by using an imaging agent that targets the synaptic vesicle glycoprotein 2A (SV2A). PET imaging allowed the authors to visualize synaptic density in both healthy and epileptic human brains in living patients. In the brains with epilepsy, synaptic density was asymmetric—consistent with damage to certain brain regions. This method opens doors to routine monitoring of the brain in patients with various neurological diseases, where synaptic loss or dynamic changes in density could provide clues to prognosis. Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer’s disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand [11C]UCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that [11C]UCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, [11C]UCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.

Impaired consciousness in epilepsy investigated by a prospective responsiveness in epilepsy scale (RES)

Purpose:  Impaired consciousness in epileptic seizures has a major negative impact on patient quality of life. Prior work on epileptic unconsciousness has mainly used retrospective and nonstandardized methods. Our goal was to validate and to obtain initial data using a standardized prospective testing battery.

A Prospective Study of Loss of Consciousness in Epilepsy Using Virtual Reality Driving Simulation and Other Video Games

Patients with epilepsy are at risk of traffic accidents when they have seizures while driving. However, driving is an essential part of normal daily life in many communities, and depriving patients of driving privileges can have profound consequences for their economic and social well-being. In the current study, we collected ictal performance data from a driving simulator and two other video games in patients undergoing continuous video/EEG monitoring. We captured 22 seizures in 13 patients and found that driving impairment during seizures differed in terms of both magnitude and character, depending on the seizure type. Our study documents the feasibility of a prospective study of driving and other behaviors during seizures through the use of computer-based tasks. This methodology may be applied to further describe differential driving impairment in specific types of seizures and to gain data on anatomical networks disrupted in seizures that impair consciousness and driving safety.

Rates and predictors of patient-reported cognitive side effects of antiepileptic drugs: An extended follow-up

PURPOSE Impact of adverse effects of antiepileptic medications (AEDs) such as cognitive side effects (CSEs) on quality of life can be significant. Here we provide an extended follow-up to our earlier study to investigate the predictors of cognitive side effects (CSEs) and relative frequency of CSEs among all commonly used AEDs. METHODS In this retrospective study, medical records of 2860 adult outpatients with epilepsy seen at our center over a 12-year period who had taken one or more AEDs were examined. RESULTS Of 2860 patients, 15% had intolerable CSEs attributed to at least one AED. On multiple logistic regression analysis, independent predictors of intolerable CSEs were lack of intellectual disability and polytherapy. In polytherapy, we found that intolerable CSEs were most commonly seen with topiramate (22.8% of 281 patients), significantly more than with almost all other AEDs. This was true in monotherapy as well, with significantly more intolerable CSEs occurring with topiramate (18.5% of 54 patients) than with gabapentin, carbamazepine, lamotrigine, and levetiracetam. AEDs with consistently low rates of ICSEs included gabapentin, pregabalin, lamotrigine, levetiracetam and carbamazepine. CONCLUSION These data can help facilitate selection of AEDs.

Testing for minimal consciousness in complex partial and generalized tonic-clonic seizures

Impaired consciousness in epilepsy has a major negative impact on quality of life. Prior work suggests that complex partial seizures (CPS) and generalized tonic–clonic seizures (GTCS), which both cause loss of consciousness, affect similar frontoparietal networks. Milder involvement in CPS than in GTCS may spare some simple behavioral responses, resembling the minimally conscious state. However, this difference in responses has not been rigorously tested previously. During video–electroencephalography (EEG) monitoring, we administered a standardized prospective testing battery including responses to questions and commands, as well as tests for reaching/grasping a ball and visual tracking in 27 CPS (in 14 patients) and 7 GTCS (in six patients). Behavioral results were analyzed in the ictal and postictal periods based on video review. During both CPS and GTCS, patients were unable to respond to questions or commands. However, during CPS, patients often retained minimally conscious ball grasping and visual tracking responses. Patients were able to successfully grasp a ball in 60% or to visually track in 58% of CPS, and could carry out both activities in 52% of CPS. In contrast, during GTCS, preserved ball grasp (10%), visual tracking (11%), or both (7%), were all significantly less than in CPS. Postictal ball grasping and visual tracking were also somewhat better following CPS than GTCS. These findings suggest that impaired consciousness in CPS is more similar to minimally conscious state than to coma. Further work may elucidate the specific brain networks underlying relatively spared functions in CPS, ultimately leading to improved treatments aimed at preventing impaired consciousness.

Cosmetic side effects of antiepileptic drugs in adults with epilepsy

OBJECTIVE Cosmetic side effects (CSEs) such as weight gain and alopecia are common, undesirable effects associated with several AEDs. The objective of the study was to compare the CSE profiles in a large specialty practice-based sample of patients taking both older and newer AEDs. METHODS As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 1903 adult patients (≥16years of age) newly started on an AED. Cosmetic side effects were determined by patient or physician report in the medical record and included acne, gingival hyperplasia, hair loss, hirsutism, and weight gain. We compared the overall rate of CSEs and intolerable CSEs (ICSEs-CSEs that led to dosage reduction or discontinuation) between different AEDs in both monotherapy and polytherapy. RESULTS Overall, CSEs occurred in 110/1903 (5.8%) patients and led to intolerability in 70/1903 (3.7%) patients. Weight gain was the most commonly reported CSE (68/1903, 3.6%) and led to intolerability in 63 (3.3%) patients. Alopecia was the second most common patient-reported CSE (36/1903, 1.9%) and was intolerable in 33/1903 (1.7%) patients. Risk factors for CSEs included female sex (7.0% vs. 4.3% in males; p<0.05) and any prior CSE (37% vs. 2.9% in patients without prior CSE; p<0.001). Significantly more CSEs were attributed to valproic acid (59/270; 21.9%; p<0.001) and pregabalin (14/143; 9.8%; p<0.001) than to all other AEDs. Significantly less CSEs were attributed to levetiracetam (7/524; 1.3%; p=0.002). Weight gain was most frequently associated with valproic acid (35/270; 13.0%; p<0.001) and pregabalin (12/143; 8.4%; p<0.001). Hair loss was most commonly reported among patients taking valproic acid (24/270; 8.9%; p<0.001). Finally, gingival hyperplasia was most commonly reported in patients taking phenytoin (10/404; 2.5%; p<0.001). Cosmetic side effects leading to dosage change or discontinuation occurred most frequently with pregabalin and valproic acid compared with all other AEDs (13.3 and 5.6% vs. 2.3%; p<0.001). For patients who had been on an AED in monotherapy (n=677), CSEs and ICSEs were still more likely to be attributed to valproic acid (30.2% and 17.1%, respectively) than to any other AED (both p<0.001). SIGNIFICANCE Weight gain and alopecia were the most common patient-reported CSEs in this study, and weight gain was the most likely cosmetic side effect to result in dosage adjustment or medication discontinuation. Particular attention should be paid to pregabalin, phenytoin, and valproic acid when considering cosmetic side effects. Female patients and patients who have had prior CSE(s) to AED(s) were more likely to report CSEs. Knowledge of specific CSE rates for each AED found in this study may be useful in clinical practice.

Impaired consciousness in partial seizures is bimodally distributed

Objective: To investigate whether impaired consciousness in partial seizures can usually be attributed to specific deficits in the content of consciousness or to a more general decrease in the overall level of consciousness. Methods: Prospective testing during partial seizures was performed in patients with epilepsy using the Responsiveness in Epilepsy Scale (n = 83 partial seizures, 30 patients). Results were compared with responsiveness scores in a cohort of patients with severe traumatic brain injury evaluated with the JFK Coma Recovery Scale–Revised (n = 552 test administrations, 184 patients). Results: Standardized testing during partial seizures reveals a bimodal scoring distribution, such that most patients were either fully impaired or relatively spared in their ability to respond on multiple cognitive tests. Seizures with impaired performance on initial test items remained consistently impaired on subsequent items, while other seizures showed spared performance throughout. In the comparison group, we found that scores of patients with brain injury were more evenly distributed across the full range in severity of impairment. Conclusions: Partial seizures can often be cleanly separated into those with vs without overall impaired responsiveness. Results from similar testing in a comparison group of patients with brain injury suggest that the bimodal nature of Responsiveness in Epilepsy Scale scores is not a result of scale bias but may be a finding unique to partial seizures. These findings support a model in which seizures either propagate or do not propagate to key structures that regulate overall arousal and thalamocortical function. Future investigations are needed to relate these behavioral findings to the physiology underlying impaired consciousness in partial seizures.

Consciousness of seizures and consciousness during seizures: Are they related?

Recent advances have been made in the network mechanisms underlying impairment of consciousness during seizures. However, less is known about patient awareness of their own seizures. Studying patient reports or documentation of their seizures is currently the most commonly utilized mechanism to scientifically measure patient awareness of seizures. The purpose of this review is to summarize the available evidence regarding the accuracy of patient seizure counts and identify the variables that may influence unreliable seizure reporting. Several groups looking at patient documentation of seizures during continuous EEG monitoring show that patients do not report as many as 50% of their seizures. These studies also suggest that seizures accompanied by loss of consciousness, arising from the left hemisphere or the temporal lobe, or occurring during sleep are associated with significantly reduced reporting. Baseline memory performance does not appear to have a major influence on the accuracy of seizure report. Further prospective studies using validated ictal behavioral testing as well as using correlation with newer electrophysiological and neuroimaging techniques for seizure localization are needed to more fully understand the mechanisms of underreporting of seizures. Better methods to alert caregivers about unrecognized seizures and to improve seizure documentation are under investigation.

Marijuana Use in Epilepsy: The Myth and the Reality

Marijuana has been utilized as a medicinal plant to treat a variety of conditions for nearly five millennia. Over the past few years, there has been an unprecedented interest in using cannabis extracts to treat epilepsy, spurred on by a few refractory pediatric cases featured in the media that had an almost miraculous response to cannabidiol-enriched marijuana extracts. This review attempts to answer the most important questions a clinician may have regarding the use of marijuana in epilepsy. First, we review the preclinical and human evidences for the anticonvulsant properties of the different cannabinoids, mainly tetrahydrocannabinol (THC) and cannabidiol (CBD). Then, we explore the safety data from animal and human studies. Lastly, we attempt to reconcile the controversy regarding physicians’ and patients’ opinions about whether the available evidence is sufficient to recommend the use of marijuana to treat epilepsy.

Cannabidiol for epilepsy: trying to see through the haze

The ultimate goal of epilepsy treatment is to abolish seizures, minimise medication side-eff ects, and maximise quality of life. Despite the availability of more than 30 antiepileptic drugs, achievement of this goal is still not possible for roughly one in three patients with epilepsy. In view of the substantial psychological and social burden that epilepsy brings to everyday life, it is not surprising that patients and families keep looking for alternative treatments. Although anecdotal reports regarding marijuana use for epilepsy exist from the past 150 years, interest in this area increased in 2013, after reports of children who experienced benefi t from cannabidiol-rich extracts of cannabis. The news quickly spread through social media, prompting many patients and families in the USA to relocate to a state such as Colorado, where medical marijuana was legal and readily available at that time. Following initiatives from aff ected individuals and their families, there has been an increased interest in research focusing on cannabidiol, the non-psychoactive compound of the cannabis plant, which has been shown to have anticonvulsant properties in preclinical seizure models. Although the anticonvulsant mechanism of cannabidiol remains unclear, the compound does not act via the cannabinoid receptors CB1 and CB2. Retrospective case series have described parental experience with the use of artisanal cannabis preparations high in cannabidiol in patients with refractory disease. In view of the uncontrolled and potentially biased results of these case series, professional associations such as the American Academy of Neurology and the American Epilepsy Society are calling for higher quality research. In The Lancet Neurology, Orrin Devinsky and colleagues present fi ndings from the fi rst large-scale prospective multicentre study examining the use of cannabidiol in patients with treatment-resistant epilepsy. 162 children and young adults (aged 1–30 years) with refractory epilepsy of multiple types were given a 99% purifi ed oil-based form of cannabidiol as an add-on treatment to their existing antiepileptic drugs. Seizure frequency and adverse events were monitored for a minimum of 12 weeks. For the primary effi cacy measure, only seizures with observable motor components were counted. Most patients were able to tolerate the treatment, although mild to moderate adverse events were common (somnolence in 25%, decreased appetite in 19%, diarrhoea in 19%, fatigue in 13%, and convulsion in 11% of the 162 patients); only fi ve (3%) patients discontinued treatment due to an adverse event. Nine (6%) patients had status epilepticus, which would not be unexpected in this population with highly refractory disease. Although other serious adverse events were reported, it is unclear whether they were truly caused by cannabidiol or by concomitant antiepileptic drugs, or if they simply refl ect the expected high morbidity of this population; only a controlled trial can address these uncertainties. Overall, this study confi rms previous fi ndings that cannabidiol seems to be safe, at least for short-term use. With regards to effi cacy, cannabidiol resulted in a median reduction in monthly motor seizures of 36·5% (IQR 0–64·7), similar to the effi cacy of commonly used antiepileptic drugs in a refractory population. Although the drug had slightly greater effi cacy in a subgroup of patients with Dravet or Lennox–Gastaut Syndromes, this fi nding was not signifi cant. Only fi ve (4%) patients were free of all motor seizures for the 12 week study period, and only two (2%) were free of all seizure types. Assessment of the true effi cacy of cannabidiol is challenging, particularly in an open-label uncontrolled study such as Devinsky and colleagues’, in which the Lancet Neurol 2016