Try a new search

Format these results:

Searched for:

in-biosketch:true

person:friedd06

Total Results:

237


Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders

Devinsky, Orrin; Cilio, Maria Roberta; Cross, Helen; Fernandez-Ruiz, Javier; French, Jacqueline; Hill, Charlotte; Katz, Russell; Di Marzo, Vincenzo; Jutras-Aswad, Didier; Notcutt, William George; Martinez-Orgado, Jose; Robson, Philip J; Rohrback, Brian G; Thiele, Elizabeth; Whalley, Benjamin; Friedman, Daniel
To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Delta9 -Tetrahydrocannabinol (Delta9 -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Delta9 -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Delta9 -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the alpha3 and alpha1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Delta9 -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
PMCID:4707667
PMID: 24854329
ISSN: 0013-9580
CID: 1013462

Anti-epileptogenic clinical trial designs in epilepsy: issues and options

Schmidt, Dieter; Friedman, Daniel; Dichter, Marc A
Although trials with anti-seizure drugs have not shown anti-epileptogenic or disease-modifying activity in humans, new compounds are on the horizon that may require novel trial designs. We briefly discuss the unique challenges and the available options to identify innovative clinical trial designs that differentiate novel anti-epileptogenic and disease-modifying compounds, preferably early in phase II, from current anti-seizure drugs. The most important challenges of clinical testing of agents for epilepsy prevention include having sufficient preclinical evidence for a suitable agent to proceed with a human trial of an anti-epileptogenic drug, and to demonstrate the feasibility of doing such a trial. Major challenges in trial design to assess agents for disease modification include the choice of suitable study parameters, the identification of a high-risk study population, the type of control, the time and duration of treatment, and a feasible follow-up period.
PMCID:3996121
PMID: 24420312
ISSN: 1878-7479
CID: 1015112

Discussing sudden unexpected death in epilepsy (SUDEP) with patients: Practices of health-care providers

Miller, Wendy R; Young, Neicole; Friedman, Daniel; Buelow, Janice M; Devinsky, Orrin
There is a lack of consensus regarding how health-care providers should address SUDEP with patients. The purpose of this study was to describe various health-care providers' practices regarding discussion of SUDEP with patients. Separate focus groups were conducted with epileptologists, neurologists, and advanced practice nurses. Across all disciplines, reasons for discussing SUDEP included Practical Accountability, Moral Accountability, Proactivity, and Reactivity. For nurses only, an additional reason was Patient Advocacy. In terms of when not to discuss SUDEP, for all disciplines, and especially the physicians, the theme Not at First emerged. Additional themes that emerged for this question included, in the case of neurologists and epileptologists, Moral Accountability and Out of Options. Ways in which SUDEP is discussed included, in all groups, Discussion and Written Materials. In addition, prevalent in all groups was the finding that procedures for discussing SUDEP with patients and families need to be somewhat standardized. Implications for practice are discussed.
PMCID:3985269
PMID: 24463308
ISSN: 1525-5050
CID: 817062

Spike-wave discharges in adult Sprague-Dawley rats and their implications for animal models of temporal lobe epilepsy

Pearce, Patrice S; Friedman, Daniel; Lafrancois, John J; Iyengar, Sloka S; Fenton, Andre A; Maclusky, Neil J; Scharfman, Helen E
Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3months of age, consistent with previous reports (Buzsaki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs. Spike-wave discharges were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7-8Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>250Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1-2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE.
PMCID:3984461
PMID: 24534480
ISSN: 1525-5050
CID: 829482

Practices of health care providers in discussing sudep with patients with epilepsy [Meeting Abstract]

Miller, W; Buelow, J; Friedman, D; Devinsky, O
Rationale: SUDEP is the most common epilepsy-related cause of death in persons with epilepsy. Evidence supports that increased SUDEP awareness and education can be translated into significantly reduced rates of epilepsy-related deaths. However, there is a lack of consensus regarding how health care practitioners should address SUDEP with patients, and a lack of evidence regarding patient educational interventions. The purpose of this study was to describe various health care providers' practices regarding discussion of SUDEP with their patients. Methods: Separate focus groups were conducted, each involving epileptologists (n=19), neurologists (n=16), or advanced practice nurses (n=8). The focus group moderator asked participants questions pertaining to reasons for and for not discussing SUDEP, and how they discuss SUDEP. Focus group data were analyzed via content analysis per each practitioner group, and comparisons were then made across groups. Data were organized via themes in order to answer the research questions. Results: Table 1 depicts final themes and definitions. Across all disciplines, reasons for discussing SUDEP included Practical Accountability, Moral Accountability, Proactivity, and Reactivity. For nurses only, an additional reason was Patient Advocacy. In terms of when not to discuss SUDEP, for all disciplines involved, and especially the physicians, the theme Not at First emerged. Additional themes that emerged for this question included, in the case of neurologists and epileptologists, Moral Accountability and Out of Options. Ways in which SUDEP is discussed included, in all groups, Discussion and Written Materials. In addition, prevalent in all groups was the finding that procedures for discussing SUDEP with patients and families need to be somewhat standardized, though the discussion should always be tailored to fit the patient's context. As well, more informative written materials should be developed. Conclusions: These results provide an initial view of the way in which var!
EMBASE:71432969
ISSN: 1535-7597
CID: 980922

Racial and ethnic differences in epilepsy classification among probands in the Epilepsy Phenome/Genome Project (EPGP)

Friedman, Daniel; Fahlstrom, Robyn
Little is known about the ethnic and racial differences in the prevalence of generalized and focal epilepsy among patients with non-acquired epilepsies. In this study, we examined epilepsy classification and race/ethnicity in 813 probands from sibling or parent-child pairs with epilepsy enrolled in the Epilepsy Genome/Phenome Project (EPGP). Subjects were classified as generalized epilepsy (GE), non-acquired focal epilepsy (NAFE), mixed epilepsy syndrome (both generalized and focal), and unclassifiable, based on consensus review of semiology and available clinical, electrophysiology, and neuroimaging data. In this cohort, 628 (77.2%) subjects identified exclusively as Caucasian/white and 65 (8.0%) subjects reported African ancestry, including subjects of mixed-race. Of the Caucasian/white subjects, 357 (56.8%) had GE, 207 (33.0%) had NAFE, 32 (5.1%) had a mixed syndrome, and 32 (5.1%) were unclassifiable. Among subjects of African ancestry, 28 (43.1%) had GE, 27 (41.5%) had NAFE, 2 (3.1%) had a mixed syndrome, and 8 (12.3%) were unclassifiable. There was a higher proportion of subjects with GE compared to other syndromes among Caucasians/whites compared to subjects with African ancestry (OR 1.74, 95% CI: 1.04-2.92, two-tailed Fisher's exact test, p=0.036). There was no difference in the rate of GE among subjects reporting Hispanic ethnicity (7.6% of total) when adjusted for race (Caucasian/white vs non-Caucasian/white; OR 0.65, 95% CI: 0.40-1.06, p>0.05). The proportion of participants with unclassifiable epilepsy was significantly greater in those of African-American descent. In a group of patients with epilepsy of unknown etiology and an affected first degree relative, GE is more common among Caucasian/white subjects than among those with African ancestry. These findings suggest there may be geographical differences in the distribution of epilepsy susceptibility genes and an effect of genetic background on epilepsy phenotype. However, the results should be interpreted with caution because of the low numbers of African-Americans in this cohort and more limited diagnostic data available for epilepsy classification in these subjects compared to Caucasians/whites.
PMCID:4176610
PMID: 24139856
ISSN: 0920-1211
CID: 666142

Designing better trials for epilepsy medications: the challenge of heterogeneity

Friedman, D; French, J A
Despite the expanding treatment options in the past two decades, a third of patients with epilepsy remain treatment resistant, and there is a continued need for new therapies. After many years of repeated success, several late-stage clinical development programs for antiseizure drugs have seen unexpected failures to demonstrate superiority of the experimental drug over placebo, which has led to a re-examination of how clinical trials are conducted in this heterogeneous and often unpredictable condition. There are numerous sources of variability in epilepsy trials that can reduce effect size. Methods to improve diagnostic accuracy and outcome assessment are needed to ensure that promising compounds have the best chance to get to patients. 2013 Future Science Ltd
EMBASE:2013649780
ISSN: 2041-6792
CID: 602882

De novo mutations in epileptic encephalopathies

Allen, Andrew S; Berkovic, Samuel F; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E; Epstein, Michael P; Glauser, Tracy; Goldstein, David B; Han, Yujun; Heinzen, Erin L; Hitomi, Yuki; Howell, Katherine B; Johnson, Michael R; Kuzniecky, Ruben; Lowenstein, Daniel H; Lu, Yi-Fan; Madou, Maura R Z; Marson, Anthony G; Mefford, Heather C; Esmaeeli Nieh, Sahar; O'Brien, Terence J; Ottman, Ruth; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K; Scheffer, Ingrid E; Sherr, Elliott H; Yuskaitis, Christopher J; Abou-Khalil, Bassel; Alldredge, Brian K; Bautista, Jocelyn F; Berkovic, Samuel F; Boro, Alex; Cascino, Gregory D; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P; Fiol, Miguel; Fountain, Nathan B; French, Jacqueline; Friedman, Daniel; Geller, Eric B; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R; Hayward, Jean; Helmers, Sandra L; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E; Knowlton, Robert C; Kossoff, Eric H; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H; McGuire, Shannon M; Motika, Paul V; Novotny, Edward J; Ottman, Ruth; Paolicchi, Juliann M; Parent, Jack M; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E; Shellhaas, Renée A; Sherr, Elliott H; Shih, Jerry J; Singh, Rani; Sirven, Joseph; Smith, Michael C; Sullivan, Joseph; Lin Thio, Liu; Venkat, Anu; Vining, Eileen P G; Von Allmen, Gretchen K; Weisenberg, Judith L; Widdess-Walsh, Peter; Winawer, Melodie R
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
PMCID:3773011
PMID: 23934111
ISSN: 1476-4687
CID: 3206122

The epilepsy phenome/genome project

Abou-Khalil, Bassel; Alldredge, Brian; Bautista, Jocelyn; Berkovic, Sam; Bluvstein, Judith; Boro, Alex; Cascino, Gregory; Consalvo, Damian; Cristofaro, Sabrina; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael; Fahlstrom, Robyn; Fiol, Miguel; Fountain, Nathan; Fox, Kristen; French, Jacqueline; Freyer Karn, Catharine; Friedman, Daniel; Geller, Eric; Glauser, Tracy; Glynn, Simon; Haut, Sheryl; Hayward, Jean; Helmers, Sandra; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi; Knowlton, Robert; Kossoff, Eric; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel; McGuire, Shannon; Motika, Paul; Nesbitt, Gerard; Novotny, Edward; Paolicchi, Juliann; Parent, Jack; Park, Kristen; Poduri, Annapurna; Risch, Neil; Sadleir, Lynette; Scheffer, Ingrid; Shellhaas, Renee; Sherr, Elliott; Shih, Jerry J; Shinnar, Shlomo; Singh, Rani; Sirven, Joseph; Smith, Michael; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen; von Allmen, Gretchen; Weisenberg, Judith; Widdess-Walsh, Peter; Winawer, Melodie
BACKGROUND: Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. RESULTS: EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. CONCLUSIONS: EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.
PMCID:5951634
PMID: 23818435
ISSN: 1740-7745
CID: 688042

A CRITICAL REVIEW OF EPILEPSY SURGERY ACROSS TWO DECADES [Meeting Abstract]

Jehi, L.; Friedman, D.; Carlson, C.; Cascino, G.; Dewar, S.; Elger, C.; Engel, J., Jr.; Knowlton, R.; Kuzniecky, R.; McIntosh, A.; O'Brien, T.; Spencer, D.; Sperling, M.; Worrell, G.; French, J.
ISI:000320472001441
ISSN: 0013-9580
CID: 654602