Tracy Dixon-Salazar presented on emerging therapies and clinical trials in Lennox-Gastaut syndrome (LGS). There have been several new drugs approved to treat LGS, including perampanel and cannabidiol, which have shown efficacy in reducing seizure frequency. A Phase 3 clinical trial is underway to evaluate the effectiveness of fenfluramine for controlling seizures in LGS patients. While treatment options have expanded, LGS remains difficult to treat as evidence for any single highly effective therapy is still limited.
LGS Foundation 2016 Conference - Friday AfternoonLGS Foundation
Topics include: Understanding Cognitive Problems in LGS presented by Michael Chez, MD, Effective Communication presented by Patricia Moore and, National Resources for Individuals with LGS presented by Jennifer Wolfenbarger, MPH
Autoimmune Encephalitis is a particularly intimidating entity, as recognition of this disease can be delayed because diagnosis can involve ambiguous neurological symptoms, leading to detrimental long-term consequences. Auto-anti-bodies (NMDA,VGKC) can be found through serum lab tests, and magnetic resonance imaging can show inflammation, and spinal tap can reveal auto antibodies and other biomarkers in the cerebrospinal fluid that point to autoimmune encephalitis. Being that autoimmune encephalitis is a recently described diagnosis, there is still a tremendous amount of investigation to be done to discover the root causes of the disease, more anti-body essays need to be developed to discover all of the phenotypes, and the best most effective treatments need to be found to treat this mysterious disease.
LGS Foundation 2016 Conference - Friday AfternoonLGS Foundation
Topics include: Understanding Cognitive Problems in LGS presented by Michael Chez, MD, Effective Communication presented by Patricia Moore and, National Resources for Individuals with LGS presented by Jennifer Wolfenbarger, MPH
Autoimmune Encephalitis is a particularly intimidating entity, as recognition of this disease can be delayed because diagnosis can involve ambiguous neurological symptoms, leading to detrimental long-term consequences. Auto-anti-bodies (NMDA,VGKC) can be found through serum lab tests, and magnetic resonance imaging can show inflammation, and spinal tap can reveal auto antibodies and other biomarkers in the cerebrospinal fluid that point to autoimmune encephalitis. Being that autoimmune encephalitis is a recently described diagnosis, there is still a tremendous amount of investigation to be done to discover the root causes of the disease, more anti-body essays need to be developed to discover all of the phenotypes, and the best most effective treatments need to be found to treat this mysterious disease.
A review of literature about Stiripentol and Rufinamide and their role in Dravets and Lennox Gastaut Syndrome respectively. It also looks at off label indications of these two orphan drugs.
Hello readers.................!!!!!!!!!!!!!!
This is my 32nd powerpoint.....its regarding a form of childhood epilepsy, known as "LENNOX-GASTAUT SYNDROME".
It has been dealt with in the Therapeutics way, and in precise format.
Do look into it and give your reviews!!!!
Thank you!!!!
@rxvichu-alwz4uh!!!!
:) :)
Anti-NMDA receptor encephalitis: Psychiatric presentation and diagnostic chal...Pawan Sharma
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, only recently first described, is an increasingly well-recognized inflammatory encephalitis that is seen in children and adults. The highlights: Pychiatric manifestations in encephalitis and the need for the psychiatrist to a have high index of suspicion when atypical symptoms (e.g., dyskinesia, seizure, fever etc.) present in acutely psychotic patients.
CPG adaptation project for Childhood CSE.
(Dissemination and Implementation Phase)
Training session for Pediatrics resident at King Khalid University Hospital, King Saud University Medical City
Clinico pathologic case conference 2019, NeurologyPramod Krishnan
This presentation was part of the annual Clinico pathologic case conference of the Bengaluru Neurological Society for the year 2019. The case was provided by the Department of Neurology and pathology, NIMHANS, Bengaluru and i was the discussant. The clinical, radiological and investigation aspects of the case are discussed in detail and the final diagnosis based on histopathology was revealed in the end.
A review of literature about Stiripentol and Rufinamide and their role in Dravets and Lennox Gastaut Syndrome respectively. It also looks at off label indications of these two orphan drugs.
Hello readers.................!!!!!!!!!!!!!!
This is my 32nd powerpoint.....its regarding a form of childhood epilepsy, known as "LENNOX-GASTAUT SYNDROME".
It has been dealt with in the Therapeutics way, and in precise format.
Do look into it and give your reviews!!!!
Thank you!!!!
@rxvichu-alwz4uh!!!!
:) :)
Anti-NMDA receptor encephalitis: Psychiatric presentation and diagnostic chal...Pawan Sharma
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, only recently first described, is an increasingly well-recognized inflammatory encephalitis that is seen in children and adults. The highlights: Pychiatric manifestations in encephalitis and the need for the psychiatrist to a have high index of suspicion when atypical symptoms (e.g., dyskinesia, seizure, fever etc.) present in acutely psychotic patients.
CPG adaptation project for Childhood CSE.
(Dissemination and Implementation Phase)
Training session for Pediatrics resident at King Khalid University Hospital, King Saud University Medical City
Clinico pathologic case conference 2019, NeurologyPramod Krishnan
This presentation was part of the annual Clinico pathologic case conference of the Bengaluru Neurological Society for the year 2019. The case was provided by the Department of Neurology and pathology, NIMHANS, Bengaluru and i was the discussant. The clinical, radiological and investigation aspects of the case are discussed in detail and the final diagnosis based on histopathology was revealed in the end.
New Treatment Devices and Clinical Trials jgreenberger
Dr. Kathryn Davis from Penn Epilepsy Center present on new treatment devices and clinical trials for epilepsy. From the 2014 Epilepsy Education Exchange.
This presentation looks at the role of Pregabalin in refractory trigeminal neuralgia and chemotherapy induced peripheral neuropathy through illustrative case studies.
Toward Precision Medicine in Neurological Disease by David GoldsteinKnome_Inc
View the webinar at http://www.knome.com/webinar-toward-precision-medicine-neurological-disease. In this presentation, Dr. Goldstein reports progress in identifying pathogenic mutations large-scale scale studies in epilepsy, in particular focusing on identifying de novo mutations as a cause of the epileptic encephalopathies. Next he discusses how sequencing is being used to diagnose rare serious unresolved genetic conditions. Finally, Dr. Goldstein describes a number of examples in which a secure genetic diagnosis has led directly to a change in clinical management.
Nueva diana hipolipemiante: terapia anti-PCSK9
02/06/2016 18:30h Casa del Corazón, Madrid
http://antipcsk9.secardiologia.es
#antiPCSK9
Resultados de la inhibición de PCSK9: superando los límites
Dr. José Luis Zamorano Gómez, Hospital Universitario Ramón y Cajal (Madrid)
@cardioXXI
Similar to Emerging therapies in Lennox-Gastaut Syndrome (20)
Topics Include; Emerging Therapies and The Clinical Trial Process presented by Dennis Dlugos, MD, MSCE, Involvement Opportunities for LGS Families presented by John Currier, MBA and Christina SanInocencio, MS, Cannabis for LGS: Overview, Experiences and Clinical Practice presented by Heather Barnes Jackson and Jeremy Toler, MD
LGS Foundation 2016 Conference - Saturday AfternoonLGS Foundation
Topics Include: Expecting to Transition - Reframing the Journey presented by Amy Miller, MSN, MA, PCNS-BC, ACHPN, Individual Education Program (IEPs) presented by Dena Hook, Telling Your Story presented by Patricia Moore and Dietary Therapies: Creative Strategies presented by Stephanie Criteser, RD, CSP and Natalie Cummings, RD
LGS Foundation 2016 Conference - Friday MorningLGS Foundation
Topics Include: Therapies for LGS (Part One) - Pharmacological, presented by Angus A WIlfong, MD and Therapies for LGS (Part 2) - Non-Pharmacological presented by Scott Demarest, MD
Medical Technology Tackles New Health Care Demand - Research Report - March 2...pchutichetpong
M Capital Group (“MCG”) predicts that with, against, despite, and even without the global pandemic, the medical technology (MedTech) industry shows signs of continuous healthy growth, driven by smaller, faster, and cheaper devices, growing demand for home-based applications, technological innovation, strategic acquisitions, investments, and SPAC listings. MCG predicts that this should reflects itself in annual growth of over 6%, well beyond 2028.
According to Chris Mouchabhani, Managing Partner at M Capital Group, “Despite all economic scenarios that one may consider, beyond overall economic shocks, medical technology should remain one of the most promising and robust sectors over the short to medium term and well beyond 2028.”
There is a movement towards home-based care for the elderly, next generation scanning and MRI devices, wearable technology, artificial intelligence incorporation, and online connectivity. Experts also see a focus on predictive, preventive, personalized, participatory, and precision medicine, with rising levels of integration of home care and technological innovation.
The average cost of treatment has been rising across the board, creating additional financial burdens to governments, healthcare providers and insurance companies. According to MCG, cost-per-inpatient-stay in the United States alone rose on average annually by over 13% between 2014 to 2021, leading MedTech to focus research efforts on optimized medical equipment at lower price points, whilst emphasizing portability and ease of use. Namely, 46% of the 1,008 medical technology companies in the 2021 MedTech Innovator (“MTI”) database are focusing on prevention, wellness, detection, or diagnosis, signaling a clear push for preventive care to also tackle costs.
In addition, there has also been a lasting impact on consumer and medical demand for home care, supported by the pandemic. Lockdowns, closure of care facilities, and healthcare systems subjected to capacity pressure, accelerated demand away from traditional inpatient care. Now, outpatient care solutions are driving industry production, with nearly 70% of recent diagnostics start-up companies producing products in areas such as ambulatory clinics, at-home care, and self-administered diagnostics.
Leading the Way in Nephrology: Dr. David Greene's Work with Stem Cells for Ki...Dr. David Greene Arizona
As we watch Dr. Greene's continued efforts and research in Arizona, it's clear that stem cell therapy holds a promising key to unlocking new doors in the treatment of kidney disease. With each study and trial, we step closer to a world where kidney disease is no longer a life sentence but a treatable condition, thanks to pioneers like Dr. David Greene.
Deep Leg Vein Thrombosis (DVT): Meaning, Causes, Symptoms, Treatment, and Mor...The Lifesciences Magazine
Deep Leg Vein Thrombosis occurs when a blood clot forms in one or more of the deep veins in the legs. These clots can impede blood flow, leading to severe complications.
How many patients does case series should have In comparison to case reports.pdfpubrica101
Pubrica’s team of researchers and writers create scientific and medical research articles, which may be important resources for authors and practitioners. Pubrica medical writers assist you in creating and revising the introduction by alerting the reader to gaps in the chosen study subject. Our professionals understand the order in which the hypothesis topic is followed by the broad subject, the issue, and the backdrop.
https://pubrica.com/academy/case-study-or-series/how-many-patients-does-case-series-should-have-in-comparison-to-case-reports/
Defecation
Normal defecation begins with movement in the left colon, moving stool toward the anus. When stool reaches the rectum, the distention causes relaxation of the internal sphincter and an awareness of the need to defecate. At the time of defecation, the external sphincter relaxes, and abdominal muscles contract, increasing intrarectal pressure and forcing the stool out
The Valsalva maneuver exerts pressure to expel faeces through a voluntary contraction of the abdominal muscles while maintaining forced expiration against a closed airway. Patients with cardiovascular disease, glaucoma, increased intracranial pressure, or a new surgical wound are at greater risk for cardiac dysrhythmias and elevated blood pressure with the Valsalva maneuver and need to avoid straining to pass the stool.
Normal defecation is painless, resulting in passage of soft, formed stool
CONSTIPATION
Constipation is a symptom, not a disease. Improper diet, reduced fluid intake, lack of exercise, and certain medications can cause constipation. For example, patients receiving opiates for pain after surgery often require a stool softener or laxative to prevent constipation. The signs of constipation include infrequent bowel movements (less than every 3 days), difficulty passing stools, excessive straining, inability to defecate at will, and hard feaces
IMPACTION
Fecal impaction results from unrelieved constipation. It is a collection of hardened feces wedged in the rectum that a person cannot expel. In cases of severe impaction the mass extends up into the sigmoid colon.
DIARRHEA
Diarrhea is an increase in the number of stools and the passage of liquid, unformed feces. It is associated with disorders affecting digestion, absorption, and secretion in the GI tract. Intestinal contents pass through the small and large intestine too quickly to allow for the usual absorption of fluid and nutrients. Irritation within the colon results in increased mucus secretion. As a result, feces become watery, and the patient is unable to control the urge to defecate. Normally an anal bag is safe and effective in long-term treatment of patients with fecal incontinence at home, in hospice, or in the hospital. Fecal incontinence is expensive and a potentially dangerous condition in terms of contamination and risk of skin ulceration
HEMORRHOIDS
Hemorrhoids are dilated, engorged veins in the lining of the rectum. They are either external or internal.
FLATULENCE
As gas accumulates in the lumen of the intestines, the bowel wall stretches and distends (flatulence). It is a common cause of abdominal fullness, pain, and cramping. Normally intestinal gas escapes through the mouth (belching) or the anus (passing of flatus)
FECAL INCONTINENCE
Fecal incontinence is the inability to control passage of feces and gas from the anus. Incontinence harms a patient’s body image
PREPARATION AND GIVING OF LAXATIVESACCORDING TO POTTER AND PERRY,
An enema is the instillation of a solution into the rectum and sig
The Importance of Community Nursing Care.pdfAD Healthcare
NDIS and Community 24/7 Nursing Care is a specific type of support that may be provided under the NDIS for individuals with complex medical needs who require ongoing nursing care in a community setting, such as their home or a supported accommodation facility.
Empowering ACOs: Leveraging Quality Management Tools for MIPS and BeyondHealth Catalyst
Join us as we delve into the crucial realm of quality reporting for MSSP (Medicare Shared Savings Program) Accountable Care Organizations (ACOs).
In this session, we will explore how a robust quality management solution can empower your organization to meet regulatory requirements and improve processes for MIPS reporting and internal quality programs. Learn how our MeasureAble application enables compliance and fosters continuous improvement.
CRISPR-Cas9, a revolutionary gene-editing tool, holds immense potential to reshape medicine, agriculture, and our understanding of life. But like any powerful tool, it comes with ethical considerations.
Unveiling CRISPR: This naturally occurring bacterial defense system (crRNA & Cas9 protein) fights viruses. Scientists repurposed it for precise gene editing (correction, deletion, insertion) by targeting specific DNA sequences.
The Promise: CRISPR offers exciting possibilities:
Gene Therapy: Correcting genetic diseases like cystic fibrosis.
Agriculture: Engineering crops resistant to pests and harsh environments.
Research: Studying gene function to unlock new knowledge.
The Peril: Ethical concerns demand attention:
Off-target Effects: Unintended DNA edits can have unforeseen consequences.
Eugenics: Misusing CRISPR for designer babies raises social and ethical questions.
Equity: High costs could limit access to this potentially life-saving technology.
The Path Forward: Responsible development is crucial:
International Collaboration: Clear guidelines are needed for research and human trials.
Public Education: Open discussions ensure informed decisions about CRISPR.
Prioritize Safety and Ethics: Safety and ethical principles must be paramount.
CRISPR offers a powerful tool for a better future, but responsible development and addressing ethical concerns are essential. By prioritizing safety, fostering open dialogue, and ensuring equitable access, we can harness CRISPR's power for the benefit of all. (2998 characters)
6. Conclusions: Cochrane review of LGS
Trials done
• Optimum treatment for Lennox-Gastaut syndrome
remains uncertain
• No study has shown any drug to be highly efficacious in
treatment of LGS
• Lamotrigine, topiramate, felbamate and rufinamide may
be helpful as add on therapy
• Evidence base for one therapy over another limited;
each patient needs to be considered individually, taking
into account potential benefit of each therapy vs risk of
adverse effects
Hancock E, Cross H. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2013;CD003277.
7. LGS first line therapy – expert opinion
Wheless et al, J Child Neurol 2005;20s1:s1-56
9. Expectations of treatment and
treatment response in epilepsy
• Common disorder vs. rare disorder treatment
• Treatment aim is seizure freedom; >50%
reduction in seizures is considered successful
• Achieved with the first drug in 70%
• Achieved with the second drug in a further 10-
20%
10. New in treatment - Drugs
i. Novel targets
a. Neuronal synapse
b. Other sites
ii. Re-purposing drugs used in other
diseases
iii. Re-visiting drugs used for other
epilepsies or abandoned in the past
11. Site of action of
AEDs at the
neuronal
synapse
Bialer & White; Nature Reviews Drug Discovery
2010: 68-82
•Consider a new drug
which acts on a
different site
•Consider synergism
12. New sites of action
• Perampanel – post-synaptic AMPA receptors
• Cannabidiol – endocannabinoid system
13. Perampanel - highly selective, non-competitive, post-synaptic
AMPA receptor antagonist
Redrawn and adapted from [2] and [3].1Hanada et al. Epilepsia 2011;52:1331–1340;
2Rogawski MA, Löscher W. Nat Rev Neurosci 2004;5:553–564; 3Rogawski MA. Epilepsy Currents 2011;11:56–63. 13
Post-synaptic neuron
Pre-synaptic
neuron
Inhibitory interneuron
Post-synaptic excitability
AMPA receptor
Glutamate
NMDA receptor
14. % of patients achieving ≥50% reduction from baseline in seizure frequency/28
days
*P<0.05 vs placebo
**P<0.005 vs placeboN=45
N=21
N=13
N=44
N=20
ITT population: studies 304,305 &306, pooled. Double-blind phase
1Data on file, Eisai Inc; 2Rosenfeld et al. 2012 CNS; 3ISE Table 14.2. 2.2
Responder rate
14
Responderrate(%)
Overall
Population1
N=1478
Adolescents
(306)2
N=60
Adolescents
(304 & 305)2
N=83
Adolescents
(Pooled)3
N=143
N=441
N=180
N=172
N=431
N=254
N=14
N=21
N13
N=12
N=31
N=32
N=20
Adolescents
*
*
*
*
*
Krauss GL et al. Neurology 2012;78(18):1408--1415; French JA et al. Neurology 2012;79:589–596: French JA et al. Epilepsia. Epub 20
Aug 2012; 4Krauss GL et al. Epilepsia. Epub 20 Aug 2012.
15. Perampanel
• It works
• Even seizure freedom
• Even 2mg can be helpful
• Prevention of evolution to
bilateral convulsive
• Long half-life
• Introduce very slowly
Side effects
• Aggression can prevent
ongoing use
• Dizziness to be expected
• Can see overshoot
• Interaction with other drugs
– exacerbates lamotrigine
side-effects
Positive results
16. Cannabis
• One of the most widely used recreational and medicinal
drugs worldwide.
– ~150 million people smoking cannabis daily (WHO)
• Likely the first non-food plant cultivated by humans
(~8000 BC)
• Best known for its psychoactive constituent, Δ9-
tetrahydrocannabinol (‘THC’).
17. Two major cannabinoids
THC
• analgesic, anti-spasmodic,
anti-tremor, anti-
inflammatory, appetite
stimulant and anti-emetic
properties
CBD
• Anti-inflammatory, anti-
convulsant, anti-psychotic,
anti-oxidant, neuroprotective
and immunomodulatory
effects.
• Lacks the psychotomimetic
and psychotropic effects of
THC
• May alleviate some of the
potentially unwanted side-
effects of THC.
18. The endocannabinoid system
• First described in the late
1980s/early 1990s
• Endogenous ligands, receptors,
synthetic and degradation
enzymes
• Cannabinoid receptors:
– cell surface receptors
– present on a wide variety of cell
types.
– two CBR types:
• CB1:
• CB2:
• Endocannabinoids:
• anandamide
• 2-arachidonoyl glycerol
• Numerous synthetic ligands for
CB1Rs and CB2Rs have also
been developed
Anandamide 2-arachidonoyl glycerol (2-AG)
Courtesy of Dr Ben Whalley
19. Cannabidiol in childhood epilepsy
• 214 patients across 11
sites
• safety & tolerability 167
• Adverse events 79%
• 137 efficacy analysis
Dravet N=32
49% responders, 3% SF
LGS N=30
37% responders, 3% SF
Lancet Neurology e-pub ahead of print 15th December 2015
20. Conclusion: cannabidiol might reduce seizure frequency and might have an adequate
safety profile in children and young adults with highly treatment-resistant epilepsy.
Lancet Neurology 2016;15:270-
8
Safety analysis (N=162)
Somnolence 41 (25%)
Decreased appetite 31 (19%)
Diarrhoea 31 (19%)
Fatigue 21 (13%)
Convuslsion 18 (11%)
Increased appetite 14 (9%)
Status epilepticus 13 (8%)
Lethargy 12 (7%)
Weight increased 12 (7%)
Weight decreased 10 (6%)
21. AED interaction; clobazam
13/25 children CBD 2—
25mg/kg/day
Mass General Hospital,
Boston
Norclobazam increased in
12/13
Side effects 10/13
• Drowsiness 6
• Ataxia
2
• Irritability 2
• Restless sleep 1
• Urinary retention 1
• Tremor 1
• Loss of appetite 1
Geffrey et al, Epilepsia, 56(8):1246–1251, 2015
23. Where are we now with cannabinoids?
Efficacy
• 50% responders, 3%
seizure free
– Devinsky, Lancet
Neurology 2015
– Friedman, NEJM 2015
Emerging experience
• Side-effects
– Somnolence
– Decreased appetite
– Diarrhoea
– Tremor
• Interaction with clobazam
– Geffrey, Epilepsia 2015
• Abnormal liver function
• Up to 25-50 mg/kg/day
• Tolerance
24. Neonatal epileptic
encephalopathies
1
month
4
months0 1 year
6
months
Epilepsy limited to females with
mental retardation
PCDH19
Early onset epileptic
encephalopathy
STXBP1, CDKL5, ARX,
PLCB1, SLC25A22,
SPTN1, SLC19A3
Early myoclonic
encephalopathy
Infantile epileptic encephalopathies
KCNQ2
encephalopathy
Epilepsy in infancy with migrating
focal seizures
SCN1A, KCNT1, PLCB1
Dravet syndrome
SCN1A
West syndrome
CDKL5 in girls
ARX in boys
Copy Number Variants 8%
Genetic basis of the Early Infantile Epileptic Encephalopathies
Slide courtesy of Prof Helen Cross
25. Repurposing & precision therapies &
re-visiting
Loss of function mutations Gain of function mutations
• SCN2A and SCN8A
• Use sodium channel
blockers
– High dose phenytoin and
carbazepine
• SCN1A
– Avoid sodium channel
blockers
– CBD
– Revisting ‘old’ drugs
26. SCN1A and LGS - re-visiting
fenfluramine
• High doses used for obesity, heart valve thickening, taken off
market
• Effective for self-induced/photosensitive seizures
– Boel, Neuropediatrics 1996
• Effective in Dravet syndrome
– Ceulemans, Epilepsia 2012
• Mechanism uncertain: stimulates serotonin; 5HT2A agonist
• Randomised placebo control trial for LGS in Europe and US
28. Summary
• Treatment options for LGS continue to expand
– Perampanel, Epidiolex (CBD), Fenfluramine trials
– Other drugs in earlier stages of development
– Using specific drugs to treat specific genetic forms of
epilepsy continues to progress
30. Fenfluramine (ZX008) LGS Phase 3 Study
L G S F a m i l y & P r o f e s s i o n a l
C o n f e r e n c e : E m e r g i n g T h e r a p i e s
& C l i n i c a l T r i a l s
D r . K e l l y K n u p p
N o v e m b e r 2 0 1 7
31. 31
Background: Fenfluramine in Epilepsy & LGS
• Timeline:
– Early 1980’s – initial case reports on potential utility for epilepsy
– 2012- Reported effectiveness in a cohort of DS patients in Belgium
– 2016 – Zogenix Initiates Phase III DS Program
– 2016 – AES poster presentation – Pilot LGS Open-Label Study
• Median 50% reduction in Major Motor Seizure Frequency
– 54% with > 50% reduction
• The most common treatment-emergent AEs reported:
– Decreased appetite (n=3; 23%)
– Decreased alertness/fatigue (n=3; 23%)
– Insomnia (n=2; 15%)
– 2017 – Zogenix to Initiate Phase III LGS Study
32. 32
ZX008 LGS Phase III: Study Design
• Part 1 – Placebo Controlled
• Part 2 – Open Label
Long-Term Safety
12 Months
All on Active Study Drug
Baseline
4 weeks
Titration
2 weeks
Maintenance
12 weeks
Transition to
Part 2 or Taper
2 weeks
Randomize
Placebo
ZX008
0.8 mg/kg/d
ZX008
0.2 mg/kg/d
33. 33
ZX008 LGS Phase III: Key Inclusion Criteria
• Male or female, age 2 to 35 years
• Diagnosis of Lennox-Gastaut syndrome, where seizures that result in
drops are not completely controlled by current antiepileptic
treatments (Add-on Treatment)
– If on Ketogenic Diet or VNS therapy, must be stable for 4 weeks prior to
screening
• Subjects must meet all of the following 4 criteria:
– Onset of seizures at 11 years of age or younger
– Multiple seizure types, including countable motor seizures that result in
drops
– Abnormal cognitive development
– Characteristic EEG Pattern consistent with LGS
• Seizure Frequency Prior to Screening
– must have had at least 8 drop seizures in the last 4 weeks prior to inclusion
• parent/guardian report to investigator or investigator medical notes
34. 34
ZX008 LGS Phase III: Key Exclusion Criteria
• Subject only has drop seizures in clusters, where individual
seizures cannot be counted reliably.
• Current or past history of cardiovascular or cerebrovascular
disease or pulmonary hypertension
• Positive result on urine tetrahydrocannabinol (THC) Panel or
whole blood cannabidiol (CBD) at the Screening Visit
• Subject does not have a reliable caregiver who can provide
seizure diary information throughout the study.
35. 35
Study Site Locations - 2017
Phillips
Tacoma, WA
Zupanc
Orange Co, CA
Perry
Fort Worth, TX
Laux
Chicago, IL
Thiele
Boston, MA
Marsh
Philadelphia, PA
Sullivan
San Francisco, CA
Devinsky
Livingston, NJ
Miller
Miami, FLTalwar
Tucson, AZ
Connolly
Vancouver, BC
Joshi
Aurora, CO
Sweney
Salt Lake City, UT
Smith
St. Paul, MN
Davis
Orlando, FL
Flamini
Atlanta, GA
Burdette
Grand Rapids, MI
Renfroe
Gulf Breeze, FL
Expected to be open by end of the year
36. 36
Additional Information
• If you are interested in participating or would like more
information:
–ClinicalTrials.gov – will be posted soon
–Contact Betty Quarles, Associate Director, Clinical
Operations
• 510-550-8308
• bquarles@Zogenix.com
• Medinfo@zogenix.com
41. Three Patients all LGS
• Etiology: All different, one had encephalitis at
3 months with prolonged status epilepticus.
One has a mutation in the SCN2A gene. One
has no known cause.
• They all have seizures that are called
generalized, that means both sides of the brain
seem to have simultaneous discharges.
• This is a key feature of LGS-generalize EEG
abnormalities.
44. Decrease in Drop Seizures Following CC
• Graham D
Graham D et al. 2017
45. Development
• Adults do not develop LGS.
• Infants and young children develop LGS.
– There often is a progression of seizure types with
age.
– Young infants will have focal or infantile spasms
then go on to develop the key generalized seizures
of LGS, Tonic and Atonic seizures.
– Why does the developing brain develop this
aberrant synchrony?
46. Multiple Etiologies
• Genetic-25-50%
• Lesion Genetic- 10-20%
• Lesion injury (early in life)-25%
• Somehow a change in the brain, often the
cortex that is present early in life and possibly
only on one side can cause the whole brain or
at least both sides to have a discharge
simultaneously.
50. Take home points
• LGS is due to a usurping of the normal
networks that develop in childhood.
Abnormalities in the cortex in one or many
sites can drive the aberrant connections. The
network becomes “to linked” and that causes
seizures and cognitive problems.
51. So what to do?
• If there is a cortical driver take it out.
– Clear from TS and focal developmental disorders
and the first patient I showed with encephalitis you
can find cortical drivers in the network and
removing them can improve seizures and
(cognition?).
• Earlier you take it out the better (probably)
• What about manipulating the network? A
work in progress?
52. Network Modulation
• Electrical-Deep Brain Stimulation- Unclear still
what target though the thalamus is the most
often targeted site.
• Genetic- There are at least 40 companies
currently in phase 1-2 trials for gene
replacement. Though rare in brain disorders,
at least 2 are showing success.
53. Epilepsy Team
• Neurologists
• Nurses
Neurosurgeons
Dieticians
• Neurodiagnostic
Technologist
• Genetic Counselor
• Study
Coordinators
Editor's Notes
Also tell why I’m so passionate about epi/epi genetics
The final common pathway in synaptic neurotransmission – post-synaptic glutamate receptors – is targeted by Fycompa,1 but not targeted selectively by any other AED.2,3
References
Hanada T et al. Perampanel: A novel, orally active, non-competitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 2011;52:1331–1340.
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004;5:553–564.
Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Currents 2011;11:56–63.
In the pooled dataset, the responder rate in perampanel treatment groups (4, 8 and 12 mg) was significantly greater than in the placebo
Results in adolescents were similar to results in the overall population – in study 306 (low-dose),2 studies 304 and 305 pooled (high dose)2 and all 3 studies pooled3 (statistical comparisons not made, because of small sample size).
References
Data on file, Eisai Inc. ISE Table 41.1 (Ad hoc).
Rosenfeld et al. Efficacy and safety of adjunctive perampanel in the subgroup of adolescent patients with refractory, partial-onset seizures included in the 3 double-blind, placebo-controlled, phase 3 clinical trials. Poster presented at Child Neurological Society meeting 2012.
Data on file, Eisai Inc. ISE Table 14.2.2.2
Phytocannabinoids, Endocannabinoids and Synthetic Cannabinoids
The term "cannabinoid" has different meanings. Cannabinoids were originally defined as a group of C21 compounds uniquely produced by the cannabis plant. Subsequent development of synthetic cannabinoids and the discovery of natural cannabinoids in the body (“endocannabinoids”) has somewhat blurred this definition. The molecules derived from the plant itself are therefore now termed “phytocannabinoids”. Synthetic cannabinoids are those which have been man-made.
Phytocannabinoid Compounds
Naturally occurring cannabis (Cannabis sativa) contains a group of chemical compounds not found in other plants known as cannabinoids. Over 60 different cannabinoids have so far been identified but the role and importance of many of these has yet to be fully understood. GW is researching a large number of cannabinoids, each of which has different effects and applications.
Currently available cannabinoids include:
D9-THC (Delta-9 Tetrahydrocannabinol)
D8-THC(Delta-8 Tetrahydrocannabinol)
THCA(Tetrahydrocannabinol – Acid)
THCV(Tetrahydrocannabivarin)
THCVA(Tetrahydrocannabivarin – Acid)
CBD(Cannabidiol)
CBDA(Cannabidiol - Acid)
CBDV(Cannabidivarin)
CBDVA(Cannabidivarin - Acid)
CBC(Cannabichromene)
CBG(Cannabigerol)
CBGA(Cannabigerol – Acid)
CBGV(Cannabigerovarin)
CBN(Cannabinol)
CBNV(Cannabinovarin)
Natural Cannabinoids (endocannabinoids)
The discovery of the cannabinoid receptors led to the demonstration of the existence of the body’s own natural cannabinoids (endocannabinoids), the most important of which are arachidonoyl-ethanolamide (anandamide), 2-arachidonoyl glycerol (2-AG) and arachidonyl glyceryl ether (noladin ether). This remains a highly dynamic field. There is evidence that anandamide can serve as a neuromodulator or neurotransmitter on its own or in conjunction with inactive precursors in what has been dubbed the “entourage effect”.
11 year old boy tonic clonic seizure.
Shows bifrontal spike and wave and with decrement.