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  • Epilepsy Treatment Update

    for Patients Suffering

    From Seizure Clusters

    Tuesday, December 3, 2019

    National Harbor, MD

    US-P-NZ-SC-1900152 12/19

  • • The speaker today is being compensated by UCB, the sponsor of this presentation

    • The use of products in any way other than that specified by the FDA approved US Prescribing

    Information is off-label and cannot be recommended by UCB

    • Disclosures: research grants from Lundbeck, Eisai; advisory boards and consulting for Abbot,

    Alliance, Aquestive, Eisai, Lundbeck, SK Life Sciences, UCB Pharma; speaker bureau for

    Aquestive, Eisai, Sunovion, UCB Pharma

    Disclaimer!

    2

  • • Seizure clusters can be broadly

    defined as acute episodes of

    consecutive seizures that occur with

    short interictal periods and may be

    distinguishable from a patient’s typical

    seizure pattern or frequency1-4

    • No consensus definition of seizure

    clusters currently exists1

    5

    What Is a Seizure Cluster?

    Flurries Acute

    Repetitive Seizures

    Serial Seizures

    Crescendo Seizures

    Cyclical Seizures

    Recurrent Seizures

    Various Alternative Names for Seizure Clusters5

    Sources: 1. Haut SR. Curr Opin Neurol. 2015;28:143-150. 2. Mitchell WG. Epilepsia. 2996;37:S74-S80. 3. Haut SR. Epilepsy Behav. 2006;8:50-55. 4. Dreifuss FE, et al. N Engl J Med. 1998;338:1869-1875.

    5. Jafarpour S, et al. Seizure. 2019;68:9-15.

  • 6

    Burden of Seizure Clusters

    10% 55%

    48%

    34%

    52%

    41%

    Driving

    Overall mood

    Work

    Independence

    Travel

    Extracurricular activities

    Impact of Seizure Clusters on Patients’ and Their Caregivers’ Lives

    Percent of Respondents, %

    Patients (N=259) Caregivers (N=263)

    Source: Penovich PE, et al. Neurologist. 2017;22:207-214.

    Seizure clusters represent substantial burdens to patients’ their caregivers’ lives

    69%

    69%

    69%

    67%

    59%

    58%

    Driving

    Overall mood

    Work

    Independence

    Travel

    Extracurricular activities

  • 7

    Gaps in Communication About Seizure Clusters

    Healthcare Professional Community Member

    Time frame • 12-hour period for children

    • 24-hour period for adults

    • Can range from daily to once a year

    Duration • Over a relatively short period of time, usually

    less than 24 hours • Ranges from a few days to a few weeks

    Frequency • Multiple seizures, usually 3 or more • No specific number of seizures

    Note: Based on qualitative reviews and analyses of the medical literature (Healthcare Professional) and of the Epilepsy Foundation

    website (Community Member). This theme refers to the understanding or the definition of seizure clusters as understood by healthcare professionals

    or epilepsy community members.

    Source: Buelow JM, et al. Epilepsy Behav. 2016;57:16-22.

  • 8

    Average Seizure Cluster Duration

    Compared With Isolated Seizures

    Seizure Cluster

    Definition

    Mean Number of

    Seizures/Cluster

    Mean (SD) Seizure Duration, Seconds Intracluster vs Terminal

    Seizure Duration

    P Valueb Intracluster

    Seizures

    Terminal

    Seizures

    Isolated

    Seizures

    2 or more seizures

    within 2 hours 2.8 71 (78) 84 (68) 90 (92) 0.014

    2 or more seizures

    within 4 hours 3.2 78 (72) 95 (98) 86 (92) 0.011

    2 or more seizures

    within 8 hours 3.8 82 (81) 83 (69) 91 (108) 0.294

    Seizure Duration Based on Position Within a Cluster Compared With Isolated (Non-Cluster) Seizuresa

    a Data based on EEG findings from 996 seizures among 92 patients. b There were no statistically significant differences between mean terminal seizure duration and mean isolated seizure duration.

    Abbreviations: EEG, electroencephalogram.

    Source: Ferastraoaru V, et al. Epilepsia. 2016;57:889-895.

  • 9

    Seizure Clusters May Involve the Failure of

    Inhibitory Mechanisms

    Single Neurons

    Transmembrane ion gradients

    Energy failure (eg, ATP or glucose loss)

    Local Network of Neurons

    Gap junction decoupling

    Changes in neuromodulator levels

    GABAergic synaptic inhibition

    Remote Brain Regions

    GABAergic synaptic inhibition

    Substantia nigra pars reticulata Seizure onset zone

    Mechanisms Reported to Be Involved in Seizure Termination1

    Binding of benzodiazepines to the GABA receptor is believed to potentiate GABAergic inhibition2

    Abbreviations: ATP, adenosine triphosphate; GABA, γ-aminobutyric acid.

    Sources: 1. Lado FA, Moshé SL. Epilepsia. 2008;49:1651-1664. 2. Riss J, et al. Acta Neurol Scand. 2008;118:69-86.

  • 10

    Seizure Clusters and Hospitalizations

    Abbreviation: SE, status epilepticus.

    Source: Haut SR, et al. Epilepsia. 2005;46:146-149.

    73%

    59%

    0% 25% 50% 75% 100%

    Seizure clustering (N=41)

    Nonclustering (N=100)

    Patients, %

    Seizure-Related Hospitalizations Among Patients With Epilepsy (non-SE)

    P=0.006

    Note: Seizure cluster defined as 3 or more seizures in 24-hour period.

  • 11

    Seizure Clusters and Status Epilepticus

    Sources: 1. Haut SR, et al. Epilepsia. 2005;46:146-149. 2. Haut SR, et al. Epilepsia. 1999;40:1832-1834.

    39% 44%

    12% 13%

    0%

    25%

    50%

    75%

    100%

    Haut SR, et al (2005) Haut SR, et al (1999)

    P a

    ti e

    n ts

    , %

    Seizure clustering Nonclustering

    History of Convulsive Status Epilepticus Among Patients

    With and Without Seizure Clusters

    16/41 12/100

    P=0.03

    16/36 5/40

    P

  • 12

    Seizure Clusters and Mortality

    Patients with seizure clusters have a

    ~3.5-fold greater risk of death*

    compared to patients without clusters

    *95% CI, 1.25-9.78

    Abbreviation: CI, confidence interval.

    Source: Sillanpää M, Schmidt D. Brain. 2008;131:938-944.

    C u

    m u

    la ti v e

    P ro

    p o

    rt io

    n S

    u rv

    iv in

    g ,

    %

    Years After Onset of Epilepsy

    Survival With and Without Seizure Clusters

    100 –

    90 –

    80 –

    70 –

    60 –

    50 –

    40 –

    30 –

    20 –

    10 –

    0 –

    0 5 10 15 20 25 30 35 40 45

    No Seizure Clusters (N=94)

    Seizure Clusters During Treatment (N=12)

  • 13

    2.3%

    4.7%

    7.8%

    8.7%

    10.5%

    10.5%

    15.4%

    51.0%

    70.6%

    0% 25% 50% 75% 100%

    Lennox-Gastaut Syndrome

    Psychogenic nonepileptic seizure

    Drop seizure

    Tonic seizure

    Nocturnal seizure

    Febrile seizures

    Status epilepticus

    Simple partial seizure

    Complex partial seizure

    Patients with clusters (N=612) Patients without clusters (N=3504)

    Prevalence of Select Risk Factors Among Patients Aged 16 Years or Older With and Without Seizure Clusters

    Patients With Risk Factor, % Risk Factor

    History of…

    Note: All P values

  • 14

    Seizure Emergency Action Plans

    30%

    Have a seizure

    emergency plan

    In a survey of 259 patients with epilepsy…

    20%

    20%

    24%

    34%

    11%

    10%

    7%

    5%

    27%

    79%

    67%

    61%

    50%

    28%

    21%

    12%

    2%

    1%

    -100% -50% 0% 50% 100%

    Patient

    Physician

    Rescue medication

    Call doctor's office

    Visit ER

    Stay calm

    Extra/increased dose of AED

    VNS

    Visit urgent care

    Other

    Typically nothing

    Clinician Recommendations and Patient

    Responses to Seizure Clusters

    Patients (N=259), % Clinicians (N=339), %

    Most patients with seizure clusters report that they do not have a seizure emergency plan

    Abbreviations: AED, antiepileptic drug; ER, emergency room, VNS, vagus nerve stimulator.

    Source: Penovich PE, et al. Neurologist. 2017;22:207-214.

    70%

    Do not have a

    seizure emergency plan Patients

    Clinicians

  • 15

    Use of Various Benzodiazepines

    as Rescue Medication

    28.9%

    7.8% 7.0% 6.9% 5.4%

    0%

    10%

    20%

    30%

    40%

    Lorazepam (oral)

    Diazepam (rectal)

    Diazepam (oral)

    Midazolam (intranasal)

    Clonazepam (oral)

    P a

    ti e

    n ts

    , %

    Rescue Medication Use for Patients With Seizure Clusters (N=612)

    n=177 n=48 n=43 n=42 n=33

    Less than half (43.5%) of patients who experienced seizure clusters had a prescription for a rescue medication

    Source: Chen B, et al. Epilepsy Res. 2017;133:98-102.

    56.5%

    No prescription

    30.6%

    1 prescription

    10.8%

    2 prescriptions

    2.1%

    3+ prescriptions

    Prescriptions for Rescue Medications Among