Epilepsy Care in Hawaii What s Important in 2016

Epilepsy Care in Hawaii What s Important in 2016 Kore Liow, MD, FACP, FAAN Hawaii Comprehensive Epilepsy and Video-EEG Center Hawaii Pacific Neuroscience Clinical Professor of Neurology University of Hawaii John Burns School of Medicine (808) 261-4476 kliow@hawaii.edu

Disclosure Kore Liow, MD Research Funding NIH, CDC, AUCD, Acorda, Novartis, Pfizer, Sunovion, Johnson and Johnson, Schwarz Biosciences, Eisai, UCB Pharma, Glaxo-SmithKline and Ortho-McNeil, Neuropace, Cyberonics, Otsuka, Intra Cellular Therapies, YKP Life Sciences, Novartis, Eli Lily Editorial/Ad Hoc Rewiever Neurology, Clinical Practice, Health Policy, Current Neuropharmacology, Epilepsia, Epilepsy and Behaviors, PIER for American College of Physicians, Pharmacoepidemiology and Drug Safety, Hawaii Journal of Medicine & Public Health

Quality Measures in Epilepsy Proper diagnosis, patient and family education, timely referrals, and access to treatment are important parts of quality epilepsy care A review of 261 patient survey responses identified gaps remaining in care delivery Opportunities for Improvement Diagnosis Challenge: Gathering of information on seizure frequency and etiology Suggests: Patient care can be improved through understanding of diagnosis Education Challenge: Patient misunderstanding of information about epilepsy Suggests: Provide situation-specific information that patients may not request Access to Treatment Challenge: Treatment success declines after first 2 AED trials Suggests: Referral to epilepsy clinic ensures all treatment options are considered Fountain NB et al. Neurology. 2015;84:1483-1487.

AAN 2014 Epilepsy Update Quality Measurement Set The AAN multidisciplinary Epilepsy Update Quality Measurement Set workgroup reviewed previous quality measures, and identified and defined new quality measures for improving epilepsy care Fountain NB et al. Neurology.2015;84:1483-1487. Quality Measures 1A 1B Seizure frequency specified at each encounter Seizure intervention specified at each encounter 2 Etiology, seizure type, and epilepsy syndrome specified at each encounter 3 Querying and intervention for side effects of ant seizure therapy specified at each encounter 4 Personalized epilepsy safety issue and education provided yearly 5 Screening for psychiatric or behavioral health disorders specified at each encounter 6 Counseling for women of childbearing potential with epilepsy yearly 7 Referral of treatment-resistant epilepsy to comprehensive epilepsy center every 2 years

Definitions Seizure : 80/100,000 per year or 9% lifetime prevalence Change in body movement, function, sensation, awareness, or behavior due to transient, hypersynchronous, abnormal electrical activity in the brain lasting seconds to minutes 1-3 Epilepsy (ICD 10 = G 40) 0.5-1% prevalence and defined by any of the following 2 : At least two unprovoked seizures occurring >24 hours apart One unprovoked seizure and a probability of further seizures Probability similar to general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years Diagnosis of an epilepsy syndrome Convulsion (ICD 10 = R 56.9) Episodes of excessive, abnormal muscle contractions, usually bilateral, which may be sustained or interrupted 1 1. Blume WT et al. Epilepsia. 2001;42:1212-1218. 2. Fisher RS et al. Epilepsia. 2014;55:475-482. 3. Institute of Medicine of the National Academies. Epilepsy Across the Spectrum: Promoting Health and Understanding. 2012.

Changes in Terminology and Concepts (2010) New Term and Concept Examples 2 Old Term and Concept Etiology 1 Genetic: genetic defect directly contributes to the epilepsy and seizures are the core symptom of the disorder Channelopathies, ion channel gene deficiency Idiopathic: presumed genetic Structural-metabolic: caused by a structural or metabolic disorder of the brain Unknown: the cause is unknown and might be genetic, structural or metabolic Cortical malformations Symptomatic: secondary to a known or presumed disorder of the brain Cryptogenic: presumed symptomatic Terminology 1,2 Terms no longer recommended Self-limited: likelihood of spontaneously remitting at a predictable age Focal seizures: seizure semiology described according to specific subjective (auras), motor, autonomic, with or without impairment of cognition Evolving to a bilateral convulsive seizure: eg, tonic, clonic, tonic-clonic Benign Complex partial Simple partial Secondarily generalized 1. Berg AT, Cross JH. Lancet. 2010;9:459-460. 2. Berg AT et al. Epilepsia. 2010;51:676-685.

ILAE Proposal for Revised Terminology for Organization of Seizures and Epilepsies (2010) Generalized Seizures 1 Arising within, and rapidly engaging, bilaterally distributed networks ICD 10: G40.3 Focal Seizures 1 Originating within networks limited to one hemisphere ICD 10: G40.0, G40.1 or G40.2 Unknown 1 Insufficient evidence to characterize as focal, generalized or both Tonic-Clonic Absence Clonic Tonic Atonic Myoclonic Myoclonic Myoclonic-atonic Myoclonic-tonic Typical Absence with special features Myoclonic absence Eyelid myoclonia Atypical Characterized according to one of more features 1,2 : Aura Motor or Autonomic Awareness/Consciousness: Altered (dyscognitive) or retained May evolve to 1 Epileptic spasms Other Bilateral convulsive seizure 1. Berg AT et al. Epilepsia. 2010;51:676-685. 2. Blume WT et al. Epilepsia. 2001;42:1212-1218.

ILAE Proposal for Revised Terminology for Organization of Seizures and Epilepsies (2010) Electroclinical Syndromes arranged by age at onset Neonatal period Benign familial neonatal epilepsy (BFNE) Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy Epilepsy of infancy with migrating focal seizures West syndrome Myoclonic epilepsy in infancy (MEI) Benign infantile epilepsy Benign familial infantile epilepsy Dravet syndrome Myoclonic encephalopathy in nonprogressive disorders Berg AT et al. Epilepsia. 2010;51:676-685. Childhood Febrile seizures plus (FS+) (can start in infancy) Panayiotopoulos syndrome Epilepsy with myoclonic atonic (previously astatic) seizures Benign epilepsy with centrotemporal spikes (BECTS) Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) Late onset childhood occipital epilepsy (Gastaut type) Epilepsy with myoclonic absences Lennox-Gastaut syndrome Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) Landau-Kleffner syndrome (LKS) Childhood absence epilepsy (CAE) Adolescence and Adulthood Juvenile absence epilepsy (JAE) Juvenile myoclonic epilepsy (JME) Epilepsy with generalized tonic clonic seizures alone Progressive myoclonus epilepsies (PME) Autosomal dominant epilepsy with auditory features (ADEAF) Other familial temporal lobe epilepsies Less specific age relationship Familial focal epilepsy with variable foci (childhood to adult) Reflex epilepsies

Manifestations of Focal Epilepsies Etiology of focal epilepsy can be 1,2 : Symptomatic/structural: known etiology Various lesions (trauma, malformations, infections, etc) 3 Causes unknown 3 Idiopathic/genetic: eg, benign rolandic epilepsy Unknown: most common Clinical manifestations of focal seizures depend on the site of onset 1 : Temporal (mesial or neocortical) Frontal Parietal Occipital 1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for Revised Classification of Epilepsies and Epileptic Syndromes. Epilepsia. 1989;30(4):389-399. 2. Berg AT et al. Epilepsia. 2010;51:676-685. 3. Besag FM, Patsalos PN. Neuropsychiatr Dis Treat. 2012:8:455-464.

Focal Temporal Lobe Seizures (aka Complex Partial Seizure) Impaired consciousness Clinical manifestations vary with site of origin and degree of spread Presence and nature of aura Automatisms Other motor activity Duration typically < 2 minutes Seizures Partial Generalized Complex Partial C-Slide 10

Focal Seizures evolving to Bilateral Convulsion (aka Secondary Generalized) Begins focally, with or without focal neurological symptoms Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases Typical duration 1-3 minutes Postictal confusion, somnolence, with or without transient focal deficit Partial Secondarily Generalized Seizures Generalized

Idiopathic Generalized Epilepsy (IGE): Continuum of Conditions Key considerations 1 A group (spectrum) of epilepsies Primary Idiopathic Genetic Onset generally early in life Relatively normal with intact neurological and mental function Responsive to treatment Often (~50%) outgrown CAE GTCA GEFS+ JME Late-onset IGE JAE 10 20 60 Age at onset (years) CAE=childhood absence epilepsy; JAE=juvenile absence epilepsy; JME=juvenile myoclonic epilepsy; GEFS+=generalized epilepsy with febrile seizures plus; GTCA=generalized tonic-clonic seizures alone. Benbadis SR. Epilepsia. 2005;46(Suppl 9):125-132.

Absence Seizures Brief staring spells ( petit mal ) with impairment of awareness 3-20 seconds Sudden onset and sudden resolution Often provoked by hyperventilation Onset typically between 4 and 14 years of age Often resolve by 18 years of age Normal development and intelligence Partial Seizures Generalized Absence

Nonepileptic Seizures 10-45% of patients referred for intractable spells Females > males Psychiatric mechanism dissociation, conversion Common association with physical, emotional, or sexual abuse Spells with non-epileptic etiology No obvious ictal eeg correlation

Whether to treat first seizure? 16-62% will recur within 5 years Relapse rate might be reduced by antiepileptic drug treatment Abnormal imaging, abnormal neurological exam, abnormal EEG or family history increase relapse risk Quality of life issues are important (ie driving) Reference: First Seizure Trial Group. Randomized Clinical Trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology 1993; 43 (3, part1): 478-483. Reference: Camfield P, Camfield C, Dooley J, Smith E, Garner B. A randomized study of carbamazepine versus no medication after a first unprovoked seizure in childhood. Neurology 1989; 39: 851-852.

AED Developments

1, 2 and 3 rd Generation AEDs

What is a Seizure? Paroxysmal depolarizing shift (PDS) Sequence of cellular events that includes a large intracellular depolarization that triggers abnormal repetitive, sustained action potentials

Physiology of Seizure Generation Seizures generally result from abnormal, excessive, and hypersynchronized neuronal discharges 1,2 This involves a disruption of balance between excitation and inhibition 3 Balance Imbalance Neuronal ~ Neuronal Excitation Inhibition When Disrupted Seizure activity may also be caused by 3 : Neuronal Excitation Neuronal Inhibitio n Increased spread and neuronal recruitment Enhanced neuronal connectivity Alteration of intrinsic neuronal properties Contributes to Seizure 2 Generation 1. McNamara JO. J Neurosci. 1994;14:3413-3425. 2. Pitkänen A, Lukasiuk K. Lancet Neurol. 2011;10:173-186. 3. Elger EE, Schmidt D. Epilepsy Behav. 2008;12:501-539.

Pathways for Seizure Propagation Seizure focus Focal Seizure Intrahemispheric commissural fibers Homotopic contralateral cortex Spread Seizure focus Secondarily Generalized Seizure = AMPA receptor In addition to their role in generating local discharges, AMPA receptors mediate the spread of excitatory signals along long pathways. Secondarily generalized seizures spread to subcortical centers via projections to the thalamus Primary Generalized Seizure Widespread thalamocortical interconnections causes rapid activation of both hemispheres Thalamus Thalamus Thalamocortical and corticothalamic transmission utilizes glutamate as neurotransmitter. The glutamate acts on AMPA receptors. Similar cortical/thalamic mechanisms come into play in secondarily generalized tonicclonic (TC) seizures and in primary generalized TC seizures. Westbrook GL. Seizures and epilepsy. In: Kandel ER et al, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; 2012.

AEDs Mechanism of Action

AED and Seizure Types Carbamazepine Gabapentin Oxcarbazepine Phenytoin Tiagabine Pregabalin (Lyrica) Lacosamide (Vimpat) Eslicarbazepine (Aptiom) Retigabine (Potiga) Brivaracetam (Briviact) Broad Spectrum AED Valproate Lamotrigine Topiramate Zonisamide Levetiracetam (Keppra) Perampanel (Fycompa) Felbamate Clobazam (Onfi) Rufinamide (Banzel) Vigabatrin (Sabril) Stiripentol (Diacomit) Ethosuximide Simple, Complex and Secondarily Generalized Seizures Focal Epilepsies Tonic-clonic Myoclonic Absence Seizures Seizures Seizures Primarily Generalized Epilepsies

AED Adverse Effects

AED Adverse Effects

When to discontinue Medications? Seizure freedom for 2 years Favorable factors Control achieved easily on one drug at low dose No previous unsuccessful attempts at withdrawal Normal neurologic exam and EEG Consider relative risks/benefits (e.g., driving, pregnancy)

Prevalence Rates of Psychiatric Disorders in Epilepsy* Disorder Epilepsy (Range), % General Population (Range), % Depression 1 11 60 2 4 Anxiety 1,2 19 45 2.5 65 Psychosis 1,3 2 8 0.5 0.7 ADHD 1,4,5 25 30 2.2 9.9 ADHD=attention deficit and hyperactivity disorder. *Table depicts the lowest and highest prevalence rates from multiple individual studies. 1. Kanner AM. Epilepsia. 2003;44(Suppl 5):3-8. 2. Weissman MM, Merikangas KR. J Clin Psychiatry. 1986;47(6 Suppl):11-17. 3. Kessler RC et al. Arch Gen Psychiatry. 1994;51:8-19. 4. Costello EJ. J Am Acad Child Adolesc Psychiatry. 1989;28:836-841. 5. Rutter M. J Child Psychol Psychiatry. 1970;11:49-62.

Postictal Symptoms of Depression Postictal Symptom Frequency (N=100) Symptoms of depression, total 43 Poor frustration tolerance 36 Anhedonia 32 Helplessness 31 Irritability 30 Self-deprecation 27 Crying bouts 26 Hopelessness 25 Guilt 23 Suicidal ideation 13 All symptoms except crying had a median duration of 24 hours Of 13 patients with suicidal ideation, 8 experienced passive and active thoughts, and 5 reported passive thought only None acted on these thoughts 10 (77%) of the 13 had a history of major depression or bipolar disorder Patients were pharmacoresistant and were taking a mean of 1.8 +/- 0.7 AEDs Kanner AM et al. Neurology. 2004;62:708-713.

Suicide in the General Population and Among Epilepsy Patients Jones JE et al. Epilepsy Behav. 2003;4(Suppl 3):S31-S38.

Women with Epilepsy Choice of AED is based on seizure type Monotherapy is best Optimize AED therapy before conception Discuss effectiveness of contraception ( by enzyme inducers, OXC and TPM > 200mg/d) Use OCP with at least 50 micrograms of ethinyl estradiol OCP LTG levels

Pregnancy and Epilepsy Guidelines Before pregnancy Re-evaluate AED therapy prior to planning pregnancy Establish baseline therapeutic levels Provide folate supplementation 0.4 4 mg/day During pregnancy Sethi NK et al. J Fam Pract. 2010;59:675-680. Monitor AED dose requirements to maximize seizure control Particularly AEDs where levels fluctuate Be cognizant of changes in PK (eg, increased clearance) Continue folate supplementation Initiate high-risk obstetric care; consider prenatal detection of malformations with more detailed level II ultrasound, particularly for those on high-risk AEDs Consider vitamin K (10 mg/day orally) supplementation starting at 36 weeks gestation Any AED should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus

Epilepsy & Bone Health Disturbance in bone health is a prevalent and serious problem in epilepsy The physiology and risk factors of AED mediated bone loss is still unknown Simple measures like lifestyle modifications, calcium and vitamin D supplements can help prevent bone loss

Why New Treatments in Epilepsy? 1 in 3 remain uncontrolled Patients (n=470) 36% 47% Seizure-free with 1st drug Seizure-free with 2nd drug Seizure-free with 3rd or multiple drugs Pharmacoresistant epilepsy 4% 13% Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

The Price of Uncontrolled Epilepsy Cognitive and memory impairment 1 Epilepsy mortality (SUDEP) highest in patients with severe, intractable epilepsy 2 Accidental injuries, some resulting in death 3 Higher depression rates 4 Reduced lifetime income 5 Increased healthcare utilization 6 1 Meador KJ. Neurology. 2002;58(suppl 5):S21-S26. 2 Lhatoo SD, et al. Postgrad Med J. 1999;75:706-709. 3 Annegers JF, et al. Epilepsia. 1998;39:206-212. 4 Epilepsy Foundation. Epilepsy Behav. 2002;3:2-3. 5 Van Ness PC. Arch Neurol. 2002;59:732-735. 6 Griffiths RI, et al. Epilepsia. 1999;40:351-358.

Epilepsy Surgery- Brain mapping

Vagal Nerve Stimulator

Responsive Nerve Stimulation: Pivotal Trial 191 subjects RCT with active vs sham stimulation After 5 th month, All received stimulation in o label 44% seizure reduction at 1 year, 50% reduction at 2 years Improvement in quality of life, Verbal ability, and memory Retention 90% at 3 years, reflecting good side effect profile, Major risks: infection and bleeding Epilepsia. 2014 Mar;55(3):432-41

Paradigm Shift in Epilepsy Care Old Goals New Goals Reduce Seizures Seizure Freedom Tolerate Side Effects No Side Effects Accept Illness Cure Illness