Disclosures NeuroVista, Inc. Neurologix, Inc. Scientific Advisory Board Scientific Advisory Board Dan Lowenstein UCSF Epilepsy Center Recent Advances in Neurology February 16th, 2012 Learning Objectives A series of clinical cases to review: Newly approved AEDs The increased role of genetics in patient assessment Evolving concepts in the management of status epilepticus Case 1: Duane 32 years 32 yo man with history of medically refractory epilepsy since severe TBI at age 16 2-3 focal seizures with secondary generalization per month, some tendency to cluster Initial response to DPH, now on lamotrigine, levetiracetam, locasamide (previously tried on oxcarbazepine, valproate, topiramate, zonisamide, pregabalin) Routine EEG reveals left temporal-parietal interictal spikes What would you do next? 1
Major AEDs Marketed in the U.S. Patient was admitted for video-eeg telemetry: o 8 seizures captured over 3 days, results showed bilateral independent foci o Repeat MRI (epilepsy protocol) verified bilateral neocortical changes consistent with prior traumatic brain injury What would you do next? Standard AEDs New AEDs Phenobarbital Phenytoin Primidone Carbamazepine Ethosuximide Valproate Felbamate Gabapentin Lamotrigine Topiramate Tiagabine Oxcarbazepine Levetiracetam Zonisamide Pregabalin Rufinamide Lacosamide Vigabatrin Dilantin Mysoline Tegretol, Carbatrol Zarontin Depakote, Depakene Felbatol Neurontin Lamictal Topamax Gabitril Trileptal Keppra Zonegran Lyrica Banzel Vimpat Sabril 1912 1938 1954 1974 1960 1978 1993 1994 1995 1996 1997 1999 2000 2000 2005 2008 2009 2009 Ezogabine/Retigabine (Potiga) Approved for adjunctive treatment for focal-onset seizures in adults (> 18 y.o.) Appears to work primarily by opening neuronal voltage-gated potassium channels of the KCNQ family. May also augment GABA currents. Broad spectrum of effectiveness across animal models of both focal and generalized epilepsy Clinical trial results show modest effects (similar to other agents): rate of seizure reduction exceeded placebo by 7-44; very few patients became seizure free Side effect profile also similar to other drugs, especially somnolence and dizziness (drop out rates in trials 9-50 and dose-related) Plasma levels reduced by DPH and CBZ. Caution during pregnancy animal data suggest possibility of fetal harm Case 2: Theresa 16 years 16 yo girl with history of medically refractory epilepsy since age 4 Seizure onset following confirmed viral encephalitis Combination of generalized tonic, atonic, myoclonic seizures Profound developmental delay since onset of illness Interictal EEG shows slow spike-wave complexes at 1.5-2.5 Hz Incomplete response to multiple AEDs, including lamotrigine, topiramate, felbamate and rufinamide; no response to steroids, ketogenic diet What is the diagnosis and what would you do next? 2
Clobazam (Onfi) Approved for adjunctive treatment of seizures associated with Lennox- Gastaut syndrome in patients >2yo Mechanism of action similar to 1,4-benzodiazepines: potentiates GABA and also some effect on calcium and sodium channels. However, this is a 1,5 benzodiazepine. Clobazam (Onfi) Initially approved in France in 1974 and is currently available in 100 countries, so substantial clinical data (>50 trials in >3,000 patients) FDA approval based on randomized, double-blind, placebo controlled study of LGS patients age 2-54 years; n=238; primary outcome reduction in atonic, tonic or myoclonic seizures Clobazam Diazepam The alternate structure leads to different affinity for BZP binding sites on the GABA A receptor, and is implicated in the relatively reduced sedative effects and increased anticonvulsant properties Ng and Collins. Neurotherapeutics (2007) 4:138-144 Ng and Collins. Neurotherapeutics (2007) 4:138-144 Clobazam (Onfi) Approximately 40 of patients experience transient adverse events (e.g. sedation, dizziness, ataxia) of mild-moderate severity, but sedation markedly less than other BZDs Serious adverse events appear unlikely; 5 patients (hepatic failure, SE, or mortality) in >1.1M patient years of exposure between 1994-2004 9 of patients (range 1-26) experience worsening of seizures Ng and Collins. Neurotherapeutics (2007) 4:138-144 Case 3: Devon 24 years 24 yo man with history of GTCS since age 1 15 seizures total, >50 associated with fever Initial response to DPH, now still with break-through seizures Normal birth and perinatal period, and no other significant medical history Mentions a 6 yo daughter with febrile seizures (last one 6 mo ago) and absence epilepsy Neurological exam normal EEG normal What is the Diagnosis? 3
One additional piece of info a detailed family history! What is the Diagnosis? Autosomal dominant inheritance Commonest phenotype is febrile seizures plus : o Childhood onset of multiple febrile seizures o Attacks assoc. w/fever continue beyond 6 years, +/- afebrile seizures Spectrum of phenotypes includes FS, FS+, myoclonic-astatic epilepsy Scheffer and Berkovic. Brain (1997) 120:479-490 The genetics behind GEFS+: locus heterogeneity and variable expressivity SCN1A SCN1B SCN2A GABRG2 (Adapted from Ruth Ottman, Columbia) GEFS+ CAE and FS Benign familial neonatal-infantile seizures Case 4: Ruby - 16 months Normal birth and perinatal period 8 months: 3 min convulsive seizure with focal features, cluster of 10 focal seizures over 3 days associated with fever 11 months further cluster Every 3 months recurrent seizures, often with fever, clusters and rare episodes of status Concern re development (compared to older brother) Normal MRI; interictal EEG no diagnostic features What is the Diagnosis? 4
Family History: mother had febrile convulsions o Seizures until age 11 years febrile & afebrile o Completed grade 10; borderline intellect o Pedigree: Case 4: Ruby - 16 months What is the Diagnosis? PCDH19 mutation (Protocadherin 19) Female only (X-linked dominant, male sparing) Familial or Sporadic PCDH19 female limited epilepsy Onset 6m-3yr Seizure semiology o Febrile seizures, Focal seizures, Generalized seizures o Clustered focal seizures o Status epilepticus Intellect varies from normal to severe MR Early development often normal with later regression Autistic spectrum features common Epilepsy severity: Wide range: mild->severe Importance in Management Genetic counseling Prognosis Treatment (benzos for clusters,?lvt as first-line) Case 5: Robert 20 years Intellectually disabled male brought by his caregiver Poorly controlled nocturnal seizures No useful history. GEFS+: locus heterogeneity and variable expressivity SCN1A Dravet: Severe myoclonic epilepsy of infancy (SMEI) History from mother: Normal infant Multiple febrile seizures, some long Never the same after 6m vaccination Refractory seizures, regression What is the Diagnosis? Dravet Syndrome - Missense mutation in SCN1A SCN1B SCN2A GABRG2 (Adapted from Ruth Ottman, Columbia) GEFS+ CAE and FS Benign familial neonatal-infantile seizures 5
Previously normal infant; seizures from ~ 6 mths o o Hemiclonic or generalized seizures Status epilepticus, often with fever o Frequent convulsive seizures Other seizure types by 1-4 years Development plateaus Regression MRI non-specific EEG patterns variable o o o Surprisingly normal early Generalized and focal epileptiform discharges Diffuse slowing Case 5: Robert 20 years Dravet: Recognition in adults (Jansen et al 2006) Early history is the key Characteristic evolution Tonic-clonic seizures; especially nocturnal Other seizures less prominent Ataxia, pyramidal signs Evolution of crouch gait Importance in Management Closure; relief of lifelong guilt Genetic counseling Case 5: Robert 20 years Avoid lamotrigine, carbamazepine, phenytoin Consioder VPA, levetiracetam, clonazepam, stiripentol Late change to Rx helps (Catarino et al Brain 2011) Case 6: Miranda 22 year old woman, first convulsion? Focal dyscognitive seizures for 6 months Right temporal epileptiform discharges No known antecedents, Normal MRI Treatment considerations? Han Chinese background HLA-B*1502 testing Pharmacogenetics Robust findings in prediction of carbamazepine sensitivity Strong association in Han Chinese with Stevens Johnson syndrome and HLA-B*1502 Initially described in Taiwan (Chung et al. Nature 2004) Subsequently confirmed in other SE Asian populations (Hong Kong, Thailand, India) FDA alert 6
Pharmacogenetics March 2011 Case 7: David 37 years 37 yo man brought into ED by paramedics after observed prolonged generalized T/C seizures at nightclub ED nurses have seen patient before and note seizures have been difficult to control in past Initial assessment shows patient is overall stable, routine labs normal, tox screen pending Patient received 10mg IV diazepam by paramedics in the field (clinical seizures stopped for 5min but then recurred) HLA-B*1502 screening effective in preventing SJS in Taiwan Different risk factors in other populations Case 7: David 37 years 37 yo man brought into ED by paramedics after observed prolonged generalized T/C seizures at nightclub ED nurses have seen patient before and note seizures have been difficult to control in past Initial assessment shows patient is overall stable, routine labs normal, tox screen pending Patient received 10mg IV diazepam by paramedics in the field (clinical seizures stopped for 5min but then recurred) ED physician gave 2X 4mg IV lorazepam followed by 1gm IV fos-phenytoin. Patient in coma and still having seizures What would you do next? 7
Treatment of Status Epilepticus circa 2010 Lorazepam Fosphenytoin 20mg/kg IV @ 150mg/min Phenytoin 20mg/kg IV @ 50 mg/min Consider IV valproate, levetiracetam Seizures continuing Phenytoin 7-10mg/kg IV @ 50 mg/min Additional emergent drug therapy may not be required if seizures stop and the etiology of status epilepticus is rapidly corrected Fosphenytoin 7-10mg/kg IV @ 150mg/min Seizures continuing Refractory Status Epilepticus VA Cooperative Trial: Treatment of Generalized Convulsive Status Epilepticus: Multicenter Comparison of Four Drug Regimens Treiman et al, NEJM 339:792, 1998 Comparison of 4 treatments: phenytoin, 18 mg/kg diazepam, 0.15 mg/kg followed by phenytoin, 18 mg/kg phenobarbital, 15 mg/kg lorazepam, 0.1 mg/kg Main endpoint: Success of Rx - no clinical or electrical seizure activity from 20-60 min post start of infusion VA Cooperative Trial - Treiman et al, 1998 Response 80 70 60 50 40 30 20 10 0 64.9 * 17.9 Main Results 58.2 55.8 24.2 43.6 8.3 7.7 97 39 91 33 95 36 101 26 LZ PB DZP/PHT PHT * Overt Subtle * P = 0.002 VA Cooperative Trial - Treiman et al (Unpublished Data) Responding Sequential Responses to Treatment 100 90 80 70 60 50 40 30 20 10 0 12 23 7 55 Overt SE n=384 50 28 3 5 15 Subtle SE n=134 1st agent 2nd agent 3rd agent Any other agent Rx failure 8
What is the best 2 nd -line treatment of status epilepticus? IV Valproate in generalized convulsive status epilepticus: a systematic review Brigo et al, European Journal of Neurology 2011, epub Three studies looking at IV VPA versus any 2 nd -line agent (PHT) Misra et al 2006 (n=68) Agrawal et al 2007 (n=100) Gilad et al 2008 (n=27) VPA given 20-30mg/Kg over 15-20 minutes Seizure freedom at 24hrs Risk Ratio w/95 CI Valproate? Total adverse effects Risk Ratio w/95 CI 0.01 0.1 1 10 100 Favors ctr Favors VPA 0.01 0.1 1 10 100 Favors ctr Favors VPA Levetiracetam? What is the evidence to use new intravenous AEDs in status epilepticus? Trinka E, Epilepsia 52 (suppl 8):35-38, 2011 At least 22 open case series have been published since 2007 Overall at least 707 patients have been reported What is the best 3rd-line treatment of status epilepticus? Initial doses 2,000-3,000mg over 15 min Success rate of 70 Adverse events in <10 and mild/transient 9
Meta-analysis of Treatment Response and Outcome in Refractory Status Epilepticus (Claassen et al, Epilepsia 43:146, 2002) Author Journal Publication year Patients with RSE treated with civ-acd Midazolam Propofol Pentobarbital Young GB et al. Can J Neurol Sci 1980 0 0 2 Rashkin MC et al. Neurology 1987 0 0 9 Lowenstein DH et al. Neurology 1988 0 0 8 Yanny HF et al. Anesthesia 1988 0 1 0 Crisp CB et al. Clin Pharm 1988 1 0 0 Osario I et al. Epilepsia 1989 0 0 12 Mackkenzie SJ et al. Anesthesia 1990 0 2 0 Chilvers CR et al. Anesthesia 1990 0 1 0 VanNess PC et al. Epilepsia 1990 0 0 7 Campostrini R et al. Nuova Riv Neurol 1991 0 4 0 Kumar A et al. Crit Care Med 1992 4 0 0 Yaffee K et al. Neurology 1993 0 0 17 Cortina J et al. Clin Neuropharm 1993 1 0 0 Pitt-Miller PL et al. Anesth Analg 1994 0 0 1 McBurney JW et al. J Epilepsy 1994 0 0 1 Borgeat A et al. Intensive Care Med 1994 0 1 0 Galdames PD Neurologia 1994 3 0 0 Hantson P et al. Intensive Care Med 1994 0 1 0 Parent JM et al. Neurology 1994 3 0 0 DeKrom MCTFM et al. Seizure 1995 0 1 0 Merigan KS et al. Acad Emerg Med 1995 0 1 0 Mirski MA et al. Crit Care Med 1995 1 0 0 Krishnamurthy KB et al. Epilepsia 1996 0 0 44 Stecker MM et al. Epilepsia 1998 2 8 6 Begemann M et al. Epilepsia 2000 0 1 0 Prasasad A et al. Epilepsia 2001 7 13 0 Claassen J et al. Neurology 2001 33 0 0 Total 55 35 106 Meta-analysis of Treatment Response and Outcome in RSE (Claassen et al, 2002) Midazolam (n=55) Propofol (n=35) Pentobarb (n=106) Total (n=196) Acute treatment failure 20 27 Withdrawal seizures 63 8 13 46 47 43 Breakthrough seizures 51 15 12 Ultimate Rx failure 21 20 3 24 10 Meta-analysis of Treatment Response and Outcome in RSE (Claassen et al, 2002) Midazolam (n=55) Propofol (n=35) Pentobarb (n=106) Total (n=196) Hypotension Requiring Pressors 77 Mortality 30 42 54 52 46 48 48 Rossetti & Lowenstein, Lancet Neurology 10:922-930, 2011 10
Impending and Early SE (5-30 min) Established and Early Refractory SE (30 min-48h) Late refractory SE (>48h) Conclusions: Ezogabine and clobazam are newly-introduced AEDs that provide new treatment options for refractory cases. Genetics is unraveling the cause of many epilepsies of previously unknown etiology. By reaching a specific diagnosis: Realistic treatment expectations can be set Treatment and counseling are tailored Patient and family are empowered Closure is reached Status epilepticus treatment protocols are evolving: Best 2 nd - line therapy is unknown SE that fails to respond to BZD and 2 nd agent is highly likely to be refractory to other current AEDs 11