Epilepsy at the Edges. Robert F Leroy MD Texas Epilepsy Group Neurological Clinic of Texas, PA

Transcription

1 Epilepsy at the Edges Robert F Leroy MD Texas Epilepsy Group Neurological Clinic of Texas, PA

2 Epilepsy at the Edges What is the current thinking about the diagnosis and treatment of epilepsy? What will be the treatments in the future?

3 What Is Epilepsy? Epilepsy is one of the most common disorders of the nervous system It affects people of all ages, races, and ethnic backgrounds 2007 National Epilepsy Walk More than 3 million Americans of all ages are living with epilepsy Each year, approximately 200,000 Americans are diagnosed with epilepsy Epilepsy can develop at any time of life, but it is more common for it to begin in young children and in people 60 and older Reference: Epilepsy Foundation. Epilepsy and seizure statistics. Available at: Accessed June 12, K

4 Definitions What is a seizure? A seizure is a paroxysmal, brief abnormal behavior due to a sudden disruption of orderly communication among nerve cells in the brain due to hypersynchronous discharging of nerve cells What is epilepsy? Epilepsy is not a single disease Epilepsy is a group of related disorders characterized by recurrent spontaneous seizures K

5 Prevalence of Epilepsy With Age Prevalence/ Epilepsy affects 50 million people worldwide and 2.5 million in the US US (Minnesota) Finland Italy Iceland Age (Years) Adapted from Hauser. In: Epilepsy: A Comprehensive Textbook ; Epilepsy Foundation. Available at: Accessed June 15, 2005; World Health Organization. Available at: a Accessed June 23, 2005.

6 Higher Incidence of Epilepsy in the Young and Elderly Incidence/100, Sweden Italy Iceland US (Minnesota) Finland Age (Years) Adapted from Hauser. In: Epilepsy: A Comprehensive Textbook

7 Current Concept 1 Epilepsy is common Epilepsy is a disease that starts in childhood and adolescence Epilepsy is a disease that starts in the elderly

8 How does Epilepsy develop? Multiple pathophysiologies Recognizable patterns of development

9 Risk Factors Predisposing Patients to Epilepsy Ascending Order of Risk Head injury Stroke CNS neoplasm CNS infection CNS degenerative diseases Multiple sclerosis Substance abuse These risk factors result in 34.5% of epilepsy cases; in the majority of cases the cause is unknown Hesdorffer,, Verity. In: Epilepsy: A Comprehensive Textbook ; Hauser. In: Epilepsy: A Comprehensive Textbook

10 Patterns of Development Insult quiescence seizures Age of gene expression Acute Insult with network alteration Foreign Epileptic Tissue

11 Insult Quiescence Seizure Kindling Model Subconvulsive brain stimulation occurring repetitively Stimulation leads to seizure at time of stimulation Stimulation leads to spontaneous seizures Stimulation leads to more intense and widespread seizures Head Trauma, Stroke, TLE with MTS

12 Age of Gene Expression Genetic expression or lack of expression of specific genome with the phenotypic expression of seizures Channelopathies Neurotransmitters Age Related Epilepsy Syndromes Infancy: Benign Febrile Convulsions Childhood: Childhood Absence Epilepsy Adolescence: Juvenile Myoclonic Epilepsy

13 Acute Insult with Network Alterations Disruption of the cortical inhibitory feedback Lack of inhibition Sprouting of aberrant excitatory feedback Brain tumors, Multiple Sclerosis, CNS degenerative diseases

14 Foreign Epileptic Tissue Aberrant neural structures that have active epileptic circuitry Cortical Dysplasia, Tuberous sclerosis hamartomas, DNET, hypothalamic hamartomas

15 Current Concept 2 There are patterns of development of epilepsy which may be discernable from history, imaging and EEG

16 Is there a Logical Treatment for Epilepsy? Diagnosis precedes treatment There is no medical cure for Epilepsy The treatment of Epilepsy is the management of Seizures There are four ways to treat Seizures

17 Diagnosis Precedes Treatment Understand the type of seizure and the type of epilepsy Clinical History Pathophysiology Anatomic Pathology Confirm that the disease is epilepsy

18 Clinical History Type of seizures Patient Observer Age and Pattern of Onset Family History Comorbid neurologic disease Response to treatments

19 Pathophysiology Electroencephalogram Interictal Ictal Cerebral Blood Flow (Ictal SPECT) Cerebral Glucose Metabolism (Interictal PET) Magnetoencepahalogram (MEG) BOLD Spike imaging (fmri)

20 Ictal SPECT Right Temporal Hyperperfusion

21 Interictal PET Right Temporal Hypometabolism

22 Anatomic Pathology MRI CAT

23 There is no medical cure for Epilepsy Epilepsy is the tendency to have seizures There are no medications that will reverse that tendency Surgery may remove the tendency for seizures Seizures may spontaneously remit

24 The Treatment of Epilepsy is the Management of Seizures and Comorbidity Antiseizure medications may inhibit the occurrence of seizures There are multiple Comorbid conditions which accompany epilepsy and seizure treatment

25 There are four ways to treat Seizures Medication Surgery Diet Neurostimulators

26 Therapeutic Selection for Patients with Epilepsy ASMs Resective Surgery Ketogenic Diet VNS

27 Ethosuximide 1968 Diazepam Primidone Phenobarbital Phenytoin First Generation 2 Felbamate 1993 Gabapentin 1995 Lamotrigine 1997 Topiramate 1997 Tiagabine 1999 Levetiracetam 2000 Oxcarbazepine 2000 Zonisamide 2005 Pregabalin 1974 Carbamazepine 1975 Clonazepam 1978 Valproate 1981 Clorazepate Number of New Drugs per Decade Introduction of Major Antiepileptic Second Generation Drugs in the US 1993 American Epilepsy Society. Available at: Accessed March 23, 23, FDA. Available at: Accessed June 13, 2005; Martin. Available at: Accessed June 13, 2005.

28 When are ASMs going generic? Newer Medications (2nd Generation) Older Medications (1st Generation) FDA Approval Trade Name Felbamate 1993 Felbatol Luminal Gabapentin 1993 Neurontin 1956 Dilantin Lamotrigine 1994 Ethosuximide 1960 Zarontin Topiramate 1996 Lamictal Topamax Diazepam 1963 Valium Tiagabine 1997 Gabitril Carbamazepine 1968 Tegretol Levetiracetam 1999 Keppra Lorazepam 1977 Ativan Oxcarbazepin e 2000 Valproic acid (VPA) 1978 Depakene Zonisamide 2000 Trileptal Zonegran Divalproex sodium 1983 Depakote Pregabalin 2005 Lyrica Carbamazepine 1986 Epitol Diazepam 1997 Diastat Carbamazepine 1997 Carbatrol Phenytoin Sodium 1998 Phenytek Year Introduced Trade Name Bromides 1857 Phenobarbital 1912 Phenytoin Sodium Generic Name K Generic Name Drugs@FDA: FDA Approved Drug Products. Available at: Accessed July 19, 2007

29 Initial AED Monotherapy: Treatment Response VA Coop I Initial AED (N=421) Success 47% Failure 53% Side effects (toxicity) 20% Kwan & Brodie Initial AED (N=470) Inadequate sz control 33% Success 47% Failure 53% Side effects (toxicity) 21% Inadequate sz control 24% Other Mattson RH et al. N Engl J Med 313:145, 1985 Kwan P, Brodie MJ. N Engl J Med 342: 314, %

30 Reduced Success Rate After Failure of Initial Therapy Percent of Patients Achieving Seizure Freedom Probability of Seizure Freedom in Epilepsy Patients According to AED Regimens st Monotherapy (470) 2nd Monotherapy (190) 3rd 4 or More Monotherapy Drug or Adjunctive Manipulations Therapy (25) (65) Dotted lines represent 95% confidence intervals. Adapted from Brodie, Kwan. Neurology. 2002;58(8 suppl 5):S25):S2-S8.

31 Optimize the early drug treatment of seizures Efficacy Minimal Side-Effects Compliance Added Value

32 Concept 3 If an ASM is going to produce seizure freedom it will be with the initial trials After three drug trials seizure freedom is unlikely to occur Consider early alternatives to exclusive ASM treatment

33 Concept 4 There are many ASMs but few differences among ASMs The differences among ASMs are in the side effects

34 Why Do Drugs Fail? Wrong Diagnosis Inappropriate Dosing Noncompliance Drug Resistant Epilepsy

35 Epilepsy Etiology Predictive for Remission % Patients >1 Year Seizure Free Idiopathic generalized epilepsy Cryptogenic partial epilepsy Symptomatic partial epilepsy Extratemporal partial epilepsy Temporal lobe epilepsy Hippocampal sclerosis (HS) Dual pathology (HS+) Dysgenesis Semah F et al. Neurology 51:1256, % 45% 35% 36% 20% 11% 3% 24%

36 Outcome in Patients According to Number of Seizures before Treatment 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Seizure Free Uncontrolled to 5 6 to to 20 >20 Kwan and Broidie NEJM 2000

37 Comorbidity Bone Health Reproductive Heath Cognitive Health Mental Health Injuries Mortality

38 Effects of Duration of Epilepsy on Cognitive Impairment Mean Full Scale IQ 110 Grade 10 > Grade * < >30 < Duration of Intractable TLE (years) TLE = temporal lobe epilepsy. *P<.05; P P<.01 Jokeit, Jokeit, Ebner. In: Progress in Brain Research. Research. 2002;135: ;135: >30

39 Epilepsy Patients Have a Higher Rate of Psychiatric Disorders Prevalence Rates of Psychiatric Disorders Epilepsy Patients (Range) General Population (Range) Depression 11% - 80% 3.3% - 17% Generalized anxiety disorders 15% - 25% 5.1% - 7.2% 2% - 9% 0.2% - 1.0% 12% - 37% 4% - 12% Psychosis Attentiondeficit/hyperactivity disorder Kanner, Palac. Palac. Curr Neurol Neurosci Rep. Rep. 2002;2: ;2:

40 Increased Mortality in Epilepsy Six deaths per thousand person-years in a cohort with refractory epilepsy Higher mortality is partly attributable to underlying etiology of epilepsy (eg, CNS trauma, cerebrovascular disease) Risk of sudden unexplained death in epilepsy (SUDEP) is 24 times the risk of sudden unexpected death in the general population Sperling. Sperling. Epilepsy Curr. Curr. 2001;1:212001;1:21-23; Langan. Langan. Seizure. 2000;9: ;9: ; Ficker et al. Neurology. 1998;51: ;51:

41 Quality of Life depends on Management of the Comorbidities Drug Resistant Epilepsy QOL does not correlate with Seizure frequency QOL correlates with freedom from treatment side effects

42 Determinants of Quality of Life in Patients with Epilepsy Relationship Between Seizure Frequency and Quality of Life QOLIE-89 Total Score 100 n = 195 (r =.01, P =.93) Average Monthly Seizure Rate Gilliam F. Neurology. 2002;58(suppl 5):S9-S19.

43 Determinants of Quality of Life in Patients with Epilepsy Relationship Between Adverse Events and Quality of Life QOLIE-89 Total Score 100 n = 195 (partial correlation r =.061, P <.001) Adverse Event Profile Score Gilliam F. Neurology. 2002;58(suppl 5):S9-S19. 75

44 Concept 5 Many of the problems that people have with epilepsy are not confined to seizures

45 New Antiseizure medications Lacosamide: phase 3 Retigabine: phase 3 Rufinamide: phase 3 FDA submitted Perampanel: phase 2 Brivaracetam: phase 2 Carisbamate: phase 3 Clobazam: phase 3 Ganaxalone phase 3

46 New Pharmacological Treatments Drug resistance proteins Glycolated proteins found in chemotherapy resistant breast cancer and drug resistant brain Blocks drugs from activity Block resistance proteins and allow ASMs to access pharmacologic targets

47 Nonpharmacological Epilepsy Treatments Surgery To remove the area of the brain producing seizures To interrupt the nerve pathways through which seizure impulses spread within the brain Vagus Nerve Stimulator (VNS) Pacemaker-like device implanted under the skin in the upper part of the chest Generates pulses of electricity to stimulate the Vagus nerve Ketogenic diet High-fat, low-carb diet Mostly used in very young children with difficult-to-control generalized epilepsies Reference: WebMD. Epilepsy Treatments Today. Available at: Accessed July 18, K

48 Epilepsy Surgery

49 Candidates for Epilepsy Surgery Partial Seizures Drug Resistant QOL improved with seizure control Surgery will not be harmful

50 Epilepsy Surgery Workup Seizure monitoring with Video EEG Ictal / Interictal SPECT Interictal PET 3T MRI Neuropsychology Possible Intracranial Electrodes

51 Intracranial EEG Electrodes

52 Temporal Lobectomy

53 Intracranial Surgery for Epilepsy Seizure Free Rate Anterior temporal lobectomy 65% - 75% Lesional neocortical resection 50% - 70% Nonlesional neocortical resection 35% - 45% Multilobar & hemispheric resections N/A Corpus callosotomy N/A

54 Concept 6 Epilepsy Surgery is under utilized Epilepsy Surgery is delayed Epilepsy Surgery can cure

55 VNS in Medically Refractory Epilepsy As adjunctive therapy in refractory epilepsy patients with a confirmed diagnosis Consider VNS after use of 3 appropriate AEDs along with the risk/benefit profile of all adjunctive therapies As an adjunct for patients experiencing intolerable AEs

56 VNS Pulse Generator & Lead Pacemaker like pulse generator Bipolar lead with two stimulating electrodes Intermittent stimulation 30 sec on/5 min off 24 hours/day On-demand therapy mode

57 On-Demand Stimulation: Magnet Activation Pass magnet over the pulse generator to start on-demand mode Potential benefits: Improve post-ictal period Stop or shorten seizures/clusters Decrease seizure severity Sense of empowerment Tape magnet over pulse generator to stop stimulation

58 VNS Programmable Parameters Parameter Units Range Typical Output current milliamps Signal frequency hertz Pulse width microseconds Signal On time seconds Signal Off time seconds/minutes 12 sec-180 min 5 min Pulse Generator cycle is 24 hours per day.

59 Success of VNS Chronic stimulation reduces seizures in 2/3 QOL improved in 1/3 Low seizure freedom Reduced seizure severity Patients remain on medication Improved Locus of Control

60 Concept 7 Drug resistant seizures may be treated with brain stimulators instead of surgery The goal for neurostimulators currently is optimal quality of life with minimal comorbidity

61 New Neurostimulator Open Loop Trigeminal Stimulator Thalamic stimulator Closed Loop Intracranial epileptic focus stimulation

62 Neuropace Device Intracranial electrode(s) over epileptic focus(i) Seizure detection software Stimulates to turn off seizure when seizure occurring Nondestructive Possible kindling

63

64 Ketogenic Diet Requires substantial parental investment Meticulous limitation of hidden sugar in other drugs, etc. Some may refuse to eat Results may not meet expectations Some achieve a level of seizure control not previously seen with ASMs Some achieve a reduction in toxicity from ASMs and cognitive and/or behavioral enhancement Sense of personal involvement important for some parents

65 New Advances Diet Therapy Atkins Diet Low Glycemic index diets

66 Concept 8 Diets producing Ketosis are as effective as any other treatment The ability to maintain the diet remains the problem

67 Concept 9 There is a logical treatment algorithm for epilepsy The treatments need to become more effective and less toxic

68 An Algorithm for the Treatment of Epilepsy First Seizure Recurrent Seizures = Epilepsy 1st Monotherapy AED 2nd Monotherapy AED 3rd Monotherapy AED Seizure Reevaluation CCTV/EEG Seizure Free Seizure Free Seizure Free Nonfocal or Multifocal Partial Epilepsy Primary Generalized Epilepsy Focal or Lesional Partial Epilepsy VNS Implanation AED Trials Surgical Treatment AED Trials VNS Implanation VNS Implanation Ketogenic Diet AED Trials Surgical Reeevaluation Ketogenic Diet Surgical Reeevaluation Surgical Reeevaluation Seizure Free

69 Current Concept 1 Epilepsy is common Epilepsy is a disease that starts in childhood and adolescence Epilepsy is a disease that starts in the elderly

70 Current Concept 2 There are patterns of development of epilepsy which may be discernable from history, imaging and EEG

71 Concept 3 If an ASM is going to produce seizure freedom it will be with the initial trials After three drug trials seizure freedom is unlikely to occur Consider early alternatives to exclusive ASM treatment

72 Concept 4 There are many ASMs but few differences among ASMs The differences among ASMs are in the side effects

73 Concept 5 Many of the problems that people have with epilepsy are not confined to seizures

74 Concept 6 Epilepsy Surgery is under utilized Epilepsy Surgery is delayed Epilepsy Surgery can cure

75 Concept 7 Drug resistant seizures may be treated with brain stimulators instead of surgery The goal for neurostimulators currently is optimal quality of life with minimal comorbidity

76 Concept 8 Diets producing Ketosis are as effective as any other treatment The ability to maintain the diet remains the problem

77 Concept 9 There is a logical treatment algorithm for epilepsy The treatments need to become more effective and less toxic