Clinical Epilepsy

1. Clinical Epilepsy www.neurology.ufl.edu/Epilepsy

2. Definition: the clinical manifestation of an abnormal and excessive excitation of a population of cortical neurons Incidence: approximately 80/100,000 per year Lifetime prevalence: 9% (1/3 benign febrile convulsions) Seizures vs Epilepsy Seizures Epilepsy • Definition: a tendency toward recurrent seizures unprovoked by systemic or neurologic insults • Incidence: approximately 45/100,000 per year Approximately 181,000 people will experience seizures or develop epilepsy each year • Point prevalence: 0.5-1% (2.5 million) • 14 years or younger 13% • 15 to 64 years 63% • 65 years and older 24% • Cumulative risk of epilepsy through 74 years old: 1.3% - 3.1%

3. Partial (focal) Seizures • Simple Partial Seizure • no loss of awareness • Complex Partial Seizure • Impaired consciousness/ level of awareness (staring) • Clinical manifestations vary with origin & degree of spread • Presence and nature of aura • Temporal lobe: smell, epigastric sensation, deja vu • Automatisms (manual, oral) • Other motor activity • Frontal: bicycling and fencing posture • Duration (typically 30 seconds to 3 minutes) • Amnesia for event • Partial Seizure with Secondary Generalization

4. Localization of Partial Seizure Focus 20% 10% 70%

5. Temporal Lobe Complex Partial Seizure Rhythmic 5-7 Hz theta from the mesial temporal lobe

6. Primarily Generalized Seizures • Absence • Typical (3 Hz spike and wave) • Atypical (2.5 to 4.5 Hz spike and wave, polyspike) • Brief staring (<30sec); automatisms rare; not post-ictal confusion • Myoclonic • Brief, shock-like muscle contractions- Head- Upper extremities • Usually bilaterally symmetrical • Consciousness preserved • Precipitated by awakening or falling asleep • May progress into clonic or tonic-clonic seizure • May be associated with a progressive neurolgic deterioration • Juvenile Myoclonic Epilepsy (JME) • Polyspike wave • Onset late adolescence • Chromosome 6p • Progressive Myoclonic Epilepsies • Atonic/ Tonic/ Tonic-Clonic

7. Absence Seizure 3 Hz spike and wave

8. Seizure vs Epilepsy Seizures Nonepileptic Epilepsy (recurrent seizures) Cardiovascular Drug related Syncope Metabolic (glucose, Na, Ca, Mg) Toxic (drugs, poisons) Poison Infectious Febrile convulsions Pseudoseizure Alcohol/drug withdrawal Substance abuse Psychiatric disorders Sleep disorders (parasomnias, cataplexy) Idiopathic (primary) Symptomatic (secondary)

9. Psychogenic Nonepileptic Seizures • Represent genuine psychiatric disease • 10-45% of refractory epilepsy at tertiary referral centers • Females > males • Psychiatric mechanism: dissociation, conversion, unconscious (unlike malingering) • Association with physical, sexual abuse • Epileptic and nonepileptic seizures may co-exist • Video-EEG monitoring often helps clarify the diagnosis • Once recognized, approximately 50% respond well to specific psychiatric treatment

10. Epidemiology of Seizures and Epilepsy Epilepsy: Incidence Rates by Seizure Type Data from Rochester, Minn (1935-1979). Adapted with permission from Annegers JF. In: The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:165-172. Hauser et al, 1992 Ramsay RE, et al. Neurology. 2004;62(5 suppl 2):S24-S29 . * Includes known etiologies such as arteriovenous malformation and venous angioma.

11. Seizure Precipitants Low (less often high) blood glucose Low sodium Low calcium Low magnesium Stimulant or other proconvulsant toxicity (i.e., cocaine) Sedative (i.e., valium or alcohol) withdrawal Severe sleep deprivation

12. EEG Abnormalities • Background abnormalities • -Significant asymmetries and/or degree of slowing inappropriate for clinical state • Transient abnormalities associated with seizures • -Spikes (< 70 m sec) • -Sharp waves (~70 – 200 msec) • -Spike-wave complexes • May be focal, lateralized or generalized

13. EEG Abnormalities

14. Medical Treatment of First Seizure(s) • Whether to treat first seizure is controversial • 16-62% will recur within 5 years • Relapse rate for second seizure is reduced by AEDs, • BUT long term prognosis of whether the patient will have refractory epilepsy is not • Increased risk of relapse • Abnormal imaging • Abnormal EEG • Family history of epilepsy • Currently, most patients are not treated for the first seizure unless there is an increased risk for relapse

15. TreatmentDoes NOT Improve Prognosis of Epilepsy First Tonic-clonic Seizure Cumulative time-dependent probability of initiating a period of seizure remission according to whether an AED was given after the first tonic-clonic seizure 1 year seizure-free 2 years seizure-free YEARS YEARS

16. Choosing Antiepileptic Drugs • Seizure type/ Epilepsy syndrome • Comorbid conditions • Adverse side effects or events • Interactions/other medical conditions • Pharmacokinetic profile • Cost • Efficacy • ALL FEMALES (and also consider in males): • Folate 1 - 4 mg/day • MVI • Calcium (1200-1330 mg per day)

17. Rational Use of AEDs: Flooding the Market First-Generation Branded Agents Dilantin phenytoin 1938 Parke-Davis Tegretol carbamazepine 1974 Novartis Depakote divalproex sodium 1978 Abbott Second-Generation Agents Felbatol felbamate 1993 Wallace Laboratories Neurontin gabapentin 1993 Parke-Davis Lamictal lamotrigine 1994 Glaxo Smith Kline Topamax topiramate 1997 Ortho-McNeil Gabitril tiagabine 1997 Abbott Laboratories Trileptaloxcarbazepine 2000 Novartis Zonegran zonisamide 2000 Elan Keppra levetiracetam 2000 UCB Pharma Lyrica pregabalin 2005 Pfizer

18. FDA Indications for AEDs:Monotherapy and/or Add-On Therapy 1Approved for conversion to monotherapy. Physician’s Desk Reference, 2004.

19. Treatment of New Onset Epilepsy Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

20. Kwan and Brodie. NEJM 2000; 342: 314-319. Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

21. Kwan and Brodie. NEJM 2000; 342: 314-319. Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

22. Kwan and Brodie. NEJM 2000; 342: 314-319. Mohanraj and Brodie. Epil Behav 2005; 6: 382-387

23. Why Should Current Prescribing Practices Change? AED Prescription Volume (%) 0-17 18-34 35-44 45-54 55-64 >65 Age Group (years) PharMetrics. April 2002 to June 2003 IMS NPA, Dec 2003. Kwan P, Brodie MJ. N Engl J Med 2000; 342: 314-9.

24. Rational Use of AEDs: All PrescriptionsMarket Dynamics for All Indications and Epilepsy AED Prescription Volume (%) 0-17 18-34 35-44 45-54 55-64 >65 Age Group (years) PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003 MAT 03/2004

25. “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus (1493-1541)

26. Summary of Serious and Non-serious Adverse Events of the Newer AEDs

27. Pregnancy and AED Therapy:Risks of Congenital Abnormalities • Congenital malformations • Most common: orofacial clefts, heart defects • Less common: microcephaly, neural tube defects • Major malformations • General population: 2% to 4% • Newborns prenatally exposed to AEDs: 4% to 8% • Multiple AEDs and higher doses may substantially increase malformation rate • Minor malformations • Increased 2 to 3 fold (10% to 30%) So EL. Med Clin North Am. 1993;77:203-214. Foldvary N. Neurol Clin. 2001;19:409-425. Schachter SC. Epilepsia. 1999;40(suppl 9):S20-S25. Holmes LB, et al. N Engl J Med. 2001;344:1132-1138.

28. AEDs and Bone Health • Increased incidence of osteopenia, osteomalacia, and fracture with some AEDs • No prospective trials have been performed to define the frequency of fractures in epilepsy • Factors associated with reduced BMD • Polypharmacy • Generalized seizures • All tested AEDs have been shown to reduce BMD • Primarily associated with enzyme-inducing AEDs and phenytoin • Strong association for decreasing bone mineral density • Carbamazepine • Phenobarbital • Phenytoin • Primidone • Conflicting findings on bone mineral density • Divalproex • Lamotrigine • Limited information on newer AEDs AED Prescription Volume (%) 0-17 18-34 35-44 45-54 55-64 >65 PharMetrics. April 2002 to June 2003. Source: IMS NPA, Dec. 2003 Pack AM, et al. Epilepsy Behav. 2003;4:169-174. Ensrud KE, et al. Neurology. 2004;62:2051-2057 Age Group (years)

29. AEDs and Bone Health

30. Rational Use of AEDsSo Why Should Prescribing Practices Change? Patients often required long term (or lifetime) treatment due to driving status • State of Florida *15A-5.004 Neurological Guidelines for Applicants with Seizures(*the following changes to the seizure guidelines became effective in August 1992 and have been used as policy since that date) • Applicants and licensed drivers should be seizure free for a period of 2 years before being approved for licensing; but if under regular medical supervision, may apply at the end of 6 months for review by the Medical Advisory Board. “Petit mal” or absence seizures and partial seizures with complex symptomology will also follow these guidelines. The isolated seizure with a normal EEG may be reviewed after 3 months. • Applicants and licensed drivers who have been approved after 6 months seizure free may be required to submit follow-up reports at the end of 1 year from the date of approval. • Applicants and licensed drivers who have a chronic recurring seizure disorder (or who have been treated for such for 1 year) and medications have been discontinued will not be licensed to drive during the period of drug withdrawal and for a period of 3 months following complete cessation of treatment. If the patient has seizures during this period, licensing may be considered after a 3 month seizure free interval upon return to adequate therapy. • If there is a question about the seizure type or the medications the applicant of licensed driver is on, it is the prerogative of the Medical Advisory Board to question the treating physician further in an effort to clarify the nature of the seizures. • Blood levels below therapeutic levels are to be considered on an individual basis. • Applicants and licensed drivers with only chronic nocturnal seizures will be considered on an individual basis. • Applicants and licensed drivers with syncopal episodes who have no clear diagnosis established will be considered on an individual basis

31. Treatment/Evaluation Sequence for Pharmacoresistent Epilepsy 1st Monotherapy AED Trial 2nd Monotherapy AED Trial 3rd Monotherapy/Polytherapy AED Trial Strongly consider videoEEG Monitoring Kwan P, Brodie MJ. NEJM;342:314-319. Non-epileptic Epilepsy Psychogenic, migraine, syncope, sleep disorders, movement disorder’s, etc. Epilepsy Surgery/VNS Therapy/ Neuropace Evaluation Polytherapy AED Trials Resective Surgery Stimulator Therapy

32. Other Treatments of Epilepsy • Medical • Experimental AED trials • Ketogenic diet • Surgical • Resective • Multiple Subpial Transection • Vagal Nerve Stimulator • Experimental • Thalamic Stimulators • Stereotactic Radiosurgery • Responsive Neurostimulators

33. Evaluation for Surgery- Neuroimaging • MRI • -hippocampal volumetrics • greater than ~0.5cc difference increases chances for seizure remission • -1.5 mm coronal cuts with sequences sensitive to gray-white differentiation and to gliosis • -inversion recovery/high resonance for cortical dysplasia • PET • Ictal/interictal SPECT • MR Spectroscopy • Decreased NAA (due to neuronal loss) • Normal to high Cho and Creatine (represents astrocytosis)

34. Epilepsy Surgery- Neuroimaging Hippocampal atrophy in temporal lobe epilepsy Ganglioglioma DNT Cortical Dysplasia AVM Cavernous Angioma

35. Evaluation for Surgery- Subdural Grid Electrodes

36. Left Anterior Temporal Loectomy