Management of Patients With Epilepsy

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Management of Patients With Epilepsy
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Definition

• Seizure
• Single provoked/unprovoked episode
• Epilepsy
• Two or more unprovoked seizures

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Numbers.Numbers

• Unprovoked seizure
• Risk in US 1/100
• Epilepsy/Recurrent unprovoked seizures
• 8th leading cause of morbidity
• 50 million people worldwide, 2 million in US
• Age-adjusted prevalence 2.7-40/1000
• Incidence and prevalence is much higher in under
  developed nations
• gt50 of seizures are untreated
• Annual cost is 12.5 billion

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Age Adjusted Incidence
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Seizure Classification

• International League Against Epilepsy (ILAE) in
  1981
• Based on Semiology/Ictal behavior and EEG

• Partial Seizures
• Simple Partial
• Complex Partial
• Secondarily GTC

• Generalized Seizures
• GTC
• Absence
• Myoclonic
• Clonic
• Tonic
• Atonic

• Epilepsy Syndrome based classification

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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 (15 sec.3 min.)

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Generalized Tonic Clonic Seizure

• Variable symmetry, intensity, and duration of
  tonic (stiffening) and clonic (jerking) phases
• Usual duration 30-120 sec.
• Postictal confusion, somnolence, with or without
  transient focal deficit
• May be primary or secondarily generalized

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Proportion of Cases By Seizure TypeRochester, MN
1935-1984
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Proportion of Cases By EtiologyRochester, MN
1935-1984
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Consequences of Epilepsy

• Morbidity
• Accidents, Injuries
• Mortality
• Sudden unexpected death in epilepsy
• Status epilepticus, Suicide, Accidents, Cancer,
  Infections etc.
• Socioeconomic Outcome
• School performance
• 56 finish high school and 15 finish college
• Intellectual functioning (seizures vs. drugs)
• Social adjustment
• Employment
• Driving

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Management

• Important to establish diagnosis and etiology
• Classify seizure type and syndrome
• Good history (from patient and spouse/friend)
• Labs
• EEG (sleep deprived vs. routine)
• Imaging (MRI is far superior to CT)
• SPECT, PET

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Everything that shakes is not a seizure!!!

• Non-epileptic spells can be extremely hard to
  differentiate from seizures
• 30 of all patients
• Risk factors
• Epilepsy
• Family member with epilepsy
• Psychiatric problems
• Most have conversion disorder
• Need video EEG monitoring to confirm diagnosis

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Medical Management

• Mid 1800s Bromides
• 1912 Phenobarbital
• 1938 Merritt and Putnam - Phenytoin

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Year Introduced
Phenobarbital 1912
Phenytoin 1938
Primidone 1954
Ethosuximide 1960
Carbamazepine 1974
Valproate 1978
Felbamate 1993
Gabapentin 1993
Lamotrigine 1994
Topiramate 1996
Tiagibine 1997
Levetiracetam 2000
Oxcarbazepine 2000
Zonisamide 2000
Other Available AEDs Diazepam, Lorazepam, Diastat, Depacon, ACTH
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Major Side Effects
Phenobarbital Sedation, Hyperactivity, Rash, Osteomalacia
Phenytoin Gingival hyperplasia, Hirsutism, Peripheral Neuropathy, Bone marrow suppression, Osteomalacia
Primidone Sedation, Hyperactivity, Rash, Osteomalacia
Ethosuximide GI Upset, Mood changes, Lethargy, Hiccups, Headache
Carbamazepine Hyponatremia, Leucopoenia, Hepatitis, Rash
Valproate Thrombocytopenia, Tremor, Hair loss, Weight gain, Hepatitis, Pancreatitis
Felbamate Hepatic Failure, Aplastic Anemia
Gabapentin Sleepiness, Weight gain
Lamotrigine Rash (increased risk with VPA)
Topiramate Cognitive slowing, Renal stones, Acute Glaucoma, Weight Loss
Tiagibine Dizziness, Somnolence, Spike Wave Stupor
Levetiracetam Sleepiness
Oxcarbazepine Hyponatremia, Rash (No Leucopoenia)
Zonisamide Rash, Renal stones
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Epilepsy in the Elderly Adverse Effects (AE) of
Medications

• dose-dependent side effects are common
• dizziness, somnolence, ataxia, diplopia
• drug-specific side effects are common
• hyponatremia, tremor, cardiac effects,
  encephalopathy, cognitive suppression
• AEs occur at lower serum concentrations
• AEs more likely to result in non-compliance

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Weight Gain/Loss

• Most medications are weight neutral
• Valproic Acid and Gabapentin typically associated
  with weight gain
• Felbamate, Topiramate and Zonisamide associated
  with weight loss
• Zonisamide
• Weight loss 28.9 of patients on ZNS compared to
  8.4 on placebo lost more than 5 lbs.
• Weight loss occurred in the first 3 months

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Hyponatremia

• Seen with carbamazepine and oxcarbazepine
• Clinically significant hyponatremia (sodium lt125
  mEq/L) has been observed in 2.5 of OXC-treated
  patients in controlled clinical trials
• Measurement of serum sodium levels should be
  considered for patients at risk for hyponatremia
• Most (79) of these patients were receiving
  concomitant sodium-depleting medications
  including carbamazepine, antidepressants,
  diuretics, and cathartics
• The observed hyponatremia was usually
  asymptomatic and occurred within the first 90
  days of treatment

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Renal Stones

• Can occur with TPM, ZNS, Ketogenic Diet
• 4 incidence of all clinically possible or
  confirmed kidney stones
• Less than 50 of calculi are symptomatic
• Analyzed stones are mostly composed of calcium or
  urate salts
• No increased risk of stone in patients on
  Ketogenic diet and ZNS or TPM
• History of calculi may not be absolute
  contraindication for use of the AEDs
• Richards et al., Neurology 2005

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Choice of Therapy

• Partial Seizure
• Oxcarbazepine
• Lamotrigine
• Zonisamide
• Levetiracetam, Pregabalin, Phenytoin
• Generalized Seizures
• Topiramate
• Lamotrigine
• Valproic Acid
• Zonisamide

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New AEDs FDA Approved Indications
Seizure Type and Age Range Initial Monotherapy
Felbamate Partial with and without generalization in adults LSG Pediatric and Adult Yes No
Gabapentin Partial with and without generalization above age 12 Partial from 3-12 No No
Lamotrigine Partial Adults LGS Pediatric and Adult No (Approved for Conversion to Monotherapy) No
Topiramate Partial Pediatric (gt2) and adults Primary GTC LGS Yes (Adults and Childrengt10)
Tiagibine Partial Adults and Children (gt12) No
Levetiracetam Partial Adults No
Oxcarbazepine Partial Adults and Children (gt2) Yes (Children and Adults gt4)
Zonisamide Partial Adults No
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Issues To Discuss

• Driving
• Interaction with contraceptives
• gt50µg ethinyl estradiol/mestranol if taking
  enzyme-inducing AED (phenobarbital, primidone,
  phenytoin, carbamazepine)
• OCs do not alter seizure control, but they may
  accelerate metabolism of enzyme-inducing AED
• Pregnancy issues
• Decreased serum drug concentrations
• Birth defects
• Eventual outcome of treatment

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Driving in Texas

• Doctors not required to report patients
• Seizure-Free Period 6 months, with doctor's
  recommendation
• Annual periodic medical updates required
• Doctors not liable for their opinions and
  recommendations
• Allowed to drive if
• Only nocturnal seizures
• Breakthrough seizure due to a physician directed
  change in medication
• Intrastate License The U.S. Department of
  Transportation (DOT) bars anyone with any history
  of epilepsy

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Interaction with Hormonal Contraception

• Definite/Possible interaction
• Carbamazepine
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Tiagabine
• Topiramate
• Lamotrigine (OCDs reduce LTG levels)

• No interaction
• Felbamate
• Gabapentin
• Levetiracetam
• Zonisamide

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Pregnancy and Delivery

• Higher fetal death rate ( 1.3-14)
• Malformations of 2 main types
• Minor malformations Cleft lip, Cleft palate,
  digit and crease abnormalities
• Fetal hydantoin syndrome
• Fetal anticonvulsant syndrome
• Major malformations Neural tube defects

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Malformations

• Risk factors
• Polytherapy
• Uncontrolled seizures
• Both GTC and CPS
• Higher plasma levels of medications
• Neural tube defects VPA
• Mechanism
• ? Association with folate metabolism
• Enzyme-inducing AEDs accelerate folate metabolism
• VPA interferes with folate absorption

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Pregnancy Recommendations

• Pre-Pregnancy
• Limit risk factors
• Genetic counseling
• High risk Obstetrician
• Folic acid supplementation 400 micrograms/day
  (70 reduction in neural tube defect incidence)
• ENROLL IN PREGNANCY REGISTRY
• Pregnancy
• Level 2 ultrasound at 16-18 weeks
• Amniocentesis if indicated
• Delivery
• Vitamin K 10 mg/day, during last week to prevent
  Hemorrhagic Disease due to reduced activity of
  Vit K-dependent clotting factors (II, VII, IX, X)
  and protein S/C with enzyme-inducing AEDs

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Pregnancy Recommendations

• VPA and PB seem to have highest risk for neural
  tube defects
• Monitor AED levels closely
• LTG levels will decrease by 50 by end of second
  trimester
• No AED is completely safe
• Association of LTG with cleft lip/palate

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Outcome of Medical Management

• Kwan and Brodie, NEJM 2000
• Prospective study
• 525 patients 9-93 yrs of age
• Patients diagnosed, treated and followed at a
  single center for 13 years
• 60 respond to the first to medications
• Significant number of patients have side effects

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Medical Intractability

• Unacceptable control despite multiple drugs
• Acceptable control with unacceptable side effects
• Reasons for unsatisfactory control
• Correct AED, but not working
• Incorrect AED
• Incorrect diagnosis
• 10-20 of patients have non-epileptic events

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Options For Medically Intractable Patients

• Epilepsy Surgery
• Other
• Brain Stimulation
• Vagal Nerve Stimulation
• Cerebellar, Caudate, Thalamus, Hippocampus

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Results of Surgical Treatment, Worldwide
(1986-1990 Retrospective Data) Engel J. NEJM
1996
Outcomes, Outcomes, Outcomes,
Surgical Procedure Patients Seizure-free Worthwhile improvement No Worthwhile improvement
Temporal lobe resections
- Anterior temporal lobectomy 3579 67.9 24.0 8.1
Amygdalohippocampectomy 413 68.8 22.3 9.0
Neocortical resection 605 45.1 35.2 19.8
Lesionectomy 293 66.6 21.5 11.9
Hemispherectomy 190 67.4 21.1 11.6
Multilobar resection 166 45.2 35.5 19.3
Callosotomy 563 7.6 60.9 31.4
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Risks of Epilepsy Surgery

• Wiebe S et al, NEJM 2001
• 10 complications in surgery group, 1 death
  (2.5) in medical management group
• Rydenhag and Silander, Neurosurgery 2000, 449
  procedures
• Major complications 3.1, Minor 8.9
• Risk is higher with
• Intracranial electrode placement
• Extra-temporal surgery especially in/around
  eloquent cortex
• Pre-operative w/u (Neuropsychological testing,
  Amobartbital test) provides assessment of
  post-operative memory problems
• Superior quadrantanopsia 30 patients
  (assymptomatic)
• Post-operative depression/psychosis

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Outpatient Management Conclusions

• Epilepsy is an extremely common condition
• 60 of patients are well controlled on a single
  first appropriate medication
• Early identification of medically refractory
  patients
• Epilepsy surgery is an effective and safe
  treatment
• Goal is Seizure Freedom

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Status Epilepticus

• Definition
• 2 or more seizures without full recovery or more
  or less continuous seizure activity lasting gt30
  minutes
• Incidence
• 50,000-150,000 cases annually in the U.S.
• Most common in children and the elderly

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Etiology

• Prior history of seizures
• Most common Medication changes or non-compliance
• Breakthrough seizures because of stress, lack of
  sleep, menstrual cycles.
• Unknown
• New Onset
• Metabolic problems e.g., electrolyte
  disturbances, renal failure, sepsis and hypoxia,
  especially in the hospitalized patient
• Head trauma, central nervous system infection and
  cerebral hemorrhage or infarction.
• Intracranial tumors, substance abuse or other
  drug toxicity/withdrawal and HIV.

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Generalized Convulsive SE

• Most common type of SE
• 70 of all cases of SE
• 65,000-150,000 new cases every year
• Responsible for considerable morbidity and
  mortality (3-53)
• Prevalence of nonconvulsive status epilepticus in
  comatose patients 8 (236 patients with no overt
  seizure activity)
• Towne et al., Neurology 2000

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Standard Treatment AlgorithmInitial Treatment

• Assess and control airway (100 oxygen,
  intubation if needed)
• Monitor vital signs (including temperature)--
  hyperthermia occurs in 29-78, passive cooling or
  cooling blanket if needed (hyperpyrexia is an
  important cause of poor outcome)
• Conduct pulse oximetry and monitor cardiac
  function
• Perform finger-stick blood glucose
• Call EEG technician and begin EEG stat.

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While you are treating

• Begin focused history and examine patient
• Known seizure disorder or other illnesses?
• Trauma? Focal neurological signs?
• Signs of medical illnesses (e.g. infection,
  hepatic or renal disease, substance abuse?)
• Throughout protocol
• Manage other medical problems
• Determine and treat underlying etiology of status

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VA cooperative trial of 384 patients with a
diagnosis of overt generalized status epilepticus
Treiman et al NEJM 1998
Lorazepam is reasonable as the initial drug of
choice in the treatment of GCSE.
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Other Medications

• Rectal Diazepam Gel (Diastat_at_)
• Midazolam
• 0.1-0.3 mg/kg slow IVP followed by 0.05-0.4
  mg/kg/hr infusion
• Propofol
• 2-2.5 mg/kg IV (40mg q10min) followed by 0.1-0.2
  mg/kg/min IV
• IV Valproate (Depacon_at_)
• 15-20 mg/kg IV followed by 250-500 mg q6 hrs

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Status Epilepticus Goal

• Stop seizures as quickly and as aggressively as
  possible
• Duration of status correlates inversely with
  outcome

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Additional Information..

• Epilepsy Foundation of America
• www.efa.org
• National Institute of Neurological Disorders and
  Stroke (NINDS)
• www.ninds.nih.gov