Management of Patients With Epilepsy. Definition Seizure Single provoked/unprovoked episode Epilepsy...
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Transcript of Management of Patients With Epilepsy. Definition Seizure Single provoked/unprovoked episode Epilepsy...
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 >50% of seizures are untreated Annual cost is $12.5 billion
Seizure Classification
Partial Seizures Simple Partial Complex Partial Secondarily GTC
Generalized Seizures
GTC Absence Myoclonic Clonic Tonic Atonic
International League Against Epilepsy (ILAE) in 1981
Based on Semiology/Ictal behavior and EEG
Epilepsy Syndrome based classification
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.)
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
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
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
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
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……
Major Side EffectsPhenobarbital 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
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
AE’s occur at lower serum concentrations
AE’s more likely to result in non-compliance
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
Hyponatremia Seen with carbamazepine and oxcarbazepine Clinically significant hyponatremia (sodium <125
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
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 AED’s Richards et al., Neurology 2005
Choice of Therapy Partial Seizure
Oxcarbazepine Lamotrigine Zonisamide Levetiracetam, Pregabalin, Phenytoin
Generalized Seizures Topiramate Lamotrigine Valproic Acid Zonisamide
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 (>2) and adults
Primary GTC
LGS
Yes (Adults and Children>10)
Tiagibine Partial: Adults and Children (>12) No
Levetiracetam Partial: Adults No
Oxcarbazepine Partial: Adults and Children (>2) Yes (Children and Adults >4)
Zonisamide Partial: Adults No
New AED’s: FDA Approved Indications
Issues To Discuss Driving Interaction with contraceptives
>50μg ethinyl estradiol/mestranol if taking enzyme-inducing AED (phenobarbital, primidone, phenytoin, carbamazepine)
OC’s 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
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
Interaction with Hormonal Contraception
Definite/Possible interaction
Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Tiagabine *Topiramate **Lamotrigine (OCD’s
reduce LTG levels)
No interaction Felbamate Gabapentin Levetiracetam Zonisamide
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
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
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
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
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
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”
Options For Medically Intractable Patients
Epilepsy Surgery Other:
Brain Stimulation Vagal Nerve Stimulation Cerebellar, Caudate, Thalamus,
Hippocampus
Results of Surgical Treatment, Worldwide (1986-1990; Retrospective Data) Engel J. NEJM 1996
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
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
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
Status Epilepticus Definition:
2 or more seizures without full recovery or more or less continuous seizure activity lasting >30 minutes
Incidence: 50,000-150,000 cases annually in the
U.S. Most common in children and the
elderly
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.
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
Standard Treatment Algorithm:Initial 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.
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
VA cooperative trial of 384 patients with a diagnosis of overt generalized status epilepticus Treiman et al: NEJM 1998
0
10
20
30
40
50
60
70
Cessation %
Lorazepam(0.1 mg/ kg)
Phenobarbital(15 mg/ kg)
Phenytoin (18mg/ kg) +Diazepam(0.15 mg/ kg)Phenytoin (18mg/ kg)
Lorazepam is reasonable as the initial drug of choice in the treatment of GCSE.
Other Medications Rectal Diazepam Gel (Diastat@) 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@) 15-20 mg/kg IV followed by 250-500 mg q6 hrs
Status Epilepticus: Goal Stop seizures as quickly and as
aggressively as possible
Duration of status correlates inversely with outcome