• Information
  1. Introduction
  2. Classification of Epileptic Seziures
  3. Causes of Seizures in Infants
  4. Causes of Seizures in Children
  5. Causes of Seizures in Adults
  6. Temporal Lobe Epilepsy
  7. Pathogenesis
  8. Diagnosis
  9. Differential Diagnosis
  10. Therapy Overview
  11. Treatment by Seizure Type
  12. Summary Of Uses Of Anti-Convulsive Agents
  13. Prognosis

A. Introduction

1. Seizures are abnormal spontaneous discharges of brain neurons
2. May affect part (focal) or all (general) of the brain
3. Nearly 2 million patients with seizure disorder (epilepsy) in USA []
   1. About 100,000 new cases per year in USA
   2. Overall incidence is ~70 per 100,000 per year
   3. Prevalence is ~9 per 1000 persons (0.9%)
   4. Highest incidences in age <10 and in age >60
   5. Overall, elderly persons have the highest incidence and prevalence of epilepsy
4. Level of consciousness and initiating focus are most important considerations
5. Level of Consciousness
   1. Simple: no loss of consciousness
   2. Complex: impairment, alteration, or loss of consciousness
6. Focus of Seizure Activity
   1. Partial: begins at specific focus (may be idiopathic or structural or due to injury)
   2. Generalized: appear to begin diffusely in large part of the brain, loss of consciousness
7. Control of Epilepsy
   1. Medications control ~80% of these patients very well
   2. Thus, over 300,000 patients with intractable or poorly controlled seizures
   3. Refractory epilepsy often due to missed opportunities for good control
8. Licensed motor vehicle drivers are required to report a seizure condition at diagnosis
9. Mortality in Patients with Epilepsy [6]
   1. Increased risk of death compared with general population
   2. Annual mortality ~1.2 per 1000 patients
   3. Peri-ictal cardiac abnormalities, particularly asystole or severe bradycardia found in 4 of 20 patients with focal epilepsy
   4. Cardiac pacemakers can mitigate risks of arrhythmia associated death
10. Epilsepsy Foundation in USA 1-800-EFA-1000, web site: www.efa.org

B. Classification of Epileptic Seziures (Summary) [2]

1. Partial Seizures
   1. Simple Partial Seizures
   2. Complex Partial Seziures
   3. Partial Seizures evolving into secondary generalized seizures
2. Generalized Seizures
   1. Absence Seizures
   2. Myoclonic Seizures
   3. Clonic Seizures
   4. Tonic Seizures
   5. Tonic-Clonic Seizures
   6. Atonic Seizures
3. Unclassified Seizures
4. Simple Partial Seizures
   1. Focal initiation
   2. No impaired consciousness
   3. Motor, sensory, autonomic or psychic signs and symptoms (depends on focus)
   4. Focal slowing and/or sharp wave activity on electroencephalogram (EEG)
5. Complex Partial Seziures
   1. Temporal lobe or psychomotor
   2. Consciousness impaired
   3. May begin without warning, or with signs/symptoms as for simple partial
   4. Automatic acts of which patient has no recollection (automatisms) may occur
   5. Lip smacking, fumbling, staring, guttural vocalization, confusion
   6. Seizure often followed by period of confusion
   7. Focal slowing and/or sharp wave activity on EEG
6. Secondarily Generalized Partial Seizures
   1. Typical generalization to tonic-clonic (grand mal)
   2. Begin as simple partial seizures
   3. Consciousness is lost; patient comatose after seizure ends, recovers slowly
   4. Tonic increase in muscle tone, with subsequent rhythmic (clonic) jerks
   5. Tongue biting or incontinence, or both, may occur
   6. Focal slowing and/or sharp wave activity on EEG
7. Absence Seizures (Petit Mal) [3]
   1. This generalized seizure begins rapidly with very short (1-10 second) "spells"
   2. In addition, 1-2 minute staring episodes occur commonly, 10-100 episodes per day
   3. Increased or decreased muscle tone, automatisms or mild clonic movements
   4. Seizure can be precipitated by hyperventilation
   5. Age at first seizure 3-20 years (usually 4-8 years)
   6. Classic spike-wave pattern of 3 cycles per second (Hz) on EEG
   7. Altered circuitry between thalamus and cerebral cortex implicated
   8. Mutation in P/Q Calcium Channel can cause absence seizures [4]
   9. T type calcium channel abnormality may also play a role
   10. May be mistaken for attention deficit disorder or daydreaming
8. Primarily Generalized Tonic-Clonic (Grand Mal) Seizures
   1. Loss of consciousness without warning or preceded by myoclonic jerks
   2. Patient comatose after seizure ends, recovers slowly
   3. Tonic increase in muscle tone, with subsequent rhythmic (clonic) jerks
   4. Tongue biting or incontinence, or both, may occur
   5. Spike-wave patter (3-5 Hz) on EEG
9. Myoclonic Seizures
   1. Primarily with uncontrolled muscle jerks, no impaired consciousness
   2. Typically associated with anoxia, ischemia, drug overdose
   3. Idiopathic and syndromic forms described
10. Status Epilepticus: continuously repeating seizures
11. Refractory Epilepsy: poor control with antiepileptic agents
12. Epileptic Syndrome [3]
    1. Group of signs and symptoms that occur together
    2. Identification of appropriate syndrome helps determine prognosis and treatment
    3. Many of these syndromes caused by mutations in ion channel proteins (Table 1, Ref [3])
    4. Seizures first occur in infants or children

C. Causes of Seizures in Infants

1. Trauma
2. Infection / Fever
3. Tumor
4. Degenerative
5. Aminoaciduria
6. Metabolic
   1. Hypoglycemia
   2. Hyponatremia
   3. Hypocalcemia
7. Developmental
   1. Arteriovenous Malformation (AVM)
   2. Hyperactive focus - usually a scar
8. Hereditary
9. Idiopathic
   1. Infantile Spasms (West's Syndrome)
   2. Lennox-Gastaut Syndrome
   3. Severe myoclonic epilepsy in infants

D. Causes of Seizures in Children

1. Hemorrhage
2. Toxins - drugs
3. Renal Failure
4. Cerebrovascular Abnormalities
5. Metabolic
6. Infection / Abscess
7. Fever
8. Juvenile myoclonic epilepsy (genetic defects unknown)
9. Idiopathic

E. Causes of Seizures in Adults [6,7]

1. Idiopathic
2. Post-Traumatic
3. Cerebrovascular Disease
   1. Post- or peri-stroke
   2. Recurrent chronic ischemia
   3. Seizures most common with large hemorrhagic areas of infarction
   4. Late onset seizures may be a risk for stroke [8]
4. Tumor - ~10% of new onset seizures
5. Recreational Drugs
   1. Alcohol - withdrawal seizures more common than during use
   2. Cocaine
   3. MDMA ("ecstasy")
6. Eclampsia
7. Autoimmune Disease
   1. Vasculitis
   2. Systemic Lupus
8. Medial Temporal Sclerosis
9. Metabolic
   1. Hypoglycemia
   2. Hyponatremia
   3. Hypocalcemia
   4. Hypernatremia
   5. Hypocalcemia or low magnesium levels increase seziure risk
   6. Uremia
   7. Cirrhosis / Liver Failure
10. Infection
    1. Meningitis
    2. Encephalitis
    3. Brain Abscess
    4. Parasitic - malarium, hydatid, toxoplasma, leishmania, helminths, cysticercosis [9]
11. Medications
    1. Anti-psychotics - phenothiazines lower seizure threshhold more than butyrphenones
    2. Tricyclic antidepressants - particularly as overdose
    3. Lidocaine
    4. ß-Lactams - especially imipenam, high dose penicillin
    5. Meperidine (Demerol®) - metabolites are epileptogenic
    6. Theophylline
    7. Interferons - may increase risk of seizures, particularly in multiple sclerosis
    8. Tramadol (Ultram®) - only in overdoses >500mg
    9. Narcotic or benzodiazepine withdrawal
12. Multiple Sclerosis - occasional seizures
13. Organ Transplantation
14. Postoperative - anesthesia related, underlying systemic disease, organ failure
15. Seizures in Elderly [6]
    1. Cerebrovascular Disease: Post-Stroke and Stroke Related, particularly with hemorrhage
    2. Post-carotid endarterectomy hyperperfusion syndrome (1% of endarterectomy)
    3. Intracranial tumors
    4. Degenerative Disorders - mainly Alzheimer Dementia and Amyloid Angiopathy
    5. Metabolic - mainly hyperglycemia related
16. Hereditary
    1. Sickle cell disease
    2. Familial encephalopathy with neuroserpin inclusions [10]
17. Seizures are precipitated in many medical patients without clear seizure focus [7]

F. Temporal Lobe Epilepsy

1. Arise in:
   1. Medial temporal lobe
   2. Amygdaloid Nucleus
   3. Hippocampus
2. Propagation to amygdala
3. Symptoms
   1. Feelings of depersonalization
   2. Emotionality
   3. Automatic Behavior
   4. Loss of memory during bizarre behavior
   5. Hypersexuality
   6. Can cause asystole - rare [1]
4. Cannot distinguish from partial complex seizures arising from frontal lobes without EEG
5. Treatment
   1. Carbamazapine
   2. Dilantin
   3. Valproate
   4. Phenobarbital

G. Pathogenesis [3]

1. Abnormal neuronal firing (compare with cardiac arrhythmias)
2. Focal (Partial) versus Generalized Seizures
   1. Partial seizures arise from focus or nidus of abnormal neurons or neuronal activity
   2. Generalized seizures arise from global disruption or dissemination of partial seizure
   3. Several inherited causes of seizures now well documented
   4. Inherited seizures due to ion channel or related gene / protein defects
   5. Abnormal glial cell structure and/or function can contribute to
3. Focal Seizures
   1. Most commonly arise secondary to specific brain trauma
   2. Anatomic malformations can lead to neuronal abnormalities
   3. Cortical malformations associated with refractory epilepsy
   4. Seizures originate from one or more localized foci
   5. Focal seizures can then generalize to involve entire brain
4. General Seizures
   1. Seizures usually begins in both cerebral hemisphres
   2. Most generalized forms have strong genetic component
5. Neuronal changes may precede clinical seizures and may be subject to therapy

H. Diagnosis [1,5,11]

1. History and observer histories most important
2. Confirmation and classification by laboratory testing is important
3. Evaluating Differential Diagnosis is Required
   1. Evaluation of cerebral dysfunction due to mass lesion or vascular cause is critical
   2. Magnetic resonance imaging (MRI) is preferred over computed tomography (CT)
   3. MRI angiography (MRA) may be useful
4. EEG within 24 hours if possible
5. Sleep deprived EEG should follow if standard EEG is negative
6. MRI in new onset seizures in adults, with new focal onset, or with persistent seizures
7. Epilepsy classification can be made in most first-seizure patients
8. Refractory epilepsy may be suspected early as it is more common in patients with [8]:
   1. More than 6 seizures before initial therapy (>40% were subsequently refractory)
   2. Poor response to first drug
   3. Only 13% of first drug failures were seizure free on second drug
9. Confirmation of accurate diagnosis should be made in all patients considered "refractory"
10. Therapy should be initiated by a specialist and comprehensive care plan agreed

I. Differential Diagnosis [5,12]

1. Syncope, Presyncope
2. Transient ischemic attack
3. Transient global amnesia
4. Cardiac Arrhythmia
5. Migraine (atypical)
6. Vertigo
7. Tremor
8. Breath-Holding / Functional or Hyperventilation
9. Sleep Apnea or other disturbance
10. Pseudoseizures (psychiatric, including malingering; psychogenic seizures)

J. Therapy Overview [1,5,12,13]

1. Considerations in Choice of Agent
   1. Use of single agent recommended whenever possible (~65% of patients)
   2. Above section (F) outlines preferred agents in most patient settings (not in elderly)
   3. Surgical evaluation may be considered if drug combinations fail
   4. Special attention to drug interactions in elderly patients
   5. Newer agents (gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and zonisamide) showed no detectable differences in efficacy in partial epilepsy [14]
2. Treatment After First Seizure [15]
   1. Unclear whether single idiopathic seizure should be treated with antiepileptic drugs
   2. Overal seizure recurrence after first seizure is ~25% [5]
   3. Seizure recurrence after first tonic-clonic seizure is ~50% after 2-3 years
   4. Risk of subsequent seizures increases with number of previous seizures
   5. Immediate treatment increased time to first and second seizures versus delayed treatment
   6. At 5 years followup, 76% of immediate treatment group and 77% in delayed treatment group were seizure free between 3-5 years after randomization
   7. Treatment is generally not warranted after a single unprovoked seizure [5,16]
3. Broad Spectrum Anti-Epileptics
   1. Generally good choices for treatment of adults
   2. Valproate, lamogrigine, topiramate, levetiracetam, zonisamide
4. Narrow Spectrum Drugs
   1. Restricted to focal epilepsy with partial and secondarily generalized seizures
   2. Carbamazepine, oxcarbazepine, phenytoin, gabapentin, tiagabine, pregabalin
5. Choice of Agent in Elderly
   1. Oxcarbazepine should be substituted for carbamazepine whenever possible
   2. Gabapentin, vigabatrin and lamotrigine are reasonable add-on choices
   3. Lamotrigine had greatest clinical efficacy overall in partial seizures in adults [27]
   4. Valproate had greatest efficacy/tolerability in generalized or unclassified adult epilepsy [28]
   5. These three agents may be used first line in partial or secondarily generilized epilepsy
   6. Gabapentin is probably best tolerated of all, and may be first line choice in elderly
   7. Phenobarbital, primidone, and clobazam are best avoided
6. Acute Therapy for Generalized Seizures
   1. Phenytoin (dilantin) 1gm load IV (hypotension common side effect)
   2. Phenobarbital 30-60mg iv repeated every 5-10 minutes
   3. Benzodiazapines: mainly for alcohol-related seizures (see below)
   4. Pentobarbital: status epilepticus; induce coma
7. Refractory Seizures
   1. Combination drug therapy
   2. Surgery
   3. Vagus nerve stimulator - for some patients with refractory seizures [26]
   4. Resistance to multiple anticonvulsants may be associated with high expression of the drug efflux pump ABCB1 (MDR1, PGP170), polymorphism C3435T [17]
8. Combination Therapy [18]
   1. Valproate and lamogrigine
   2. Valproate and carbamazepine
   3. Carbamazepine and vigabatrin
   4. Lamogrigine and topiramate
9. Surgery for Seizures [19,20]
   1. Generally reserved for medically intractable seizures
   2. Also indicated for epilepsy with clear focus of activity
   3. Surgery may be helpful for temporal lobe seizures
   4. Anterior temporal lobectomy for intractable temporal lobe seizures effective
   5. ~70% with intractable temporal lobe seizures are seizure free at 5 years [20]
   6. For other seizure types, lesionectomy, subpial transection, callosotomy may be used
10. Discontinuing Antiepileptic Agents [2,18]
    1. >60% of persons who remain free of seizures can have medications discontinued
    2. Most physicians wait 2-5 years of seizure-free time before slow reductions in dose
    3. About 77% of those who respond to initial drug are seizure free on its discontinuation [21]
    4. Patients on single agents who are seizure free are most likely to discontinue therapy
11. All of the studied agents cause birth defects with ~1% risk of spina bifida (see below)

K. Treatment by Seizure Type

1. Drug Abbreviations
   1. cbz = carbamazepine
   2. clon = clonazepam, clonazepate
   3. esm = ethosuximide
   4. fel = felbamate
   5. gab = gabapentin
   6. lam = lamotrigine
   7. lev = levatiracetam
   8. oxc = oxcarbazepine
   9. pb = phenobarbital
   10. pht = phenytoin (Dilantin®)
   11. prim = primidone (Mysoline®)
   12. tiag = tiagabine
   13. top = topiramate
   14. vpa = valproate
   15. vig = vigabatrin
   16. zon = zonisamide
2. Treating Symptomatic Partial Epilepsy [2,12,22]
   1. Traditional: cbz, prim, pb, pht, vpa
   2. Newer Agents: tiag, lam, top, gab, oxc, zon
3. Generalized Tonic-Clonic [1]
   1. First Line: cbz, lam, val, top
   2. Second Line: clobazam, lev, oxc, zon
   3. Other agents: acetazolamide, clon, pb, pht
   4. Avoid tiag, vig as they may worsen
4. Treating Absence Idiopathic Generalized Epilepsy [12]
   1. Absence seizures (onset in childhood): esm > vpa = lam
   2. Absence seizures (onset in adulthood): vpa > esm = lam
   3. Newer Agents: lam, top, zon
5. Myoclonic
   1. First Line: val, top
   2. Second Line: clobazam, clon, lam, lev, zon
   3. Avoid cbz, gab, oxc, pregabalin, tiag, vig
6. Focal With or Without Secondary Generalization
   1. First Line: cbz, lam, oxc, vpt, top
   2. Second Line: cloabazam, gab, lev, pregabalin, tiag, zon
   3. Other agents: acetazolamide, clon, pb, pht
7. Neonatal Seizures [23]
   1. Phenobarbital
   2. Phenytoin
   3. Single agents are effective in ~45% of cases of neonatal seizures
   4. Combination therapy should be considered
8. Seizures in Elderly [6]
   1. Thorough understanding of drug metabolism is required
   2. Lam is better tolerated than most of the traditional drugs
   3. Gab is well tolerated as an adjunctive therapy
   4. Controlled release vpa is reasonably well tolerated
   5. Oxc is easier to use than carbamazepine and has less drug interactions
9. Other Epileptic Syndromes
   1. Juvenile Monoclonic Epilepsy: vpa > lam = clon = prim
   2. Infantile Spasms (West's Syndrome): corticotropin > clon = vpa
   3. Lennox-Gastaut Syndrome: vpa = lam > cbz
   4. Severe myoclonic epilepsy in infants: vpa = benzodiazepines, stiripentol (experimental)

L. Summary Of Uses Of Anti-Convulsive Agents [18]

1. Over 60% of patients whose seizures begin in childhood are seizure-free as adults
2. For those that become seizure-free, there was no difference in socioeconomic status compared with matched controls
3. There is an increased risk of death in patients whose seizures continue into adulthood
4. Likewise, a reduction in socioeconomic status is found when seizures continue as adults
5. Children with febrile seizures have no long term consequences compared with children who do not have febrile seizures [25]

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