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Published: January 2009

Epilepsy

Dileep R. Nair

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Definition

Seizures result from paroxysmal and excessive electrical neuronal discharges in the brain that cause a variety of clinical manifestations. The term epilepsy is usually restricted to those cases with a tendency for recurrent seizures. The identification of a seizure as a symptom and not a disease diagnosis is an important distinction. Seizures are the clinical manifestation of epilepsy; the challenge is to identify the disease that explains the symptom. Often the underlying disease is epilepsy, but at other times it may be a nonepileptic disorder that causes symptoms that resemble an epileptic seizure.

The term epilepsy encompasses a group of syndromes that vary in its associated pathology and seizure types. The diagnosis of the epileptic syndrome is one of the primary objectives undertaken when managing a patient with seizures.

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Prevalence

Epilepsy can manifest itself at any age; however, the incidence and prevalence are highest in the very young and the elderly. Depending on age at manifestation, the causes for epilepsy can differ widely. In the United States, there are approximately 1.6 million people who have epilepsy (roughly 0.6% of the population). Epilepsy has a lifetime prevalence of 3%—that is, 7.2 million persons will become affected by this disorder.1 Almost 10% of the population will experience at least one epileptic seizure in 80 years of life.

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Pathophysiology

Two sets of changes can determine the epileptogenic properties of neuronal tissues. Abnormal neuronal excitability is believed to occur as a result of disruption of the depolarization and repolarization mechanisms of the cell (this is termed the excitability of neuronal tissue). Aberrant neuronal networks that develop abnormal synchronization of a group of neurons can result in the development and propagation of an epileptic seizure (this is termed the synchronization of neuronal tissue).2

A hyperexcitability of neurons that results in random firing of cells, by itself, may not lead to propagation of an epileptic seizure. Indeed, both normal and abnormal patterns of behavior require a certain degree of synchronization of firing in a population of neurons. Epileptic seizures originate in a setting of both altered excitability and altered synchronization of neurons. The excitability of individual neurons is affected by

  • Cell membrane properties and the microenvironment of the neuron
  • Intracellular processes
  • Structural features of neuronal elements
  • Interneuronal connections

The membrane properties and microenvironment of neurons, which maintain potential differences of electrical charge, are determined by selective ion permeability and ionic pumps. Excitatory neurotransmitters usually act by opening Na+ or Ca2+ channels, whereas inhibitory neurotransmitters usually open K+ or Cl channels. The mechanism of action of certain anticonvulsant medications is by Na+ or Ca2+ channel blockade, which likely prevents repetitive neuronal firing. Extracellular ionic concentrations also can contribute to neuronal excitability; for example, an increase in extracellular K+ concentrations (such as in rapid neuronal firing or dysfunction of glia, which are mainly responsible for K+ reuptake) causes membrane depolarization.

Various intracellular processes are controlled by genetic information. Neuronal excitability can be preprogrammed by DNA-controlled effects on cell structure, energy metabolism, receptor functions, transmitter release, and ionic channels. The mechanisms that induce these changes, either phasic or long term, appear to be linked to ionic currents, especially Ca2+ influx. Intracellular Ca2+ mediates changes in membrane proteins to initiate transmitter release and ion channel opening; it also activates enzymes to allow neurons to cover or uncover receptor sites that alter neuronal sensitivity. Various plastic or persistent changes in excitability can result by influencing the expression of genetic information through Ca2+ influx. This may occur by selectively inducing genes to synthesize a protein for a specific reason. One example is the induction of the c-fos gene to produce c-fos protein in neurons involved in an epileptic seizure by the administration of pentylenetetrazol. The exact effects of this coupling are not known, but it provides a means to study the effects of neuronal excitation on cell growth and differentiation as a model for epilepsy, learning, and memory.3

In regard to the structural features of neuronal elements in relation to epilepsy, the two primary regions of the brain that are involved in epilepsy are the cerebral neocortex and the hippocampus. In the neocortex, excitatory synapses are made primarily on the dendritic spines and shaft. The release of neurotransmitters at these sites gives rise to excitatory postsynaptic potentials. The inhibitory synapses are more prominent on the soma or proximal dendrites, and give rise to inhibitory postsynaptic potentials. The placement of these synapses effectively prevents distal excitatory events from reaching the axon hillock. Alterations of neuronal morphology, either spontaneously or as a response to injury, could enhance excitability with either an actual increase in the number of excitatory synapses or a decrease in the number of inhibitory synapses. Such alterations could consist of reduced dendritic branching with excitatory synapses placed closer to the axon hillock, or loss of spines, allowing more excitatory synapses to occur directly on the shaft. Lesions in the neuronal cell body or tracts lead to degeneration of the axon terminal and a new terminal may sprout to make contact with the vacated postsynaptic membrane. This may in turn lead to an increase in the excitatory potential of the neuron.4 Ca2+ currents that occur predominantly at the dendrites causing a high-amplitude prolonged depolarization that can evoke a rapid train of Na+ action potentials (burst-firing of Na+), which is followed by a prolonged after-hyperpolarization. These discharges are believed to contribute to the paroxysmal depolarization shifts and after-hyperpolarization in experimental epileptic foci.5

Neurons are influenced by synaptic and nonsynaptic interconnections. Neurochemical transmission between neurons involves a number of steps that can be selectively altered to affect neuronal excitability. These steps result in the release of neurotransmitters into the synaptic cleft and the postsynaptic membrane, resulting in excitatory or inhibitory postsynaptic potentials via Ca2+ and other second messengers. The transmitters are deactivated by enzymes, by reuptake into axon terminals, or by uptake by glia. The primary excitatory neurotransmitters in the central nervous system are the amino acids glutamate and aspartate. The primary inhibitory neurotransmitters in the central nervous system are gamma-aminobutyric acid (GABA) and glycine. Neurotransmitters and neuromodulators exert their effects by acting on receptors. Specific properties of receptors have been identified on the basis of the effects of certain agonist and antagonist agents, some of which are anticonvulsant drugs. GABAA receptor drugs, which activate Cl, appear to be more effective as anticonvulsants than GABAB receptor agents, which activate K+. The GABAA receptor is of primary importance in absence epilepsy due to its role in the synchronization and desynchronization of thalamocortical pathways. The oscillatory and burst-firing of these circuits is attributed to neurons in the reticular nucleus of the thalamus and leads to synchronization and desynchronization of the electroencephalogram (EEG). Alterations of this mechanism produce absence seizures. Kainic acid, quisqualic acid, and N-methyl-d-aspartate (NMDA) are excitatory amino acid analogues used to define the classes of receptors responsive to glutamate and aspartate. NMDA antagonists are one potential mechanism for some of the anticonvulsants.

Two hypotheses are associated with cortical dysplasia, which is a frequent cause of medically intractable focal epilepsy. The first hypothesis suggests that epileptogenesis results from a change in the synaptic properties of interneurons. The second hypothesis suggests abnormal intrinsic properties in the neurons, such as a mutation in the ion channel.

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Signs and symptoms

The diversity of symptoms that can result from an epileptic seizure arises from the differing brain regions that gives rise to the particular features of an individual seizure. The determination of seizure types can often help in the identification of the epileptic syndrome (Table 1). In spite of the technologic advances that have contributed to the understanding and treatment of epilepsy, the initiation and selection of treatment rely on the observed details of the seizure phenomenology. In this regard, obtaining an accurate seizure history from the patient as well as from observers who have witnessed the patient's seizures is extremely important.

Table 1: Features of Primary Generalized and Partial Epilepsies
Epilepsy Primary Generalized Epilepsy Focal or Partial
Seizure Features
Auras Not present Present
Prodrome Occasionally present Occasionally present
Starting with LOC Present Present
Starting with automatisms Not usually present Present
Prolonged postictal confusion without generalization Not usually present Present
Generalized tonic-clonic seizure Present Present
True versive head movements Not present Present
Focal motor clonic or tonic seizures Not usually present Present
Risk Factors for Epilepsy
Family history of seizures May be present Not usually present
History of CNS infections, significant head trauma, febrile seizures, CNS tumors, CNS vascular malformation Not usually present May be present
Examination Findings
Neurologic examination Usually normal May be abnormal
Neuroimaging Findings
Brain MRI Usually normal May be abnormal
EEG Findings
Generalized epileptiform activity Present Not present
Focal epileptiform activity Not present Present

CNS, central nervous system; EEG, encephalogram; LOC, loss of consciousness; MRI, magnetic resonance imaging.
Data from Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.

There have been many attempts at a classification system for epileptic seizures. The most widely used classification system is the one developed by the International League Against Epilepsy (ILAE), which is an electroclinical classification system (Table 2).6 This classification assumes that there is a one-to-one correlation between the phenomenology of the actual seizures and electrical abnormalities on the EEG seen with the seizure. This, however, is not always the case and these exceptions highlight the main weakness of the ILAE classification.

Table 2: International League Against Epilepsy Classification of Epileptic Seizures
Seizure Types Features
Partial Seizures *EEG findings suggest focal onset
Simple Partial Seizures Consciousness not impaired
With motor symptoms
Focal motor
Focal motor march (Jacksonian)
Versive
Postural
Phonatory Vocalization arrest of speech
With somatosensory or special sensory symptoms Simple hallucinations
Somatosensory
Visual
Auditory
Olfactory
Gustatory
Vertiginous
With autonomic symptoms or signs Epigastric sensations, pallor, sweating, flushing, piloerection, pupillary dilation
With psychic symptoms Disturbance of higher cortical function
Complex partial seizures Consciousness impaired
Absence Seizures
Typical absence Regular and symmetrical 3-Hz SWC on EEG
Atypical absence Irregular slow SWC on EEG
Myoclonic Seizures Polyspike or slow SWC on EEG
Clonic Seizures Fast activity or slow SWC on EEG
Tonic Seizures Low-voltage fast EEG
Tonic-Clonic Seizures Rhythm of less than 10 Hz on EEG
Atonic Seizures Poly SWC or low-voltage fast

*EEG, encephalogram.
SWC, spike-wave complex.Data from Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.

There is an active effort to improve the ILAE classification. One such classification system is already in use in many centers that perform evaluations for epilepsy surgery.7 The advantage of such a semiologic classification is that it does not rely on knowledge of the electrical abnormalities in a patient, which are frequently unavailable. The classification of seizures can be either vague or more specific with this type of classification, depending on the accuracy of the information available.

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Diagnosis

The initial evaluation in patients who present with spells or seizures is to determine whether these episodes are epileptic in nature. A false diagnosis can have severe repercussions for the patient, including the expense of medications as well as their potential adverse effects. Other hazards include the loss of driving privileges, loss of income, and the expense of unnecessary visits to the emergency department. Disorders that can be confused with epilepsy include migraine, syncope, transient ischemic attacks, nonepileptic events (pseudoseizures), movement disorders, Menière's disease, and rage attacks. In pediatric patients, the differential also includes breath-holding spells, pallid infantile syncope, tics, night terrors, somnambulism, and long QT syndrome.8

As soon as epileptic seizures are diagnosed, the next step is to determine the epileptic syndrome and then the seizure type. This is helpful for choosing medications as well as for evaluating a patient for surgical treatment. The epileptic syndrome is determined based on the history, physical examination, EEG findings, and neuroimaging studies. Epileptic syndromes can be divided primarily into two types: generalized epilepsies and focal (or partial) epilepsies. The primary distinction is that the generalized epilepsies have generalized epileptiform abnormalities on EEG, whereas focal epilepsies have focal abnormalities on EEG. Table 1 shows some of the differentiating points between these two types of epilepsies.

The patients with focal epilepsies are candidates for epilepsy surgery if their seizures are intractable to medications. Wilder Penfield in 1956 established the concept of the epileptogenic anatomic lesion and the epileptogenic physiologic lesion.9 The physiologic epileptic lesion was the part of the brain that demonstrated abnormalities on EEG that appeared to extend beyond the anatomic boundaries of the identified pathology responsible for the epilepsy. These areas are not always contiguous.

There are further subdivisions that one can use to differentiate regions associated with epileptogenicity. For example, the epileptogenic lesion may be mesial temporal sclerosis, which may have a surrounding large region of interictal epileptiform activity (abnormal EEG activity not associated with a clinical seizure) described as the irritative zone. The area representing the detected ictal onset (the EEG findings during an epileptic seizure) is referred to as the ictal-onset zone. The area which, when removed by surgery and results in rendering the patient seizure free, is referred to as the epileptogenic zone. The epileptogenic zone can be inferred only retrospectively after surgery. For epilepsy surgery to be successful, the various defined areas usually need to converge in one particular region (Figure 1).10

The EEG helps to confirm the diagnosis of epilepsy and provides information regarding the epileptic syndrome and, in focal epilepsies, the location of the seizure focus. However, the EEG records cerebral activity only during the time of recording, and so its information is only a snapshot in time—it cannot confirm the diagnosis of epilepsy in all patients with epilepsy. Certain activation procedures such as sleep deprivation, photic stimulation, and hyperventilation can improve the detection of epileptiform activity as can obtaining more prolonged EEG recordings. In some cases, when the diagnosis is uncertain, video EEG monitoring can help clarify the epileptic syndrome or identify nonepileptic events. In about 10% of patients with epilepsy, multiple EEG studies could show no abnormalities.8

Neuroimaging, especially with magnetic resonance imaging, is likely to show abnormalities in patients with focal epilepsy. These include vascular abnormalities such as strokes, arteriovenous malformations, cavernous angiomas, brain tumors, mesial temporal sclerosis, cortical dysplasia, and encephalomalacias.

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Treatment

The first-line treatment of epilepsy is administration of an antiepileptic drug (AED). The selection of an appropriate AED is based on diagnosis of the epileptic syndrome of the patient (Table 3). First-line therapy for patients with focal seizures includes phenytoin, carbamazepine, and valproate. Drugs for adjunctive therapy for focal seizures include levetiracetam, topiramate, zonisamide, lamotrigine, gabapentin, oxcarbazepine, phenobarbital, and tiagabine. Drugs used in generalized seizures include valproate, lamotrigine, phenytoin, phenobarbital, and ethosuximide, which is specific for absence seizures.

Table 3: Characteristics of Various Antiepileptic Drugs (AEDs)
AED Efficacy Comments
Carbamazepine Partial seizures, generalized seizures Cytochrome P-450 (autoinducer); active metabolite
Ethosuximide Absence seizures No cytochrome P-450 induction or inhibition; can induce SLE-like syndrome
Gabapentin Partial seizures Minimal drug control; renal clearance of unmetabolized form
Lacosamide Partial seizures Minimal drug interactions
Lamotrigine Generalized and partial seizures Induced by phenytoin, carbamazepine; inhibited by valproate
Levetiracetam Partial seizures Minimal drug control; renal metabolism
Oxcarbazepine Partial seizures Prodrug of monohydroxy-carbamazepine
Phenobarbital Generalized and partial seizures Cytochrome P-450 inducer; excessive sedative effects
Phenytoin Generalized and partial seizures Cytochrome P-450 inducer
Pregabalin Partial seizures Minimal drug interactions
Tiagabine Partial seizures High protein binding; no enzyme induction or inhibition; may precipitate spike-wave stupor
Topiramate Generalized and partial seizures May increase phenytoin levels; no AED enzyme induction; alters efficacy of birth control medication
Valproate Generalized and partial seizures Cytochrome P-450 inhibitor; active metabolites
Zonisamide Partial seizures Minimal drug interactions

AEDs, antiepileptic drugs; SLE, systemic lupus erythematosus.
Data from Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.

These drugs have initial starting doses, and subsequent titration is based on response to medication and side-effect profile (Table 4). In patients who do not respond to medication, epilepsy surgery is a potential mode of treatment that can offer up to a 70% to 90% chance of seizure freedom (defined as no seizures or auras only, on medication) in some patients. Other novel modes of therapy include the vagal nerve stimulator (VNS), which is usually reserved for those patients with intractable epilepsy who are not surgical candidates. The VNS usually is as effective as a typical AED and usually does not provide a seizure-free state. Its mechanism of action is not known. The benefits of the VNS as opposed to AEDs is that it does not have the neurotoxicities associated with AEDs. Some adverse effects of the VNS include coughing, hoarse voice, bradycardia, and exacerbation of sleep apnea.

Table 4: Characteristics of Various Antiepileptic Drugs (AEDs)
AED Typical Adult Starting Dose (mg/day) Titration Some Common Side Effects
Carbamazepine 400 200 mg/day at 1-wk intervals Neurocognitive effects, rash, nausea, vomiting, hyponatremia
Ethosuximide 250-500 250 mg/day at 1-wk intervals Neurocognitive effects, anorexia, nausea, vomiting, weight loss, diarrhea, abdominal pain, headache, mood changes, rash, hirsutism, and gingival hyperplasia
Gabapentin 300-900 300 mg/day at 24-hr intervals Neurocognitive effects, weight gain, mood changes, dry mouth, periorbital edema, myalgias
Lacosamide 100 100 mg/day at 1-wk intervals Neurocognitive, nausea, vomiting, cardiac conduction abnormalities
Lamotrigine 25-50 50 mg/day at 2-wk intervals Neurocognitive effects, headache, rash, mood changes, nausea, vomiting
Levetiracetam 500-1000 1000 mg/day at 2-wk intervals Neurocognitive effects, mood changes, behavior changes, anesthesia
Oxcarbazepine 600 600 mg/day at 1-wk intervals Neurocognitive effects, rash, nausea, vomiting, hyponatremia
Phenobarbital 30-90 30 mg/day at 4-wk intervals Neurocognitive effects, mood changes, nausea, vomiting, rash, porphyria exacerbation, physical dependence
Phenytoin 300 100 mg/day at 4-wk intervals Neurocognitive effects, hirsutism, gingival hyperplasia, nausea, vomiting, coarse facies, headache, lymphadenopathy, osteomalacia
Pregabalin 150 150 mg/day at 1-wk intervals Neurocognitive effects, weight gain, peripheral edema
Tiagabine 4 4-8 mg/day at 1-wk intervals Neurocognitive effects, mood changes, asthenia, nausea, vomiting
Topiramate 25-50 25-50 mg/day at 1-wk intervals Neurocognitive effects, language problems, psychomotor slowing, mood changes, paresthesia, weight loss, renal stones
Valproate 250-500 250 mg/day at 1-wk intervals Neurocognitive effects, weight gain, nausea, vomiting, headache, hair loss, menstrual irregularities
Zonisamide 50-100 100 mg/day at 2-wk intervals Neurocognitive effects, mood changes, insomnia

Neurocognitive side effects include dizziness, drowsiness, unsteadiness, blurred vision, ataxia, tremor, nystagmus, impaired memory, and fatigue.
Data from Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501.

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Outcomes

Seizures are well controlled with a single anticonvulsant in most patients with epilepsy. However, approximately 20% of patients with primary generalized epilepsy and 35% of patients with focal epilepsy have medically intractable seizures.11,12 If seizures are not controlled with the initial dose of a first-line AED and there is no evidence of toxicity, the dose of the drug should be systematically increased. If the seizures are still not under control, a second first-line drug should be tried as monotherapy. If a second monotherapy trial fails, some experts may attempt a combination of two anticonvulsants. The practice of rational polytherapy is the use of two AEDs with differing modes of action, and that do not lead to worsening of adverse effects for the patient. After the third or fourth AED has been tried at appropriate levels and the patient still has seizures, the likelihood of finding an AED that will render that patient seizure free drops to as low as 5%. These patients who are recalcitrant to medical therapy should be referred to an epilepsy surgery center to determine if they are candidates for surgery.

In those patients who become seizure free with medications, withdrawal of the AED can be considered after a seizure-free interval has been maintained for 2 years. The risk of recurrent seizures after discontinuation is 25% in those patients without risk factors and 50% in those patients with risk factors (e.g., structural lesion, abnormal EEGs, or history of intractable epilepsy). The decision to stop medications should be individualized, and discontinuation should be done gradually, such as by decreasing the daily dose by 25% every 2 or 4 weeks.13

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Summary

  • Epilepsy is a disorder that gives rise to seizures of various pathologies and etiologies—an abnormal, synchronized electrical discharge within the brain causes the seizure.
  • Seizures are currently based on an electroclinical classification; however, in addition to history, EEG recordings, imaging studies (such as MRI) may help in the diagnosis of epilepsy.
  • Epilepsy surgery may be helpful the treatment of medically refractory focal epilepsy and should be considered once it has been established that medications have failed.

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References

  1. Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes and Consequences. New York: Demos, 1990.
  2. Engel J Jr. Seizures and Epilepsy. Philadelphia: FA Davis, 1989.
  3. Morgan JI, Cohen DR, Hempstead JL, Curran T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science. 1987, 237: 192-197.
  4. Messenheimer JA, Harris EW, Steward O. Sprouting fibers gain access to circuitry transsynaptically altered by kindling. Exp Neurol. 1979, 64: 469-481.
  5. Matsumoto H, Ajmone-Marsan C. Cortical cellular phenomena in experimental epilepsy: Interictal manifestations. Exp Neurol. 1964, 9: 286-304.
  6. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981, 22: 489-501.
  7. Lüders H, Acharya J, Baumgartner C, et al: Semiological seizure classification. Epilepsia. 1998, 39: 1006-1013.
  8. Browne TR, Holmes GL. Epilepsy [comments]. N Engl J Med. 2001, 344: 1145-1151.
  9. Penfield W. Epileptic lesions. Acta Neurol Psychiatry Belg. 1956, 2: 75-88.
  10. Dinner DS, Lüders HO, Klem G. Chronic electrocorticography: Cleveland Clinic experience. Electroencephalogr Clin Neurophysiol. 1998, 48: (suppl): 58-69.
  11. Cascino GD. Intractable partial epilepsy: Evaluation and treatment. Mayo Clin Proc. 1990, 65: 1578-1586.
  12. Reutens DC, Berkovic SF. Idiopathic generalized epilepsy of adolescence: Are the syndromes clinically distinct? Neurology. 1995, 45: 1469-1476.
  13. Spencer SS, Spencer DD, Williamson PD, Mattson RH. Ictal effects of anticonvulsant medication withdrawal in epileptic patients. Epilepsia. 1981, 22: 297-307.

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Suggested Readings

  • Browne TR, Holmes GL. Epilepsy [comments]. N Engl J Med. 2001, 344: 1145-1151.
  • Cascino GD. Intractable partial epilepsy: Evaluation and treatment. Mayo Clin Proc. 1990, 65: 1578-1586.
  • Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981, 22: 489-501.
  • Dinner DS, Lüders HO, Klem G. Chronic electrocorticography: Cleveland Clinic experience. Electroencephalogr Clin Neurophysiol. 1998, 48: (suppl): 58-69.
  • Engel J Jr. Seizures and Epilepsy. Philadelphia: FA Davis, 1989.
  • Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes and Consequences. New York: Demos, 1990.
  • Lüders H, Acharya J, Baumgartner C, et al: Semiological seizure classification. Epilepsia. 1998, 39: 1006-1013.
  • Matsumoto H, Ajmone-Marsan C. Cortical cellular phenomena in experimental epilepsy: Interictal manifestations. Exp Neurol. 1964, 9: 286-304.
  • Messenheimer JA, Harris EW, Steward O. Sprouting fibers gain access to circuitry transsynaptically altered by kindling. Exp Neurol. 1979, 64: 469-481.
  • Morgan JI, Cohen DR, Hempstead JL, Curran T. Mapping patterns of c-fos expression in the central nervous system after seizure. Science. 1987, 237: 192-197.
  • Penfield W. Epileptic lesions. Acta Neurol Psychiatry Belg. 1956, 2: 75-88.
  • Reutens DC, Berkovic SF. Idiopathic generalized epilepsy of adolescence: Are the syndromes clinically distinct? Neurology. 1995, 45: 1469-1476.
  • Spencer SS, Spencer DD, Williamson PD, Mattson RH. Ictal effects of anticonvulsant medication withdrawal in epileptic patients. Epilepsia. 1981, 22: 297-307.

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