Introduction
Background
Temporal lobe epilepsy (TLE) was defined in 1985 by the International League Against Epilepsy (ILAE) as a condition characterized by recurrent unprovoked seizures originating from the medial or lateral temporal lobe. The seizures associated with temporal lobe epilepsy consist of simple partial seizures without loss of awareness and complex partial seizures (ie, with loss of awareness). The individual loses awareness during a complex partial seizure because the seizure spreads to involve both temporal lobes, which causes impairment of memory. The partial seizures may secondarily generalize.
Temporal lobe epilepsy was first recognized in 1881 by John Hughlings Jackson, who described "uncinate fits" seizures arising from the uncal part of temporal lobe and the "dreamy state." In the 1940s, Gibbs et al introduced the term psychomotor epilepsy.6 The international classification of epileptic seizures (1981) replaced the term psychomotor seizures with complex partial seizures. The ILAE classification of the epilepsies uses the term temporal lobe epilepsy and divides the etiologies into cryptogenic (presumed unidentified etiology), idiopathic (genetic), and symptomatic (cause known, eg, tumor).
Pathophysiology
Although the causes of temporal lobe epilepsy are widely varied, hippocampal sclerosis is the most common pathologic finding. Hippocampal sclerosis involves hippocampal cell loss in the CA1 and CA3 regions and the dentate hilus. The CA2 region is relatively spared. The clinical correlate on neuroimaging on MRI is called mesial temporal lobe sclerosis.
For more information, see Pathophysiology in the article Seizures and Epilepsy: Overview and Classification.
Frequency
United States
Approximately 50% of patients with epilepsy have partial epilepsy. Partial epilepsy is often of temporal lobe origin. However, the true prevalence of temporal lobe epilepsy is not known, since not all cases of presumed temporal lobe epilepsy are confirmed by video-EEG and most cases are classified by clinical history and interictal EEG findings alone. The temporal lobe is the most epileptogenic region of the brain. In fact, 90% of patients with temporal interictal epileptiform abnormalities on their EEG have a history of seizures.
Sex
Temporal lobe epilepsy is not more common in one sex but female patients may experience catamenial epilepsy, which is an increase of seizures during the menstrual period.
Age
Epilepsy occurs in all age groups, but a group where it was underrecognized is in elderly persons. Epilepsy in elderly persons may not be as dramatic and often may present as confusion or memory lapses. The index for suspicion should be low as patients are often misdiagnosed and not treated appropriately.
Clinical
History
* Aura
o Auras occur in approximately 80% of temporal lobe seizures. They are a common feature of simple partial seizures and usually precede complex partial seizures of temporal lobe origin.
o Auras may be classified by symptom type; the types comprise somatosensory, special sensory, autonomic, or psychic symptoms.
* Somatosensory and special sensory phenomena
o Olfactory and gustatory illusions and hallucinations may occur. Acharya et al found that olfactory auras are more commonly associated with temporal lobe tumors than with other causes of temporal lobe epilepsy.1
o Auditory hallucinations consist of a buzzing sound, a voice or voices, or muffling of ambient sounds. This type of aura is more common with neocortical temporal lobe epilepsy than with other types of temporal lobe epilepsy.
o Patients may report distortions of shape, size, and distance of objects.
o These visual illusions are unlike the visual hallucinations associated with occipital lobe seizure in that no formed elementary visual image is noted, such as the visual image of a face that may be seen with seizures arising from the fusiform or the inferior temporal gyrus.
o Things may appear shrunken (micropsia) or larger (macropsia) than usual.
o Tilting of structures has been reported. Vertigo has been described with seizures in the posterior superior temporal gyrus.
* Psychic phenomena
o Patients may have a feeling of déjà vu or jamais vu, a sense of familiarity or unfamiliarity, respectively.
o Patients may experience depersonalization (ie, feeling of detachment from oneself) or derealization (ie, surroundings appear unreal).
o Fear or anxiety usually is associated with seizures arising from the amygdala. Sometimes, the fear is strong, described as an "impending sense of doom."
o Patients may describe a sense of dissociation or autoscopy, in which they report seeing their own body from outside.
* Autonomic phenomena are characterized by changes in heart rate, piloerection, and sweating. Patients may experience an epigastric "rising" sensation or nausea.
Physical
* Following the aura, a temporal lobe complex partial seizure begins with a wide-eyed, motionless stare, dilated pupils, and behavioral arrest. Oral alimentary automatisms such as lip smacking, chewing, and swallowing may be noted. Manual automatisms or unilateral dystonic posturing of a limb also may be observed.
* Patients may continue their ongoing motor activity or react to their surroundings in a semipurposeful manner (ie, reactive automatisms). They can have repetitive stereotyped manual automatisms.
* A complex partial seizure may evolve to a secondarily generalized tonic-clonic seizure. Often, the documentation of a seizure only notes the generalized tonic-clonic component of the seizure. A careful history from the patient or an observer is needed to elicit the partial features of either a simple seizure or a complex partial seizure before the secondarily generalized seizure is important.
* Patients usually experience a postictal period of confusion, which distinguishes temporal lobe epilepsy from absence seizures, which are not associated with postictal confusion. In addition, absence seizures are not associated with auras nor with complex automatisms. Postictal aphasia suggests onset in the language-dominant temporal lobe.
* Most auras and automatisms last a very short period—seconds or 1-2 minutes. The postictal phase may last for a longer period (several minutes). By definition, amnesia occurs during a complex partial seizure because of bilateral hemispheric involvement.
Causes
* Approximately two thirds of patients with temporal lobe epilepsy treated surgically have hippocampal sclerosis as the pathologic substrate.
* The etiologies of temporal lobe epilepsy include the following:
o Infections, eg, herpes encephalitis, bacterial meningitis, neurocysticercosis
o Trauma producing contusion or hemorrhage that results in encephalomalacia or cortical scarring; difficult traumatic delivery such as forceps deliveries
o Hamartomas
o Malignancies (eg, meningiomas, gliomas, gangliomas)
o Vascular malformations (ie, arteriovenous malformation, cavernous angioma)
o Cryptogenic: A cause is presumed but has not been identified.
o Idiopathic (genetic): This is rare. Familial temporal lobe epilepsy was described by Berkovic and colleagues3 , and partial epilepsy with auditory features was described by Scheffer and colleagues.
* Hippocampal sclerosis produces a clinical syndrome called mesial temporal lobe epilepsy (MTLE).
* Febrile seizures: The association of simple febrile seizure with temporal lobe epilepsy has been controversial. However, a subset of children with complex febrile convulsions appear to be at risk of developing temporal lobe epilepsy in later life. Complex febrile seizures are febrile seizures that last longer than 15 minutes, have focal features, or recur within 24 hours.Differential Diagnoses
Absence Seizures
Frontal Lobe Epilepsy
Narcolepsy
Periodic Limb Movement Disorder
Tardive Dyskinesia
Other Problems to Be Considered
Panic disorder: This may be associated with autonomic phenomena and anxiety similar to those observed in the simple partial phase of a temporal lobe seizure. However, unlike temporal lobe epilepsy, which lasts seconds to 2 minutes, panic attacks last several minutes (usually longer than 10 minutes).
Occipital lobe epilepsy: This type of epilepsy may propagate to the temporal lobe and be clinically indistinguishable from a temporal lobe seizure (see article Identification of Potential Epilepsy Surgery Candidates).
Excessive daytime somnolence: This may be due to a sleep-related breathing disorder or narcolepsy. It causes episodes of loss of time due to falling asleep frequently.
Psychogenic seizures: Approximately 10-30% of patients with psychogenic seizures also have epileptic seizures.
Frontal lobe epilepsy: Frontal lobe complex partial seizures have certain distinctive characteristics. They appear in clusters of many brief seizures with rapid onset and ending and minimal, if any, postictal state. Prominent features include bizarre behavioral changes including vocalizations and complex motor and sexual automatisms. However, distinguishing frontal lobe complex partial seizures from those of the temporal lobe based solely on clinical features may be difficult; EEG is invaluable for localization.
Absence epilepsy: Generalized absence seizures have an abrupt onset with no aura, usually last less than 30 seconds, and have no postictal state. EEG in absence shows generalized, bilaterally synchronous spike-and-wave discharges and photosensitivity. Complex partial seizures usually are preceded by a distinct aura, last longer than a minute, and have a period of postictal confusion. EEG shows focal spikes in complex partial seizures.
Workup
Imaging Studies
* CT scan of the head is often obtained in the emergency department, but the resolution is quite poor compared with MRI.
* MRI is the neuroimaging modality of choice for patients with temporal lobe epilepsy. Most brain MRI do not include coronal images, but for temporal lobe epilepsy this sequence is more informative than the axial and sagittal cuts.
o Thin coronal oblique slices of 1.5-2 mm with no gap using spoiled gradient recall images (SPGR) are recommended.
o All patients with newly diagnosed temporal lobe epilepsy should have a high-resolution MRI with at least a 1.5-Tesla MRI, although the availability of a stronger magnet is increasing resolution.
o High-resolution MRI shows hippocampal atrophy in many patients with temporal lobe epilepsy by visual analysis alone. Hippocampal atrophy is bilateral in 10-15% of cases. An increase in the T2-weighted signal intensity in the hippocampus may be seen on fluid-attenuated recovery (FLAIR) MRI; this finding is also consistent with hippocampal sclerosis.
* Positron emission tomography with 18-fluorodeoxyglucose (PET-FDG) is a useful tool for interictal seizure localization in surgical candidates when the MRI result is normal.
o It usually is performed as an adjunctive measure to delineate the epileptogenic zone.
o Interictal deficits include reduced glucose metabolism in the medial and lateral temporal lobe.
o Ictal PET recordings are rare.
* Single-photon emission computed tomography (SPECT) is also an adjunctive imaging modality useful only for surgical candidates; the accuracy of seizure localization is about 80-90%.
o Ictal SPECT done with hexamethylpropyleneamine oxime (HMPAO) shows hyperperfusion in the region of seizure onset. The characteristic pattern is hyperperfusion of the medial and lateral temporal lobe. This requires ictal injection within 30 seconds of seizure onset.
o Interictal SPECT testing is less sensitive than FDG-PET and ictal SPECT and is not used routinely for localization of the epileptogenic zone.
* Investigational techniques such as MR spectroscopy may become clinically useful in the future in selected surgical candidates with normal MRI.
Other Tests
* EEG should be performed in all patients with suspected temporal lobe epilepsy.
o Interictal abnormalities, consisting of spike/sharp and slow complexes, usually are located in the anterior temporal region (F7/F8 and T3/T4 electrodes) or basal temporal electrodes (most commonly T1/T2 and in research settings T9/T10 and F9/F10). During video-EEG monitoring sphenoidal electrodes can be useful.
o One third of patients with temporal lobe epilepsy have bilaterally independent, temporal interictal epileptiform abnormalities.
o Ictal recordings from patients with typical temporal lobe epilepsy usually exhibit 5-7 Hz, rhythmic, sharp theta activity, maximal in the sphenoidal and the basal temporal electrodes on the side of seizure origin.
o In documented temporal lobe seizures, lateralized postictal slowing, when present, is a reliable lateralizing finding.
o A patient with temporal lobe epilepsy can have a normal EEG. The yield of the EEG can be increased on a repeat study with prolonged recordings, and, in certain patients, activation with sleep deprivation can be useful.
o Video-EEG telemetry is used as part of the presurgical evaluation. It also is used if the diagnosis of temporal lobe epilepsy is suspected but still in question.
o Intracranial EEG with placement of intracranial subdural electrodes is done only if the patient is a surgical candidate and MRI and other non-invasive EEG data are not sufficiently localizing (see article Presurgical Evaluation of Medically Refractory Epilepsy).
* Another complementary method to assess cerebral physiologic activity similar to EEG is magnetoencephalography (MEG), which measures the magnetic fields generated by the epileptic spikes. The main use of MEG is the co-registration with the MRI to give magnetic source imaging (MSI) in 3-dimensional space.
More on Temporal Lobe Epilepsy.Treatment
Medical Care
* About 47-60% of new-onset partial seizures are controlled effectively by the first drug. Studies in 1985 and 1992 by the Department of Veterans Affairs (VA) have shown that the 4 major antiepileptic drugs (AEDs), phenytoin, phenobarbital, carbamazepine, and valproate, are equally effective in controlling partial seizures; however, phenobarbital has more severe adverse effects.
* The newer AEDs, such gabapentin, topiramate, lamotrigine, levetiracetam, oxcarbazepine, and zonisamide have similar efficacy than the older AEDs but standout predominantly in having much less side effects both in day-to-day use as well as in long-term side effects. In 2005, pregabalin became the latest drug available.
* In patients with newly diagnosed epilepsy, oxcarbazepine appears to be significantly better than carbamazepine in terms of tolerability and health-related quality of life issues. The newer drugs are easier to use in terms of having much less drug-drug interactions than the older AEDs.
* About 40% of patients continue to have seizures in spite of trials with 3 AEDs. Semah and colleagues showed that seizures are more likely to be refractory to AEDs in patients with hippocampal sclerosis.17
Surgical Care
* Vagus nerve stimulation
o Vagus nerve stimulation (VNS) was approved by the FDA in 1997 for treatment of intractable partial epilepsy for patients aged 12 years and older. VNS with a high-frequency stimulation rate resulted in a mean reduction in seizure frequency of 25-28% at 3 months but improves to about 40% by year one. The exact mechanism by which it exerts its antiepileptic effect is not known. A battery-operated stimulator device is implanted in the chest and an electrode is attached to left vagus nerve in the neck.
o Adverse effects include hoarseness of voice, cough, local pain, paresthesias, dysphagia, and dyspnea when the device is on and almost none when the device is off, but the settings can be titrated so side effects can be minimized. VNS does not have the adverse effects associated with AEDs and is used adjunctively with AEDs.
* Anterior temporal lobectomy
o Temporal lobectomy is the definitive treatment for medically intractable temporal lobe epilepsy (see article Identification of Potential Epilepsy Surgery Candidates). When seizures are not controlled by 2 different AED trials, the patient should be considered for a presurgical evaluation. These patients are not likely to achieve seizure control with medications alone (5-10% chance of becoming seizure free).
o The presence of unilateral hippocampal sclerosis and concordant EEG findings predict seizure-free outcome in patients considered for surgery. Foldvary and colleagues showed that a higher monthly preoperative seizure frequency is associated with a less favorable surgical outcome (see article Outcome of Epilepsy Surgery).5
o An extensive presurgical assessment for the feasibility of surgery is essential. This includes MRI, interictal and ictal EEG, neuropsychological testing, and the intracarotid amobarbital test called the Wada test.
o Seizure-free state at 2 years postoperatively is predictive of long-term seizure-free outcome. In well-selected cases, 70-80% of patients with refractory temporal lobe epilepsy become seizure free after surgery (see article Outcome of Epilepsy Surgery).
Medication
Until a few years ago, 4 principal medications were used for partial seizures: phenytoin, carbamazepine, valproate, and phenobarbital. In recent years, a number of newer medications have been approved by the FDA. Some of these newer AEDs are approved as monotherapy, but how they compare to the older AEDs is not known. The initial choice of medication depends on many factors including side effect profile and dosage schedule and comorbid conditions. The major VA trials did not show any significant difference in seizure control among the 4 older AEDs. Adverse effects were greater with phenobarbital and with primidone.
Single-drug therapy is the goal, and the dosage of each medication prescribed should be increased until either seizures are controlled or adverse effects occur.
Rufinamide (Banzel), a new anticonvulsant, was recently approved as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome.
Anticonvulsants
These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.
Carbamazepine (Tegretol, Carbatrol, Epitol)
Affects sodium channels during sustained rapid repetitive firing.
Extended release form preferred (Tegretol XR or Carbatrol) because of bid dosing, which improves compliance and leads to more stable blood levels. No IV formulation available.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
600-2000 mg/d PO
Pediatric
5 mg/kg/d PO initially, followed by maintenance dose of 15-20 mg/kg/d
* Dosing
* Interactions
* Contraindications
* Precautions
Danazol may increase serum levels significantly within 30 d; do not coadminister with MAOIs; cimetidine and erythromycin may increase toxicity; may decrease primidone and phenobarbital levels (their coadministration may increase carbamazepine levels); CBZ can decrease efficacy of oral contraceptive pills
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; concurrent MAOIs
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Obtain CBCs and serum iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness; long-term use has been associated with osteopenia. In patients with Asian ancestry a recent alert recommends checking for HLA B-1502 before starting CBZ because of the risk of rash.
Phenytoin (Dilantin)
One of oldest drugs known for treatment of seizures. In young women, can coarsen facial features and can cause hirsutism and gingival hyperplasia. In addition, requires frequent blood level determinations because of nonlinear pharmacokinetics. Long-term use associated with peripheral neuropathy and osteopenia.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Loading dose: 15-20 mg/kg/d PO/IV at rate no faster than 50 mg/min
Can be mixed only with isotonic saline since D5W causes phenytoin to precipitate fosphenytoin (prodrug of phenytoin) measured in units of phenytoin equivalents (PE; fosphenytoin can be diluted with either saline or D5W)
Maintenance: 3-5 mg/kg/d PO/IV
Fosphenytoin loading dose: 20 mg PE/kg infused IV at maximal rate of 150 mg/min
Pediatric
Initial dose: 5-7 mg/kg/d PO/IV
Maintenance: 5-7 mg/kg/d PO/IV
* Dosing
* Interactions
* Contraindications
* Precautions
Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimides, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity
Barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate may decrease effects
May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, valproic acid
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Perform blood counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue use if skin rash appears and do not resume use if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest, marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood glucose); discontinue use if hepatic dysfunction occurs
Valproate (Depacon, Depakene, Depakote, Depakote ER)
Anticonvulsant effective for broad spectrum of seizure types, believed to exert anticonvulsant effect by increasing GABA levels in brain. Approved for monotherapy or adjunctive therapy for partial seizures and generalized tonic-clonic seizures. Depakene capsule or syrup, Depakote tablet or sprinkle.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
10-15 mg/kg/d IV initially at rate of 20 mg/min; increase by 5-20 mg/kg/wk to maximum 60 mg/kg/d or as tolerated
(Depakote ER the once-a-day formulation is not bioequivalent to Depakote DR, so adjustment requires 8-20% more on conversion, but levels can be checked.)
Pediatric
20 mg/kg/d IV initially followed by maintenance dose of 20-40 mg/kg/d
* Dosing
* Interactions
* Contraindications
* Precautions
Cimetidine, salicylates, felbamate, and erythromycin may increase toxicity; rifampin may significantly reduce levels; in children, salicylates decrease protein binding and metabolism; may result in variable changes of carbamazepine concentration with possible loss of seizure control; may increase diazepam and ethosuximide toxicity (monitor closely); may increase phenobarbital and phenytoin levels, while either may decrease valproate levels; may displace warfarin from protein-binding sites (monitor coagulation tests); may increase zidovudine levels in HIV-seropositive patients
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; hepatic disease/dysfunction
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Thrombocytopenia and abnormal coagulation parameters have occurred; risk of thrombocytopenia increases significantly at total trough valproate plasma concentrations >110 mcg/mL in females and >135 mcg/mL in males; at periodic intervals and prior to surgery, determine platelet counts and bleeding time before initiating therapy; reduce dose or discontinue therapy if hemorrhage, bruising, or hemostasis/coagulation disorder occurs; hyperammonemia may occur, resulting in hepatotoxicity; monitor patients closely for appearance of malaise, weakness, facial edema, anorexia, jaundice, and vomiting; may cause drowsiness
Phenobarbital (Barbita, Luminal, Solfoton)
One of first major AEDs, introduced in 1919. FDA approved for initial or adjunctive therapy for partial-onset seizures. Has major cognitive adverse effects, which have limited its use in favor of newer AEDs that have better side-effect profiles. Long-term use has been associated with osteopenia.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
90 mg PO qd initially; increase by 30 mg/d every mo to usual maintenance dose of 90-120 mg/d
Pediatric
3-5 mg/kg/d PO initially, followed by maintenance dose of 3-5 mg/kg/d
* Dosing
* Interactions
* Contraindications
* Precautions
May decrease effects of chloramphenicol, digoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of oral contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may also occur)
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia since adverse reactions can occur; caution in myasthenia gravis and myxedema
Lamotrigine (Lamictal)
Newer AED approved as adjunctive therapy and crossover monotherapy for partial seizures. Also blocks sodium channels during sustained rapid repetitive neuronal firing. FDA approved for children younger than 16 years only for Lennox-Gastaut syndrome; not FDA approved for children with partial seizures because of increased incidence of rash.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Weeks 1 and 2: 50 mg/d PO; if given as adjunctive therapy with valproic acid, then 25 mg qod
Weeks 3 and 4: 100 mg/d PO in divided doses; if given as adjunctive therapy with valproic acid, then 25 mg/d, increase by 100 mg/d PO every wk; if coadministered with valproic acid, increase by 25-50 mg PO every other wk
Maintenance dose: 300-500 mg/d PO in divided doses; if coadministered with valproic acid, 100-200 mg/d
Pediatric
Initial dose: 1-2 mg/kg PO
Maintenance dose: 5-10 mg/kg PO
* Dosing
* Interactions
* Contraindications
* Precautions
Acetaminophen increases renal clearance, decreasing effects; similarly, phenobarbital and phenytoin increase metabolism, decreasing levels; valproic acid increases half-life significantly to 63 h; lamotrigine has no effect on oral contraceptives pill (OCP), but OCPs decrease levels of lamotrigine (7 days without active hormonal medication lamotrigine levels can rise as much as 40%)
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Incidence of severe rash is 1% in pediatric and 0.3% in adult patients; almost all cases occur within 2-8 wk of treatment; incidence of rashes of all types is 3.3% in monotherapy and with adjunctive therapy with enzyme-inducing AEDs (eg, phenytoin, carbamazepine); with enzyme-inhibiting AEDS (eg, valproate), incidence of rash is 10%; risk of rash reduced with slow titration; severe rash can develop into Stevens-Johnson syndrome
Gabapentin (Neurontin)
Approved by FDA as adjunctive therapy for partial seizures. Structurally related to GABA but does not affect GABA directly, although it is thought to modulate calcium channel.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
Start at 300 or 400 mg PO tid and increase prn not to exceed 4800 mg/d
Usual minimum effective dose for partial seizures as an adjunct is 1200 mg; if CrCl 30-60 mL/min, 300 mg PO bid; if CrCl 15-30 mL/min, 300 mg PO qd
Hemodialysis patients: 200-300 mg after every hemodialysis
Pediatric
4-13 mg/kg/d PO initially
Maintenance: 10-50 mg/kg/d PO
* Dosing
* Interactions
* Contraindications
* Precautions
Antacids may reduce bioavailability significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly. Absorbed through the amino acid transport system, which is saturable.
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe renal disease; dizziness or somnolence may occur when starting therapy, so patients should be warned not to drive or operate heavy machinery during initial phase of treatment
Topiramate (Topamax)
Approved by FDA as monotherapy or adjunctive therapy for partial seizures and symptomatic generalized seizures. Exerts action by 4 mechanisms: sodium channel blockade, enhancement of GABA activity, antagonism of AMPA/kainate-type glutamate excitatory receptors, and weak inhibition of carbonic anhydrase.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
400 mg PO qd in 2 divided doses; initial starting dose 25 mg/d with gradual increase of 25 mg/wk
Therapeutic response may be observed at dose of 200 mg/d; if renal CrCl <70 mL/min, then reduce dose by half
Pediatric
1-9 mg/kg/d PO
* Dosing
* Interactions
* Contraindications
* Precautions
Phenytoin, carbamazepine, and valproic acid can significantly decrease levels; carbonic anhydrase inhibitors may increase risk of renal stone formation; use with extreme caution when administering concurrently with CNS depressants since may have additive effect in CNS depression, as well as other cognitive or neuropsychiatric adverse events; has dose-related effect on oral contraceptives efficacy above 200 mg/d
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
1.5% of patients develop kidney stones, because is weak carbonic anhydrase inhibitor; can cause metabolic acidosis and serum bicarbonate may be measured in those who may be symptomatic
Tiagabine (Gabitril)
Enhances GABA activity by inhibiting uptake in neurons and astrocytes. Can be used as add-on therapy for partial seizures. Has been known to exacerbate seizures with spike wave stupor. Recently, some patients who were receiving off label and never had seizures had seizures induced with tiagabine when used with another medication, which lowers the seizure threshold.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
4 mg PO qd to start, increase by 4-8 mg/d every wk to maintenance dose of 32-56 mg in 2-4 divided doses
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
Cleared more rapidly in patients treated with carbamazepine, phenytoin, primidone, or phenobarbital than in patients who have not received one of these drugs
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Patients receiving valproate monotherapy may require lower doses or slower dose titration for clinical response; has caused moderately severe to incapacitating generalized weakness in as many as 1% of patients with epilepsy; weakness may resolve after reduction in dose or discontinuation of tiagabine; should be withdrawn slowly to reduce potential for increased seizure frequency
Zonisamide (Zonegran)
Approved in United States for adjunctive use for partial seizure. Has been studied extensively in Japanese and European trials for primary generalized seizures. Blocks T-type calcium currents and prolongs sodium-channel inactivation. Also weak carbonic anhydrase inhibitor. In monotherapy, has long half-life of 70 h.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
100 mg PO qd initially for 2 wk, then increase by 100 mg/d qwk to q2wk to maintenance dose of 100-300 mg bid
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May increase serum carbamazepine levels; carbamazepine may increase concentrations; phenobarbital may decrease levels
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; history of urolithiasis
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Administration associated with 2-3.5% risk of urolithiasis; anorexia, nausea, ataxia, impaired concentration, and other cognitive side effects have been reported; cleared by hepatic conjugation and oxidation; therefore, dose should be reduced in patients with hepatic insufficiency
Oxcarbazepine (Trileptal)
Approved by FDA as monotherapy and adjunctive therapy for partial epilepsy in adults and children aged 2-16 years. Blocks sodium-activated channels during sustained rapid repetitive firing. Oxcarbazepine has antiepileptic activity, but its monohydroxy (MHD) metabolite is the most active compound. Different than carbamazepine, which generates 10-11 epoxide metabolite.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
300 mg PO initially bid; increase by 300 mg bid qwk to maintenance of 600-1200 mg bid
Pediatric
Start with 8-10 mg/kg/d given bid and titrate to 18.5 to 48 mg/kg/d; not to exceed 2100 mg/d
* Dosing
* Interactions
* Contraindications
* Precautions
May decrease levels of dihydropyridine calcium antagonists and oral contraceptives; can reduce serum concentrations of carbamazepine, phenobarbital, phenytoin, and valproic acid; when given in doses >1200 mg/d, may increase phenytoin and phenobarbital serum concentrations significantly; can reduce serum concentrations of oral contraceptives and make oral contraceptives ineffective; can increase clearance of felodipine
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; hypersensitivity to carbamazepine (25-30% have cross-sensitivity)
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Among persons with hypersensitivity to carbamazepine, 25-30% will have hypersensitivity to oxcarbazepine; can cause cognitive adverse effects such as psychomotor slowing, impaired concentration, impaired speech and impaired language; in persons with impaired renal function (CrCl <30 mL/min), dose should begin at half usual starting dose, and dose increments should be made more slowly; can cause hyponatremia (sodium <125 mmol/L); rapid withdrawal can cause exacerbation of seizures; observe for adverse effects and monitor plasma levels of concomitant anticonvulsants during dose titration
Levetiracetam (Keppra)
Approved by FDA in 1999 as add-on therapy for partial seizures. Also FDA approved as add-on therapy for juvenile myoclonic epilepsy and primary generalized tonic clonic seizures. Mechanism of action is thought to be related to its binding to presynaptic vesicle protein. Has favorable adverse effect profile overall except for behavioral changes.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
500 mg PO bid initially; increase by 500 mg PO bid q2wk; not to exceed 1500 mg PO bid in adults; lower doses recommended in elderly (start at 250 mg PO bid) and in patients with renal impairment. There is also an oral solution and IV formulation
Pediatric
Recommended starting dose is 20 mg/kg PO divided bid and can be increased over time to 60 mg/kg
* Dosing
* Interactions
* Contraindications
* Precautions
None reported
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Renally excreted (67%) and, thus, dose should be lowered in renal impairment; major side effects include somnolence, asthenia, incoordination, mild leukopenia (3%), and behavioral changes such as anxiety, hostility, emotional lability, depression and psychosis (1-2%), and depersonalization
Felbamate (Felbatol)
Approved for medically refractory partial seizures and Lennox-Gastaut syndrome. Has multiple mechanisms of action, including blockade of glycine site of NMDA receptor, potentiation of GABAergic activity, and inhibition of voltage-sensitive sodium channels. High rate of life-threatening side effects, so benefit risk needs to be carefully addressed.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
600 mg PO tid initially; increase by 600-1200 mg/d qwk; not to exceed 1200-1600 mg PO tid
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May increase steady-state phenytoin levels—40% dose-reduction of phenytoin may be necessary in some patients; phenytoin may double clearance, resulting in more than 45% decrease in steady-state levels; phenobarbital may cause increase in phenobarbital plasma concentrations; phenobarbital may reduce plasma levels; may decrease steady-state carbamazepine levels and increase steady-state carbamazepine metabolite levels; may increase steady-state valproic acid levels
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity; blood dyscrasias; hepatic dysfunction
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Associated with marked increase in incidence of aplastic anemia (monitor CBC periodically); marked increase in fatal hepatic failure reported in patients receiving felbamate; perform liver function testing (ALT, AST, bilirubin) before therapy and at 1- to 2-wk intervals during therapy; discontinue immediately if liver abnormalities detected during treatment
Pregabalin (Lyrica)
A new medication approved in 2005 for adjunctive use in partial seizures in adults. Has similar mechanism as gabapentin by modulating calcium channel but is more potent and has linear pharmacokinetics.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
75 mg PO bid or 50 mg PO tid initially; if needed, may increase dose to maximum of 600 mg/d
Pediatric
Not established
* Dosing
* Interactions
* Contraindications
* Precautions
May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
* Dosing
* Interactions
* Contraindications
* Precautions
Documented hypersensitivity
* Dosing
* Interactions
* Contraindications
* Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min)
Rufinamide (Banzel)
Antiepileptic agent. Structurally unrelated to current antiepileptics. Modulates sodium channel activity, particularly prolongation of the channel's inactive state. Significantly slows sodium channel recovery and limits sustained repetitive firing of sodium-dependent action potentials. Indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.
* Dosing
* Interactions
* Contraindications
* Precautions
Adult
400-800 mg/d PO divided bid initially; increase in 400-800-mg/d increments q2d; not to exceed 3200 mg/d; administer with food
Adding to valproate: Initiate at dose <400 mg/d PO divided bid
Pediatric
<4 years: Not established
>4 years: 10 mg/kg/d PO divided bid initially, may increase in 10-mg/kg increments qod; not to exceed 45 mg/kg/d or 3200 mg/d; administer with food.Follow-up
Prognosis
* Morbidity and mortality are increased compared with those in the general population due to increased accidents from the episodes of loss of consciousness. Mortality also occurs from sudden unexplained death in epilepsy (SUDEP). Patients with refractory temporal lobe epilepsy have an increased risk of sudden death that is 50 times greater than that in the general population. For more information, see the article Sudden Unexpected Death in Epilepsy. Epilepsy surgery seems to modify the risk of SUDEP if the patient remains seizure free. In patients who have undergone surgery, the mortality rate becomes equivalent to that of the general age- and sex-matched population.
* Seizure-free state 2 years after anterior temporal lobectomy is predictive of long-term seizure-free outcome.
* About 47-60% of patients become seizure free with medical treatment. After 3 first-line AEDs have failed, the chance for seizure freedom is 5-10%. Surgery in well-selected patients with refractory temporal lobe epilepsy yields a seizure-free outcome rate of 70-80%.
* Patients with refractory temporal lobe epilepsy typically have material-specific deficits in memory function. Those patients with dominant temporal lobe epilepsy often have impaired language function as demonstrated by reduced naming ability on the Boston Naming Test.
Patient Education
For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.
Miscellaneous
Medicolegal Pitfalls
The most common medicolegal pitfall arises from the fact that different states in the United States have different rules regarding the physician's responsibility to report a patient with newly diagnosed epilepsy. For example, California state law mandates that the physician is responsible for reporting a patient with new-onset epilepsy to the Department of Motor Vehicles (DMV). If a doctor fails to report to DMV and the patient has an accident in which a third party is injured, the injured third party is able to sue the doctor for failure to report to the DMV and the DMV for failure to take away the patient's driver's license. Furthermore, even patients who report only simple partial seizures may have unrecognized complex partial seizures.
Special Concerns
Fetal anomalies due to antiepileptic medications: Physicians should carefully document on the chart that they have explained to their female patients with epilepsy about the increased risk of fetal anomalies associated with antiepileptic medications, a 2-fold increase (4-6%), and the increased risk of neural tube defects with valproate (1.5-2.0%) and carbamazepine (0.5%). Patients should be told that most women with epilepsy have healthy children (90-95%). They also should be told that the chance of a normal pregnancy outcome is increased with planned pregnancies, improved seizure control, folate supplementation (1-2 mg each day prior to pregnancy), minimizing the number of AEDs used, and never abruptly discontinuing AEDs without consulting the physician. Soon data from the Mass General AED pregnancy registry will be released, which will give some information about these medications.
