Epilepsy

Introduction

Epilepsy is defined by the occurrence of at least two unprovoked seizures with or without convulsions (i.e., violent, involuntary contraction[s] of the voluntary muscles) separated by at least 24 hours. A seizure results from an excessive discharge of cortical neurons and is characterized by changes in electrical activity as measured by the electroencephalogram (EEG).

Seizures result from excessive excitation or from disordered inhibition of neurons. Initially, a small number of neurons fire abnormally. Normal membrane conductances and inhibitory synaptic currents then break down, and excitability spreads locally (focal seizure) or more widely (generalized seizure).

• Mechanisms that may contribute to synchronous hyperexcitability include (1) alterations of ion channels in neuronal membranes, (2) biochemical modifications of receptors, (3) modulation of second messaging systems and gene expression, (4) changes in extracellular ion concentrations, (5) alterations in neurotransmitter uptake and metabolism in glial cells, (6) modification in the ratio and function of inhibitory circuits, and (7) local imbalances between the main neurotransmitters (eg, glutamate, γ-aminobutyric acid [GABA]) and neuromodulators (e.g., acetylcholine, norepinephrine, and serotonin)
• Prolonged seizures and continued exposure to glutamate can result in neuronal injury, functional deficits, and rewiring of neuronal circuitry.

International Classification of Epileptic Seizures

I. Partial seizures (seizures begin locally)

A. Simple (without impairment of consciousness)

1. With motor symptoms
2. With special sensory or somatosensory symptoms
3. With psychic symptoms

B. Complex (with impairment of consciousness)

1. Simple partial onset followed by impairment of consciousness—with or without automatisms
2. Impaired consciousness at onset—with or without automatisms

C. Secondarily generalized (partial onset evolving to generalized tonic–clonic seizures)

II. Generalized seizures (bilaterally symmetrical and without local onset)

A. Absence, B. Myoclonic, C. Clonic, D. Tonic, E. Tonic–clonic ,F. Atonic ,G. Infantile spasms

III. Unclassified seizures

IV. Status epilepticus

Symptoms And Signs

• Symptoms depend on seizure type. Although seizures can vary between patients, they tend to be stereotyped within an individual.
• Partial (focal) seizures begin in one hemisphere of the brain and, unless they become secondarily generalized, result in an asymmetric seizure. Partial seizures manifest as alterations in motor functions, sensory or somatosensory symptoms, or automatisms. Patients may have memory loss or aberrations of behavior. A partial seizure that becomes generalized is termed a secondarily generalized seizure. In complex partial seizures, there is impairment of consciousness and no memory of the event.
• Absence seizures generally occur in young children or adolescents and exhibit a sudden onset, interruption of ongoing activities, a blank stare, and possibly a brief upward rotation of the eyes. There is only a very brief (seconds) period of altered consciousness. Absence seizures have a characteristic two to four cycles per second spike and slow-wave EEG pattern.
• GTC seizures are major convulsive episodes and are always associated with a loss of consciousness. Motor symptoms are bilateral. GTC seizures may be preceded by premonitory symptoms (i.e., an aura). A tonic-clonic seizure that is preceded by an aura is likely a partial seizure that is secondarily generalized. Tonic-clonic seizures begin with a short tonic contraction of muscles followed by a period of rigidity and clonic movements. The patient may lose sphincter control, bite the tongue, or become cyanotic. The episode is frequently followed by a deep sleep.

Diagnosis

Ask the patient and family to characterize the seizure for frequency, duration, precipitating factors, time of occurrence, presence of an aura, ictal activity, and postictal state.

• Physical and neurologic examination and laboratory examination may identify an etiology.

LABORATORY TESTS

• In some cases, particularly following GTC (or perhaps complex partial) seizures, serum prolactin levels may be transiently elevated. A serum prolactin level obtained within 10 to 20 minutes of a tonic-clonic seizure can help differentiate seizure activity from pseudoseizure activity but not from syncope.
• Laboratory tests (SMA-20 [sequential multichannel analysis], complete blood cell count, urinalysis, and special blood chemistries) may be done to rule out treatable causes of seizures (hypoglycemia, altered serum electrolyte concentrations, infections, etc.) that do not represent epilepsy. A lumbar puncture may be indicated if there is fever.

Treatment

Goals of Treatment: The goals are to control or reduce the frequency and severity of seizures, minimize side effects, and ensure compliance, allowing the patient to live as normal a life as possible. Complete suppression of seizures must be balanced against tolerability of side effects, and the patient should be involved in defining the balance. Side effects and comorbidities (eg, anxiety, depression) as well as social issues (e.g., driving, job security, relationships, social stigma) have significant impact on quality of life.

GENERAL APPROACH

• Begin with monotherapy. About 65% of patients can be maintained on one antiepileptic drug (AED) and be well controlled, although not necessarily seizure free.
• Up to 60% of patients with epilepsy are noncompliant; this is the most common reason for treatment failure.
• Drug therapy may not be indicated in patients who have had only one seizure or those whose seizures have minimal impact on their lives. Patients who have had two or more seizures should generally be started on AEDs.
• Factors favoring successful withdrawal of AEDs include a seizure-free period of 2 to 4 years, complete seizure control within 1 year of onset, an onset of seizures after age 2 years and before age 35 years, and a normal EEG and neurologic examination. Poor prognostic factors include a history of a high frequency of seizures, repeated episodes of status epilepticus, a combination of seizure types, and development of abnormal mental functioning. A 2-year, seizure-free period is suggested for absence and rolandic epilepsy, whereas a 4-year, seizure-free period is suggested for simple partial, complex partial, and absence associated with tonic-clonic seizures. According to the American Academy of Neurology Guidelines, discontinuation of AEDs may be considered in patients’ seizure free for 2 to 5 years, if there is a single type of partial seizure or primary GTC seizures, if the neurologic examination and IQ are normal, and if the EEG normalized with treatment. Always withdraw AEDs gradually.

Special Considerations In The Female Patient

Estrogen has a seizure-activating effect, whereas progesterone has a seizure-protective effect. Enzyme-inducing AEDs (e.g., phenobarbital, phenytoin, carbamazepine, topiramate, oxcarbazepine, and perhaps rufinamide, lamotrigine, clobazam, and felbamate) may cause treatment failures in women taking oral contraceptives; a supplemental form of birth control is advised if breakthrough bleeding occurs.

• For catamenial epilepsy (seizures just before or during menses) or seizures that occur at the time of ovulation, conventional AEDs should be tried first, but intermittent supplementation with higher-dose AEDs or benzodiazepines should be considered. Acetazolamide has been used with limited success. Progestational agents may also be effective.
• About 25% to 30% of women have increased seizure frequency during pregnancy, and a similar percentage have decreased frequency.
• AED monotherapy is preferred in pregnancy. Clearance of phenytoin, carbamazepine, phenobarbital, ethosuximide, lamotrigine, oxcarbazepine, levetiracetam, topiramate, and clorazepate increases during pregnancy, and protein binding may be reduced. There is a higher incidence of adverse pregnancy outcomes in women with epilepsy, and the risk of congenital malformations is 4% to 6% (twice as high as in nonepileptic women).
• Barbiturates and phenytoin are associated with congenital heart malformations and facial clefts. Carbamazepine has a 0.5% to 1% risk for spina bifida and hypospadias. Topiramate may have a negative effect on birth weight and increase the risk for oral cleft and hypospadias.
• Valproic acid has a 1% to 2% risk of neural tube defects and an increased risk of neurodevelopmental deficits, reduced verbal abilities, and poorer attentional tasks. Teratogenicity can occur at lower doses, but the risk for major congenital malformations significantly increases at doses of 600 mg/day and largest risk is seen at doses greater than 1000 mg/day.
• Other adverse outcomes of maternal seizures are growth, psychomotor, and mental retardation. Some teratogenic events can be prevented by adequate folate intake; prenatal vitamins with folic acid (~0.4–5 mg/day) should be given to women of childbearing potential who are taking AEDs. Higher folate doses should be used in women with a history of a previous pregnancy with a neural tube defect or taking valproic acid. Vitamin K, 10 mg/day orally, given to the mother during the last month before delivery can prevent neonatal hemorrhagic disorder. Alternatively, parenteral vitamin K can be given to the newborn at delivery.

Drugs of Choice for Specific Seizure Disorders

Partial seizures (newly diagnosed) U.S. guideline Adults and adolescents: Carbamazepine, Gabapentin Oxcarbazepine, Phenobarbital, Phenytoin, Topiramate, Valproic acid.

Partial seizures (refractory monotherapy) U.S. guidelines Lamotrigine, Oxcarbazepine, Topiramate.

Generalized seizures absence (newly diagnosed) U.S. guidelines Lamotrigine.

Primary generalized (tonic–clonic) U.S. guidelines Topiramate

Antiepileptic Drugs Dosing and Target Serum Concentration Ranges

Phenobarbital Various, Initial dose 1–3 mg/kg/day (10–20 mg/kg LD), Usual dose 180–300 mg

Clonazepam (Rivotril), initial dose1.5 mg/day. Usual dose 20 mg

Lorazepam Ativan, initial dose PO: 2–6 mg IV: 0.05 mg/kg IM: 0.05 mg/kg, Usual dose PO: 10 mg IV: 0.05 mg/kg.

Phenytoin Dilantin, initial dose PO: 3–5 mg/kg (200–400 mg) (15–20 mg/kg LD), usual dose PO: 500–600 mg

Carbamazepine (Tegral), Initial dose,400 mg/day, Usual dose 400–2,400 mg

Gabapentin (Neogab), initial dose 300–900 mg/day, Maximum dose 4,800 mg

Levetiracetam (Lerace), Initial dose 500–1,000 mg/day, Max dose 3,000–4,000 mg.

Valproic acid (Epival), Initial dose 15 mg/kg (500–1,000 mg) 60 mg/kg, Max dose (3,000–5,000 mg)