Adolescent Health Care: A Practical Guide
Wendy G. Mitchell
Lawrence S. Neinstein
Epilepsy is the most common chronic neurological condition in adolescents. It is defined as recurrent, usually transient, episodes of disturbed central nervous system (CNS) function (seizures), excluding extracerebral causes such as syncope, hypoglycemia, or episodic psychiatric syndromes. Epilepsy has been reported since biblical times and has been seen differently by various cultures. Views have ranged from veneration of patients with epilepsy as mystics to imprisoning them or placing them in mental hospitals. As recently as 1965, two states prohibited marriage if a person had epilepsy, and until the early 1970s, immigration into the United States was prohibited for people with epilepsy. Most adolescents with epilepsy have the potential for excellent control with medication and a high likelihood of eventual remission of their epilepsy. Recent advances in basic science and neurogenetics have contributed to the understanding of mechanisms of epilepsy and seizures. New medications and surgical techniques have improved the outcome of severe, intractable epilepsy. Despite this, fears, prejudices, and social stigma remain common. Epilepsy is therefore somewhat more challenging to treat in teens than other chronic illnesses.
Epilepsy is a difficult condition for patients of all ages. However, for the adolescent concurrently undergoing the stresses of peer relationships, independence, and body image, epilepsy can be particularly trying. The goals of management of epilepsy include proper diagnosis, evaluation, treatment of underlying etiologies, appropriate use of anticonvulsant drugs, and recognizing and dealing with the many associated psychosocial problems.
Seizures are caused by an excessive discharge of a population of cortical neurons. The location and pattern of spread of activity determine the clinical expression. Seizures may be due to acute physiological or neurological disturbances or due to epilepsy. Recurrent unprovoked seizures are the hallmark of epilepsy. The diagnosis of epilepsy does not imply a specific etiological factor in the individual. Epilepsy may be genetic, idiopathic, or secondary, due to remote insult to the nervous system. Infection, trauma, metabolic disturbances, drugs, drug withdrawal, syncope or fever may also provoke seizures acutely. Seizures that occur only in the setting of an acute provocation are not generally classified as epilepsy, although in some epileptics, specific stimuli or situations provoke seizures. Seizures acutely provocable by specific stimuli such as strobe lights (reflex seizures) may be due to genetic epilepsies or may be nonepileptic isolated provoked seizures.
- Prevalence: 1 of 200 in the general population, with a higher prevalence in children.
- Incidence: Annual incidence is 1:1,000.
- Onset: Peak periods for the onset of idiopathic and age-related primary epilepsies are during the early school years and during adolescence. The onset of secondary (remote symptomatic) seizures is highest during infancy and in the geriatric age-group but may occur at any age.
- Gender: Epilepsy occurs slightly more often in males than in females (relative risk for males, 1.1–2.4 in various studies).
- Socioeconomic, racial, and ethnic factors: In the United States and Western Europe, epilepsy is slightly more common among lower socioeconomic groups. Epilepsy is more common in Mexico, South America, and Central America, and in immigrants from these areas in the United States, at least partially due to the high incidence of cerebral cysticercosis. Epilepsy is more prevalent among African-Americans than among Whites in the United States.
- Mental retardation and cerebral palsy are associated with higher rates of epilepsy, as well as lower rates of remission of childhood-onset epilepsy.
- Epilepsy is associated with an increased risk of death, including sudden unexplained death, but the risk in adolescents with epilepsy is low.
Table 21.1 lists classifications of seizures, based on international classifications.
The progression of a seizure is characterized by several temporal components, variably present:
- Prodrome: Altered behavior or mood occurring hours to days before the actual seizure; infrequent.
- Aura: Altered sensation or psychic symptom occurring just before other ictal manifestations. The aura is actually part of the seizure, representing a simple partial seizure, usually with sensory, special sensory, or psychic symptoms.
- Ictus: The observed seizure event, usually with motor activity.
- Postictal state: Altered neurological function ranging from coma to mild lethargy, hemiplegia to minimal focal motor dysfunction, lasting minutes to 24 hours.
Grand Mal Seizures (Generalized Tonic-Clonic Seizures)
- Aura: May have brief, nondescript aura
- Tonic phase: Forceful, postural contractions in flexion or extension. Usually, the early phase, momentary to several minutes, occasionally longer, may include the following:
- Deviation of head
- A cry at the onset
- Loss of consciousness at the start of the seizure
- Fall to ground
- Bites tongue or cheeks
- Clonic phase: Bilateral, generally symmetrical, brisk jerking movements. Clonic movements have a discernible fast–slow component, as distinguished from other types of movement (writhing, sustained posturing, random bilateral nonsynchronous movements), which are less likely a part of a convulsion.
- After the tonic-clonic phase, the patient usually becomes flaccid, with or without incontinence of urine or stool, as 0seizure stops.
- Postictal state
- Early: Unconscious state, with decreased tone and reflexes. Patients may have fixed pupils.
- Recovery phase: Sleeplike state, but patient is responsive to arousal.
- Late phase: Confusion or headache.
Petit Mal and Other Absence Seizures
- Prodrome: None, but often cluster on rising in the morning.
- Aura: None; abrupt onset of ictus.
- Ictus: Brief period (few seconds–30 seconds) of blank staring.
- Loss of consciousness, usually without fall.
- Typical absence: Minor automatisms; may have blinking of eyes; movement of fingers common. Onset
is abrupt and seizure ends with near-immediate return to normal.
- Atypical absence: May be associated with automatisms, myoclonic movements or loss of tone; may be longer than 30 seconds; onset is more likely gradual and end is not as abrupt.
- Postictal: No postictal confusion, but amnesia of seizure is usual.
- One third of absence seizures remit during adolescence (most likely in childhood—onset simple absence; less likely in adolescence—onset absence).
- The electroencephalogram (EEG) is characteristic, showing 3-Hz spike and wave activity in typical petit mal seizure. Other absence syndromes show generalized polyspike wave discharges, slow spike wave (Lennox-Gastaut syndrome), or 4- to 5-Hz spike wave (juvenile myoclonic epilepsy [JME] of Janz).
- Specific epileptic syndromes with onset in adolescence combine absence with myoclonic seizures and occasional grand mal seizures, most prominent on arising in the morning. Early morning myoclonus may be viewed as “normal” by the patient and not reported without specific questioning (JME of Janz).
- Patients with absence or absence plus myoclonic seizures are more likely to be photosensitive than those with other seizure types. “Video game”–related seizures are generally limited to these patients.
- Myoclonic jerks are brisk and irregular and may involve the trunk or extremities, symmetrically or asymmetrically. Jerks may be of small amplitude or massive, causing the patient to fall.
- Patients are generally aware of the jerks if they are isolated. They may be unaware if myoclonic jerks are part of absence seizures.
- Differential diagnosis includes tics, nonepileptic myoclonus, and other movement disorders.
- Myoclonus, usually occurring on rising in the morning, with adolescent onset, are a characteristic part of JME. Absence or generalized tonic-clonic seizures often occur in these patients.
- Myoclonic seizures may be part of an epileptic encephalopathy, such as Lennox-Gastaut syndrome, beginning in early childhood and continuing in adolescence.
- Photomyoclonus may occur with exposure to a strobe or to strobe-like conditions in teens with photosensitive epilepsy. They may have other generalized seizures, or this may be their only symptom.
- Various degenerative conditions, including progressive myoclonic epilepsies, sialidosis, and subacute sclerosing panencephalitis, may present in the teen years and may be characterized by myoclonic seizures.
- There is no prodrome, aura, or postictal period.
- EEG usually shows bursts of spike wave or polyspike and wave in a generalized distribution. Photosensitivity may be demonstrated on EEG using strobe.
Partial Simple Seizures
- Benign focal epilepsy of childhood (also known as benign Rolandic epilepsy) is the most common cause of focal motor seizures in childhood and early adolescence.
- Seizures are partial simple seizures usually involving the face or arm; seizures may secondarily generalize.
- Episodes are most likely to occur during drowsiness or sleep onset, or upon awakening.
- Seizures usually resolve by the midteen years.
- There is no underlying structural lesion.
- Partial simple seizures with onset in adolescence or adulthood are more commonly associated with structural pathology (e.g., tumor, arteriovenous malformation, head injury, malformation, and stroke).
- Sensory phenomena (aura) may be the only manifestation of a brief limited seizure.
- Ictus: Most partial simple seizures are focal motor.
- Consciousness is retained. Speech arrest may occur with dominant hemisphere seizure origin (usually with the seizure involving the right face and left brain in the right-handed person). Drooling is common.
- Clonic activity may “march” up an extremity or spread from arm to face or arm to leg, and so on (or vice versa).
- Postictal: Headache, postictal hemiparesis (Todd paralysis).
- Benign focal epilepsy of childhood is associated with central temporal spikes, which are more commonly seen in light sleep. EEG abnormality is commonly bilateral, even if all observed seizures were on the same side.
- Other partial seizures may be associated with spikes or slowing in a unilateral distribution.
Partial Seizures with Complex Symptomatology
Partial seizures with complex symptomatology are seizures of focal onset with altered consciousness. Older terms include psychomotor seizures and temporal lobe seizures, although not all partial complex seizures originate in the temporal lobe and not all temporal lobe seizures are complex partial (i.e., they may be simple partial).
- May begin at any age.
- Structural pathology is more common than in generalized epilepsies or benign focal epilepsy of childhood. Mesial temporal sclerosis may cause seizures of temporal lobe origin with onset in adolescence.
- Prodrome: Patients may report that “they know a seizure is coming.”
- May occur hours or days before a seizure.
- Includes mood change, headache, and change in appetite.
- Typical partial complex seizures consist of the following sequence (any of these components may be omitted other than the altered state of consciousness):
- Aura: Initial sensory, autonomic, or psychic symptoms lasting seconds to minutes; common phenomena include fear, déjà vu, “rising feeling” in abdomen, tingling, and visual, auditory, olfactory, or gustatory hallucination. Flushing or pallor may be observed. Consciousness is generally retained, and patient remembers this part of the seizure.
- Blank stare with impairment of responsiveness and consciousness: The patient is motionless and does not remember events clearly during this phase, if at all.
- Automatisms: Hand wringing, picking, lip smacking, walking aimlessly, grunting, gagging, or swallowing. Although destructive or injurious behavior may
occur, directed deliberate violence does not. Consciousness is impaired or lost during this phase, and the patient does not remember it. Frontal lobe–origin complex partial seizures may produce thrashing, agitated movements, bicycling leg movements, or pelvic thrusting, which are difficult to distinguish from hysterical behavior.
- Postictal state: Confusion, stupor, headache, and lethargy may last seconds to hours.
- Precipitants: Sleep deprivation, alcohol, or drug ingestion.
- EEG: Focal spikes in temporal, frontal, or parietal areas, usually unilateral. EEG findings may be normal. Special procedures such as sleep deprivation, special leads, and prolonged monitoring may be useful for diagnosis.
Features that help differentiate various seizures reported as “little seizures” or “staring spells” (partial complex, petit mal, and atypical absence) are listed in Table 21.2.
- Symptomatic seizures (due to acute systemic disturbance or trauma)
- Acute metabolic disturbance (e.g., hypoglycemia, hyponatremia, and hypocalcemia)
- Acute CNS infection (e.g., encephalitis and meningitis)
- Intoxication (e.g., cocaine, alcohol, stimulants, “ecstasy”, phencyclidine (PCP), ketamine, and inhalants)
- Drug or alcohol withdrawal (e.g., barbiturates, sedatives, and benzodiazepines after prolonged use)
- Acute head trauma (impact seizure and seizure in first few days after significant head trauma)
- Syncopal seizure: Brief tonic or clonic seizure occurring after primary syncope
- Acute stroke
- Acquired (symptomatic or secondary) epilepsies due to remote history of CNS insult
- Cerebral malformations: Macroscopic or microscopic (cortical dysgenesis)
- Intrauterine infections (e.g., cytomegalovirus and toxoplasmosis)
- Perinatal insults
- Postneonatal infections (e.g., meningitis, encephalitis, and brain abscess)
- Posttraumatic epilepsy
- Tuberous sclerosis
- Brain tumors and other mass lesions
- Vascular malformations and infarctions
- Genetic changes due to progressive or degenerative conditions
- Unknown but presumed symptomatic: Epileptic encephalopathies such as Lennox-Gastaut syndrome and early myoclonic encephalopathy
- Idiopathic epilepsy (also called age-related epilepsies)
- Primary generalized epilepsies
- Benign focal epilepsy of childhood
Other Paroxysmal Events That May Suggest Seizure Activity
- Vasovagal syncope
- Cardiac disease
- Low-output states
- Mitral valve prolapse
- Hyperventilation and anxiety states
- Orthostatic hypotension
- Sleep disturbances
- Narcolepsy: Catalepsy, sleep attacks, sleep paralysis, and hypnagogic hallucinations
- Drowsiness or sleep attacks in patients with obstructive sleep apnea or sleep deprivation
- Sleepwalking, rapid eye movement (REM) sleep disturbance, and other parasomnias
- Night terrors
- Periodic leg movements in sleep
- Movement disorders
- Paroxysmal kinesiogenic choreoathetosis
- Stiff-man syndrome and other syndromes of continuous muscle fiber activity
- Dystonias (paroxysmal torticollis, activity-related dystonias, dystonia musculorum deformans, and drug-related)
- Pseudohypoparathyroidism: Teens with hypocalcemia secondary to pseudohypoparathyroidism may present with seizure-like episodes that are primarily dystonic.
- Restless leg syndrome
- Pseudoseizures (hysterical symptoms)
- Episodic “staring” and inattention
- Attention deficit disorder
- Disorders of arousal
Epilepsy is primarily a clinical diagnosis based on the history. An astute observer of the event is more important than any “test.”
- Review the following with the observers of the event:
- What was the teen doing before the episode began—sleeping, quiet, watching television, exercising, reading, or anxious?
- Where did the event occur?
- At what time of the day?
- Relation to sleep state: Did the seizure occur just as the teen was falling asleep, just after awakening, or during deep sleep?
- What was the first abnormality noted? Did the teen seem to be aware that something was wrong?
- What happened during the seizure?
- Could the teen be aroused? Respond to commands? At what point did unresponsiveness start? How long did unconsciousness last?
- Was there incontinence of urine or stool?
- What happened after the seizure?
- Review the following with the patient:
- What was the last event he or she remembers before the seizure?
- Could the patient hear or understand people talking during the seizure? Could he or she respond?
- What happened after the seizure? What is the first thing recalled after the event?
- Precipitating events: Sensory stimulation, activity, drugs, meals, medications, sleep pattern, stress, and menses.
- Earlier seizures or similar events.
- Family history of epilepsy, neurocutaneous syndromes, and other neurological conditions
- Perinatal history, particularly birth injury, prematurity, and maternal infections
- History of CNS infections or trauma
- Drug history, including prescribed, over-the-counter, and “street” drugs and alcohol
- Any other recent changes in health or function: Any changes in cognition, motor function, or others to suggest onset of neurological disease other than the seizure
- Travel history and/or household exposure to recent immigrants from areas with endemic cysticercosis/Taenia solium.
- Perform general physical examination for evidence of systemic disease.
- Skin: Look for signs of a neurocutaneous syndrome such as café au lait spots, depigmented macules, adenoma sebaceum, shagreen patch, and subungual fibromas.
- Eyes: Perform funduscopic examination for optic disc edema (papilledema).
- Neurological examination: Look for evidence of focal abnormalities. Observe gait and movements at rest and with activity for evidence of movement disorder as alternative explanation of symptoms.
- Blood pressure: Assess pressure while the teen is lying and standing.
- Pulse: Check for irregularities, if arrhythmia is suspected.
- Cardiac examination: Check for evidence of mitral valve prolapse, heart failure, or other abnormalities that might lead to arrhythmias.
- Hyperventilation: Hyperventilate for 2 to 3 minutes to induce an episode if absence (petit mal) seizures are suspected or if symptoms are thought to be directly due to hyperventilation.
- Complete blood cell count and routine chemistries including liver function tests are indicated before initiating anticonvulsant therapy (as baseline). Platelet count should be included if valproic acid is to be used.
- In an apparently well teenager without underlying medical problems, electrolytes, phosphorus, or magnesium have a very low yield for finding a cause of seizures. Rarely, an adolescent presenting with seizure-like episodes is found to have very low blood calcium concentration because of pseudohypoparathyroidism, although the condition is congenital and the calcium concentration is low from infancy. Blood sugar measurements may be helpful if hypoglycemia is suspected only if the blood sample is drawn while the patient is symptomatic. These tests are not indicated on a routine basis in most teens with seizures.
- EEG: Routine study should consist of waking EEG, hyperventilation, and photic stimulation. Hyperventilation is particularly useful if absence (petit mal) seizures are suspected. Photic stimulation is particularly helpful if the patient reports that seizures occur when exposed to video games, television, rapid flashing lights, or in the car. Sleep deprived EEG increases the yield in patients with complex partial seizures, benign focal epilepsy of childhood, and some generalized epilepsies.
- Neuroimaging: Computed tomography scan or magnetic resonance imaging is indicated for focal seizures (except clear-cut benign Rolandic epilepsy of childhood), seizures associated with neurological abnormalities, papilledema, neurocutaneous stigmata, or suspected degenerative conditions.
- Lumbar puncture is indicated if infection or hemorrhage is suspected.
Grand Mal Seizures Versus Syncopal Episode
Table 21.3 compares grand mal seizures with syncopal episodes.
Hysterical Episodes (Pseudoseizures) Versus Epilepsy
Table 21.4 compares pseudoseizures with epilepsy.
After the diagnosis of epilepsy is made, two major components of therapy exist: Drug therapy to control the seizures and counseling regarding psychosocial issues.
- Start with a single anticonvulsant medication. The choice of an anticonvulsant should consider the side effect profile, because this will influence both safety and compliance. For example, sodium valproate, which may be effective in many seizure types, may be associated with some side effects that limit its use by adolescents, particularly female teens. These include an increase in appetite, weight gain, transient hair loss, and menstrual irregularities.
- Increase the medication slowly by time increments equal to five times the half-life of the drug until seizures are controlled or toxicity occurs, except when control is urgent (frequent seizures or status epilepticus).
- Use serum levels only as guidelines: Clinical response is more important. Do not evaluate serum levels frequently. At least five half-lives are necessary for medication level to reach steady state after starting or altering the dose.
- Give medication each day on the basis of half-life. Give a drug more frequently only with refractory seizures, otherwise unmanageable adverse effects or demonstrated rapid metabolism is encountered. Most medications can be given twice a day (b.i.d.), and adherence is better with b.i.d. than thrice-a-day (t.i.d.) schedules.
- The teen should have close follow-up, including monitoring of seizure frequency, physical examination, and evaluation for drug toxicity. Note that frequent follow-up also allows for early detection of nonmedical effects (social, academic, independence, and vocational).
- Substitute a second drug only when the first is pushed to tolerance without controlling the seizure, unless allergic or serious idiosyncratic effects are evident. When the second drug is at adequate serum levels, wean the first. Polytherapy is reserved for refractory patients unresponsive to trials of monotherapy with at least two
to three different anticonvulsants at maximum tolerated levels.
- Discontinuation criteria: After some time, the clinician must assess the risks and benefits of continued therapy with anticonvulsants. Medications may be tapered and discontinued after the patient is seizure free for 2 to 4 years. The estimated risk for recurrence on tapering is 30% to 40%, greatest during the period of taper or in the first 6 months after discontinuation of the medication. Risk factors for recurrence are somewhat controversial but include the following in at least some studies:
- Mental retardation or neurological abnormalities
- Long duration of seizures or many seizures before full control with medication
- Partial seizures (other than the benign focal epilepsies of childhood such as Rolandic epilepsy)
- Abnormal EEG findings despite seizure-free period (highest risk: combination of focal slowing and focal epileptiform spikes)
- Adolescent-onset seizures less likely to remit than seizures with onset in earlier childhood
Medication should be tapered one drug at a time (generally sedating drugs first), tapering each drug over 6 weeks to 3 months.
Drugs for Specific Seizure Types
- Generalized tonic-clonic seizures (grand mal), either primarily or secondarily generalized:
- Phenobarbital: Least expensive, can be given once a day. In developing countries, it is often the only drug available. In the United States, it is less often used as first-line therapy due to concerns about cognitive slowing.
- Carbamazepine (Tegretol, Carbatrol): Generics are acceptable if same generic is consistently available; avoid switching brands. Two extended-release carbamazepine preparations allow b.i.d. dosing but are more expensive (Tegretol-XR and Carbatrol).
- Phenytoin (Dilantin): Brand-name capsules can be used once a day. Using most generic capsules, liquid or chewable tablets, dose must be divided b.i.d. or t.i.d.
- Valproic acid (Depakene or Depakote): Depakote is preferred. An extended-release form (Depakote ER) is available that is appropriate for once-a-day use in selected patients.
- Primidone (Mysoline): Reserve for refractory patients.
- Lamotrigine (Lamictal): Useful for partial and generalized seizures, including adolescents with JME. Generally reserved for teens intolerant of valproic acid and recommended as first-line monotherapy for idiopathic generalized epilepsy among women of reproductive age (including those who are pregnant or breast-feeding).
- Topiramate (Topamax): Effective but often significantly sedating and/or cognitively impairing, at least upon initiation. Tendency to cause mild anorexia and weight loss is viewed by some teens as an advantage over other anticonvulsants, which tend to promote weight gain. When used, dosage should be titrated very slowly to avoid cognitive dulling.
- Felbamate (Felbatol): is effective for several seizure types including generalized convulsive (tonic-clonic) seizures, drop attacks, and atypical absence seizures. It is only approved for children with Lennox-Gastaut syndrome (mixed generalized epilepsy). An initial alarming incidence of aplastic anemia associated with felbamate has limited the use of this medication to refractory patients able to give informed consent to its risks and comply with the requirement for frequent laboratory monitoring. Actual risk is probably very low, except in patients with other autoimmune conditions such as systemic lupus erythematosus (SLE).
- Other newer anticonvulsants, occasionally useful for generalized convulsions, particularly those thought to be partial with secondary generalization, include levitiracetam (Keppra), and oxcarbazepine (Trileptal).
Many practitioners favor either carbamazepine or valproic acid for first-line use. Phenytoin is an effective medication but may cause unacceptable side effects (e.g., gum hypertrophy and hirsutism), particularly in children and young adolescents. In patients with mixed generalized seizures (i.e., generalized tonic-clonic plus myoclonic or absence seizures), carbamazepine, phenytoin or oxcarbazepine occasionally may induce or exacerbate myoclonic or drop attacks. Valproic acid, preferably in the long-acting capsules (Depakote), or extended-release capsules (Depakote ER) is the drug of choice in mixed generalized epilepsies (grand mal plus myoclonic or absence).
- Petit mal epilepsy:
- Ethosuximide (Zarontin): Standard therapy usually well tolerated for typical childhood petit mal (3-Hz spike wave EEG pattern).
- Valproic acid (Depakote): First choice if absence and generalized tonic-clonic seizures coexist, for atypical absence, or for JME.
- Clonazepam, clorazepate, or other benzodiazepines: Occasionally effective as monotherapy, but rapid development of tolerance and sedation are significant problems. May increase salivation and respiratory difficulties in adolescents with multiple disabilities.
- Felbamate (Felbatol): This is effective for several seizure types but is approved only for children with Lennox-Gastaut syndrome (mixed generalized epilepsy).
- Simple partial seizures (focal motor, focal sensory) and complex partial seizures with or without automatisms:
- Carbamazepine (Tegretol): See previous discussion regarding generic forms and long-acting preparations.
- Phenobarbital: See earlier discussion.
- Phenytoin (Dilantin): See earlier discussion regarding generic forms.
- Primidone (Mysoline): Reserve for refractory patients.
- Gabapentin (Neurontin): Approved for monotherapy and adjunctive treatment of partial onset seizures. This anticonvulsant is not metabolized and does not change metabolism of other medications. Consider use in teens with multisystem disease when avoidance of alteration of drug metabolism of other agents is important (i.e., transplant patients, patients on chemotherapy, etc).
- Lamotrigine (Lamictal): See earlier discussion. First-line or adjunctive treatment of partial seizures.
- Topiramate (Topamax): See earlier discussion. First-line or adjunctive treatment of partial seizures.
- Tiagabine (Gabitril): Adjunctive treatment of partial seizures.
- Levetiracetam (Keppra): First-line or adjunctive treatment of partial seizures. Often used as first-line therapy in patients with hepatic dysfunction or during chemotherapy because it is excreted by kidneys and is not dependent on the P-450 system for its metabolism. The major concern is the relatively higher risk of behavior disturbance, particularly in teens who already have a history of agitated or aggressive behavior.
- Zonisamide (Zonegran): First-line or adjunctive therapy for partial seizures. Risks are similar to those of topiramate (sedation, renal stones, acidosis, anorexia, rash, oligohydrosis). Very long half-life makes it appropriate for once-daily dosing.
- Oxcarbazepine (Trileptal): An alternative to carbamazepine for patients who had an adverse behavioral reaction to carbamazepine at the therapeutic dose. Patients allergic to carbamazepine may also react to oxcarbazepine. Oxcarbazepine does not have an active metabolite. Pharmacokinetic interactions are less problematic than with carbamazepine, making it appropriate for patients on other medications that are affected by or affect the cytochrome P-450 system such as teens with multisystem disease needing many other medications (e.g., during chemotherapy or patients with acquired immunodeficiency syndrome).
- Felbamate (Felbatol): See earlier discussion. Reserve for refractory patients.
Table 21.5 provides metabolism guidelines for older-generation antiepileptic drugs and Table 21.6 shows metabolism of newer anticonvulsant drugs.
Side Effects of Anticonvulsant Drugs
Adverse effects of anticonvulsants can be divided into two major groups: Dose-related reactions andidiosyncratic reactions unrelated to drug level. Mild sedation is common with initiation of any anticonvulsant. This effect generally wanes after a few weeks. Sedation and ataxia with initiation of treatment is more significant with carbamazepine, so treatment is generally started at low doses and increased over several weeks. Potential reproductive effects are also important to consider in teenage girls of childbearing potential.
- Toxic CNS effects are shared among most anticonvulsants.
- Excessive levels (or deliberate overdoses) produce ataxia, nystagmus, and sedation progressing to coma, with respiratory and cardiac depression at extremely high doses.
- Movement disorders (chorea) and tremor may be seen at toxic drug levels, primarily with phenytoin or carbamazepine.
- Non-CNS dose-related effects are common.
- Alterations in vitamin D metabolism produce “chemical rickets,” generally without clinically symptomatic abnormalities. Clinical rickets is occasionally seen in adolescents with multiple disabilities receiving anticonvulsants but having limited sun exposure and lacking vitamin D supplementation. Osteopenia is frequently found in studies of patients of all ages taking chronic anticonvulsants. Consider supplementing with oral calcium and vitamin D in teens taking anticonvulsants if dietary intake is low.
- Some anticonvulsants (phenytoin and carbamazepine) may have deleterious effects on bone density by directly interfering with osteoblast proliferation.
- Folate metabolism is altered, producing megaloblastic changes, usually without anemia. For most adolescents on anticonvulsants physician should consider routinely supplementing with a multivitamin containing at least 400 µg of folic acid. Adolescent girls taking anticonvulsants, particularly those with a potential for future childbearing, should be supplemented with folic acid 1 to 4 mg daily, depending upon which anticonvulsant they are taking. Those taking valproic acid are of particular concern.
- Thyroid function tests are commonly altered without clinical evidence of hypothyroidism.
- Gastrointestinal (GI): Gastric distress is common with valproic acid, ethosuximide, and felbamate. These side effects may be minimized if the dose is divided or given with food.
- Drug interactions are also common.
- Virtually all anticonvulsants induce hepatic microsomal enzymes, increasing clearance of themselves (autoinduction), each other, and various other medications including steroids, estrogens, anticoagulants, and so forth. Exceptions are the second-generation anticonvulsants, gabapentin (Neurontin), and levetiracetam (Keppra), which are excreted unchanged in the urine and do not affect other drug metabolisms.
- Conversely, several drugs significantly inhibit the metabolism of carbamazepine and to a lesser extent, of phenytoin. The most commonly encountered problematic interaction is with erythromycin (and the newer macrolides), which competitively inhibits carbamazepine metabolism to an extent that previously stable patients may develop significant toxicity <24 hours after the addition of the antibiotic. A similar effect is seen with propoxyphene (Darvon) and with grapefruit juice. Therefore, these drugs and grapefruit juice should be avoided in a patient taking carbamazepine.
- Isoniazid (INH) inhibits both carbamazepine and phenytoin metabolism. Because it is generally used on a long-term basis, the anticonvulsant drug can be adjusted to account for the decreased clearance.
Idiosyncratic (Non–Dose-Related Side Effects)
The following side effects may occur with any anticonvulsant:
- Allergic reactions: Skin rash, Stevens-Johnson syndrome, lupus-like syndromes, and even death can occur with any anticonvulsant, although most reported cases are associated with phenobarbital, phenytoin, or carbamazepine.
- Bone marrow toxicity, usually reversible, has been reported with several anticonvulsants. Fatal aplastic anemia has been reported with carbamazepine and felbamate, primarily in older adults. High serum levels of valproic acid are associated with reversible bone marrow suppression, most commonly thrombocytopenia.
- Hepatic toxicity and metabolic abnormalities are seen in patients receiving valproic acid, primarily in infants, but can rarely occur with any anticonvulsant, at any age. These may include hyperammonemia, lactic acidosis, and Reye-like syndrome. Carnitine depletion, usually asymptomatic, may occur with valproic acid, particularly with long-term use in patients with poor muscle bulk.
- Adenopathy, “mononucleosis syndrome,” and pseudolymphoma are primarily associated with hydantoin.
- Hair loss: Moderate hair thinning is relatively common with valproic acid. Frank alopecia does not occur. Other anticonvulsants may produce hair loss as part of allergic reactions.
- Weight changes: Weight gain is most frequently problematic with valproic acid but has been reported with many anticonvulsants. Weight loss is common with felbamate, particularly at higher doses, and with valproic acid in young children. Topiramate and zonisamide often produce short-term anorexia and weight loss.
- Pancreatitis: Valproic acid can rarely cause serious pancreatitis. In a patient taking valproic acid with abdominal pain or vomiting, serum lipase should be assessed.
There is a moderately increased risk of abnormal pregnancy outcome in women with epilepsy, regardless of specific drug treatment.
- Facial malformations, particularly cleft palate, microcephaly, congenital heart disease, and minor malformations such as hypoplastic nails have been related to phenytoin, and possibly other anticonvulsants. Some authors feel that these nonspecific malformations are more frequent in offspring of epileptic mothers, regardless of treatment.
- Open neural tube defects may be more frequent in fetuses exposed to valproic acid and carbamazepine. It is prudent to supplement all female patients taking these anticonvulsants with a multivitamin containing at least 400 µg of folic acid. Some authors advise that female patients on anticonvulsants anticipating pregnancy take 1 to 4 mg/day of folic acid. Unfortunately, a few case reports suggest that even higher doses of periconceptional folic acid may not be protective against the development of malformations.
- It is difficult to choose an anticonvulsant that is “completely safe.” Risk of fetal damage must be balanced against the risk of recurrent convulsions if medications are withdrawn.
- There is no reason to withhold oral contraceptives from a woman receiving anticonvulsants, but higher estrogen doses may be needed because of more rapid metabolism of the component hormones, because of induction of cytochrome P-450 system.
Other Problems with Anticonvulsant Therapy
- Because teens in whom epilepsy is well controlled often have no symptoms except for the drug side effects, it is tempting for them to take their medications only intermittently. These and other adherence problems are common (see the suggestions for improving adherence in the “Community Resources” section).
- Medications may increase preexisting behavioral problems and occasionally cause depression.
- Some drugs can increase seizure frequency as their dose is increased.
Alternative Treatments of Refractory Epilepsy
Vagal Nerve Stimulation
Vagal nerve stimulation (VNS) is a therapeutic option used as an adjunctive treatment for adolescents and adults with medically refractory epilepsy. The VNS device consists of a programmable battery-operated generator and a silastic-coated lead, which are implanted subcutaneously in the chest, with the lead attached to the left vagal nerve. Multicenter trials evaluating the efficacy of the vagal nerve stimulator demonstrated a 50% or more reduction in approximately one third of patients with refractory partial seizures. New uncontrolled data suggests that VNS may be as effective for idiopathic and symptomatic generalized epilepsies. The common side effects include hoarseness of voice, local pain, paresthesias, dyspnea, and dysphagia. Uncommon complications include vocal cord paralysis and lower facial muscle weakness.
The Ketogenic Diet
The ketogenic diet is a tightly controlled, high-fat, low-carbohydrate diet used in the treatment of intractable epilepsy. The diet is designed to place the body in a state simulating starvation, which results in the production of high levels of ketone bodies. Undertaking this diet requires a strong commitment from both the patient and care givers and the expertise of a dietician and clinician familiar with the program. Expense may be substantial, including dietitian visits and special foods, which are not generally covered by health insurance.
Cortical resection or hemispherectomy may result in cessation or dramatic reduction of seizures for selected adolescents with intractable localization-related epilepsy. Key elements of surgical candidacy include intractability, disabling epilepsy; a localized epileptic zone; and a low risk for new postoperative neurological deficits. Surgical options include temporal lobectomy, extratemporal and multilobar resections, functional hemispherectomy, and corpus callosotomy. Teens with uncontrolled or complicated epilepsy warrant referral to specialized centers with extensive pediatric epilepsy surgery experience that can offer comprehensive risk-benefit evaluation for each child. There is some evidence that early temporal lobectomy in teens with intractable complex partial seizures and mesial temporal sclerosis may improve long-term quality of life and overall outcome.
Other Important Treatment Issues
The care of the epileptic teen extends beyond drug therapy. Total care involves dispelling myths and educating, providing for community resources, and providing counseling for the teen's voiced or unvoiced concerns.
Dispelling Myths and Educating
Many myths about epilepsy can be eliminated by reassuring the teenager on the following:
- Epilepsy is not contagious.
- The seizures may disappear with age.
- Most seizures can be prevented with medication.
- Epilepsy does not lower the teenager's intelligence.
- He or she can participate in almost all activities.
- Epilepsy is not a “mental illness.”
The parent should also be given these reassurances, in addition to the following:
- There is no need to feel guilty. It is unlikely that anything the parent did (or did not do) caused the epilepsy.
- There is no need for special schooling solely because of epilepsy.
- Neither epilepsy nor anticonvulsants causelearning disabilities or cognitive loss, although the prevalence of learning disabilities is higher in children and adolescents with epilepsy as a group.
The teen and family should be educated about the following:
- Importance of careful observation and record keeping.
- Avoidance of precipitating factors, if any.
- Side effects of medication.
- Prognosis and follow-up.
- Precautions and restrictions, particularly regarding driving, swimming, and bicycle and motorcycle riding, until seizure control is ensured: State requirements regarding reports to the Department of Motor Vehicles should be explained. Restrictions may need to be imposed regarding use of hazardous equipment such as power tools.
- For women and adolescent girls of childbearing age, the need for adequate birth control while receiving most anticonvulsant drugs (see Chapter 42 for recommendations regarding interactions of anticonvulsants and contraceptives). Supplementation with folic acid should be discussed with all women epilepsy patients with childbearing potential.
Family members should be aware of first aid for seizure episodes:
- Generalized convulsion (tonic, tonic-clonic, and clonic)
- Help the person into a lying position if there is adequate warning.
- Do not try to restrain the person.
- Clear the area of dangerous objects.
- Remove glasses and loosen tight clothing.
- Turn the head to one side (or roll the person onto his or her side) to allow saliva to drain out.
- Do not put anything into the person's mouth.
- Report what you observe. Try to time the episode with a watch.
- Family members should be given specific criteria to call for paramedic help: If the seizure lasts longer than 5 to 10 minutes, or if seizures cluster without recovery, call for emergency medical help. Specific advice should be individualized, on the basis of the patient's seizure history.
- In teens with epilepsy, who have clusters of seizures or prolonged breakthrough seizures that require emergency care, family members can be taught to use a rectal dose of diazepam. In the United States, a rectal gel form of diazepam is available in premeasured syringes as Diastat. The dose for teens is 0.2 mg/kg, rounded up to the next available size, with a maximum of 20 mg/dose. Intranasal or buccal midazolam has also been used to abort prolonged seizures or interrupt seizure clusters, but is “off-label” usage.
- Partial seizures (simple and complex)
- Do not restrain the person.
- Remove harmful objects from the area.
- Petit mal
- No first aid is necessary.
- Protect from harm if in dangerous situation until the episode passes.
Teenagers and parents should be provided with references and should be informed of community resources about epilepsy. Many local epilepsy societies sponsor job search training; some have vocational training and placement programs. Some sponsor teen groups for peer support, camps, and family programs. Local chapters of the Epilepsy Foundation have videotapes, pamphlets, and other educational materials for patients and families.
- Epilepsy Foundation
- 8301 Professional Place
- Landover, MD 20785; http://www.epilepsyfoundation.org
o Local chapters can be located through the national offices, through an online search, or in telephone directories under “Social Service Organizations.”
- Sports and activity: No need for restriction of activities once seizures are controlled, except for swimming alone, scuba diving, mountain climbing, or bicycling in areas with traffic. Contact sports are generally restricted until seizures are controlled.
- Medical identification: The teen with epilepsy should wear a medical identification bracelet or necklace. This may avoid unnecessary trips to emergency facilities or unneeded testing if a seizure occurs away from home.
- Driving: Health care professionals should be aware of their state's driving laws regarding epilepsy. These should be explained to the teen, with the reasons for the laws. The wish to be seizure free to receive a license may enhance compliance. Laws regarding mandatory reporting to the state's Department of Motor Vehicles vary among the states.
- School: The adolescent's school should be informed if seizures are a recurring problem. If the teenager has been seizure free for an extended time, there is often no need to inform the teachers of diagnosis, because this may cause unnecessary restrictions and lowered expectations.
- Alcohol: Although abstinence is not always necessary, more than a couple of drinks of alcohol a day may increase the risk of seizures in teens with epilepsy secondary to a lowering of the seizure threshold.
- Anticipate other concerns: Seizures, because of their unpredictable and abrupt onset, threat of injury, and embarrassment, can have profound effects on the developing adolescent. Try to anticipate and be sensitive to these concerns. Young teens may be concerned
about whether their body is normal. Middle teens will have concerns about their peers, driving, and sports restrictions. Older adolescents will be more concerned regarding vocational planning and perhaps future health insurance. Depression can occur in adolescents with epilepsy and these teens should be assessed for their degree of depression and their suicidality (Baker, 2006).
- Adherence: As stated earlier, adherence can be a significant problem in dealing with an epileptic teenager. Suggestions for improving adherence include the following:
- Provide clear explanations of medications used and their expected side effects.
- Give the adolescent the responsibility for taking medications.
- Discuss possible consequences of noncompliance with the teen, such as recurrent seizures and inability to get or keep a driver's license.
- Referral to a teen group sponsored by a local chapter of the Epilepsy Foundation may be helpful.
- “Day-of-the-week” pillboxes, filled and checked weekly, with parental supervision, may enable a young teen to manage his or her own medications.
- Attempt to simplify dosing schedules. Use b.i.d. or once-daily dosing if possible.
- Use medications with acceptable side effects for the involved teen.
Special Considerations in Epilepsy in Female Patients
Hormonal Influences on Seizures
Some women with epilepsy experience changes in seizure activity that relate to changes in pubertal status, menstrual cycle, or pregnancy. In general, estrogen increases excitation and reduces inhibition, whereas progesterone has the opposite effect.
Effect of Puberty on Epilepsy
Seizures can have their onset or change in frequency during puberty. Both JME and photosensitive seizures often present during puberty. Childhood absence epilepsy and benign Rolandic epilepsy often remit during puberty.
Effect of Menses on Seizures
As expected, with the rise of estrogen at ovulation and with the fall in progesterone during menses, seizures are more common during these times. Foldvary-Schaefer and Falcone (2003) provide a comprehensive review of catamenial epilepsy.
Fertility in women with epilepsy is approximately one third that of nonepileptic siblings (Morrell, 1999). This may reflect either a fear of consequences of pregnancy, social pressure not to become a parent, or physiological disruptions to reproductive cycles. Anovulation is more common in women with epilepsy. Women with epilepsy appear to have a higher frequency of reproductive endocrine abnormalities including alterations of daily basal and pulsatile release of luteinizing hormone. Women with epilepsy may also have hormonal abnormalities, which appear to be reversible with cessation of anticonvulsant medication. Valproic acid in particular is associated with a syndrome similar to polycystic ovary syndrome as well as isolated rise in circulating androgens.
As discussed earlier, there is an increased risk of abnormal pregnancy outcomes in women with epilepsy regardless of the specific drug treatment.
The major issues with the use of contraception in adolescents with epilepsy are the interactions between certain anticonvulsants and their effect on the metabolism of hormonal contraceptives. The most significant problems are with those hormonal contraceptives with low doses of hormones used in combination with anticonvulsants that induce the cytochrome P-450 system (e.g. phenobarbital, primidone, phenytoin, carbamazepine, felbamate, topiramate, and vigabatrin). See Chapter 42 for a full discussion on these interactions and Table 42.4 for World Health Organization guidelines on the appropriateness of each contraceptive device in women on certain anticonvulsants.
For Teenagers and Parents
http://www.epilepsyfoundation.org. Lots of information from the Epilepsy Foundation including driving laws, e-communities, educational information, and most frequently asked questions. Special sections on living with epilepsy and concerns of adolescents can be accessed via the home page. Detailed information about medications are available.
http://www.epilepsy.org.uk/. Information from the British Epilepsy Association.
http://www.epilepsy.ca/eng/mainSet.html. Much information on epilepsy and links elsewhere from Epilepsy, Canadian site.
http://www.nlm.nih.gov/medlineplus/epilepsy.html. National Institutes of Health search and links on epilepsy, with information forms in Spanish.
http://www.cdc.gov/Epilepsy/index.htm. Information from the Centers for Disease Control and Prevention on epilepsy, including an excellent “Toolkit” entitled “You are not alone” for parents of teens with epilepsy.
For Health Professionals
http://www.aesnet.org/. The American Epilepsy Society's official web site.
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