be counseled that her symptoms will likely rebound severely

for 48 to 72 hours, but approximately 4 to 7 days later her

symptoms should gradually return to baseline or pretreatment

state.149

With the discontinuation of carbidopa/levodopa in J.J., an

alternative therapy should be selected. The selection of an alternative agent in cases in which the initial therapy failed or augmentation occurs must be approached on an individual basis.

Although a number of agents are available to choose from, clinical

experience generally guides the decision as lack of comparative

trials precludes development of any formal recommendations.

Because J.J. describes increasing pain with her RLS, it would

be appropriate to initiate a trial of gabapentin. If gabapentin is

ineffective or not tolerated, J.J. could be prescribed an opiate,

which is also an acceptable choice in patients with RLS who have

neuropathy or painful dysesthesias. Hydrocodone, oxycodone,

methadone, codeine, and tramadol have all demonstrated efficacy in RLS.149 Augmentation does not prevent a future reintroduction of dopaminergic therapy; in J.J.’s case, a dopamine

agonist could be added after an extended dopaminergicfree period if her symptoms are not completely controlled on

gabapentin.

ESSENTIAL TREMOR

Clinical Presentation

CASE 57-6

QUESTION 1: K.H. is a 52-year-old white female office manager who was referred to a neurologist for evaluation of

bilateral tremor. She is otherwise healthy and reports not

taking any regularly prescribed medications. She describes

her tremor as being present mainly when she performs

voluntary movements. The tremor is not noticeable during rest. She also notices the tremor seems to disappear

in the evening after drinking a couple of glasses of wine.

The tremor interferes with several of her ADLs, including

writing, eating, drinking from a cup, and inserting her keys

into the ignition. She reports mild interference with her job

function and some social embarrassment. No bradykinesia

or rigidity is elicited on physical examination. A handwriting

sample reveals large characters that are difficult to decipher.

Family history reveals that her maternal grandmother and

mother both had similar symptoms. What signs and symptoms are consistent with essential tremor in K.H.?

Beginning in the mid-20th century, the term essential tremor

(ET) has been consistently used to describe a kinetic tremor

for which no definite cause has been established. ET is a common neurologic disorder with an estimated incidence of 616

cases per 100,000 person-years, and a prevalence of about 0.9%

to 4.6%.168,169 Despite its commonness, it is underrecognized

and undertreated, likely because it has been traditionally viewed

as a monosymptomatic disorder of little consequence; more

recently, it is recognized to be complex and progressive, resulting in significant disability in ADLs and job performance, and

social embarrassment.170 Both the incidence and prevalence of

ET increase with age. In addition, ethnicity and family history of

ET are consistently identified risk factors; it is approximately five

times more common in whites than blacks, and approximately

50% of patients report a positive family history. The latter finding

suggests that genetic predisposition may play a role in ET; however, differences in intrafamilial onset and severity suggest environmental factors may also influence underlying susceptibility

to the disease. Several environmental toxins have been proposed

as causes of ET, including β-carboline alkaloids (e.g., harmane

and harmine) and lead, both of which have been found in elevated concentrations in patients with ET compared with normal

control subjects.171,172

Because parkinsonian tremor and ET are the most common

forms of tremor observed in practice, it is important to distinguish between the two because the treatments differ substantially.

Diagnostic criteria for ET developed by the Movement Disorder

Society are summarized in Table 57-8.173 Tremor should first be

identified as either an action or resting tremor. Action tremors

include kinetic, postural, and isometric tremors. The defining feature of ET is a bilateral, largely symmetrical, 5- to 10-Hz kinetic

and postural tremor of the arms. The tremor can also affect head

or voice. Kinetic tremor can be elicited in patients during voluntary movement, such as finger-to-nose test, signing their name,

drawing spirals, or drinking water from a cup. Postural tremor

occurs during sustained arm extension. Although both types of

action tremors (kinetic or postural) can be present in ET and PD,

TABLE 57-8

Diagnostic Criteria for Essential Tremor

Inclusion Criteria

Bilateral postural tremor with or without kinetic tremor, involving

hands and forearms, that is visible and persistent

Duration >5 years

Exclusion Criteria

Other abnormal neurological signs (except Froment sign)

Presence of known causes of increased physiological tremor

Concurrent or recent exposure to tremorogenic drugs or the presence

of a drug withdrawal state

Direct or indirect trauma to the nervous system within 3 months

before the onset of tremor

Historical or clinical evidence of psychogenic origins

Convincing evidence of sudden onset or evidence of stepwise

deterioration

1384Section 13 Neurologic Disorders

TABLE 57-9

Differentiation of Essential Tremor and Parkinson Disease

Characteristic Essential Tremor Parkinson Disease

Kinetic tremor in arms, hands, or head ++ ++

Hemibody (arm and leg) tremor 0 ++

Kinetic tremor > resting tremor ++ +

Resting tremor > kinetic tremor 0 ++

Rigidity or bradykinesia 0 ++

Postural instability 0 ++

Usual age of onset (years) 15–25, 45–55 55–65

Symmetry Bilateral Unilateral > Bilateral

Family history of tremor +++ +

Response to alcohol +++ 0

Response to anticholinergics 0 ++

Response to levodopa 0 +++

Response to primidone +++ 0

Response to propranolol +++ +

Handwriting analysis Large, tremulous script Micrographia

0, not observed; +, rarely observed; ++, sometimes observed; +++, often observed.

the presence of resting tremor is much more common in PD. Lack

of resting tremor and absence of bradykinesia or rigidity in K.H.

suggest the tremor is not parkinsonian. She describes interference of her tremor occurring with voluntary movement, such as

in her ADLs and drinking from a cup. Other signs and symptoms

that support a diagnosis of ET include her age, family history,

large and tremulous handwriting (as opposed to micrographia

in PD), and improvement in tremor with alcohol consumption.

Table 57-9 summarizes the similarities and differences of ET and

parkinsonian tremor.

Several medications and substances are known to cause

tremors. All patients with tremor should have thorough medication history to rule out these possible causes. Medications

commonly implicated include corticosteroids, metoclopramide,

valproate, sympathomimetics (e.g., albuterol, amphetamines,

pseudoephedrine), SSRIs, tricyclic antidepressants, theophylline,

and thyroid preparations.174 In addition, caffeine, tobacco, and

chronic alcohol use can cause tremor that resembles ET. K.H.

does not report taking any regularly prescribed medications;

however, she should be questioned regarding any over-thecounter medication use as well as her caffeine and smoking

habits, and alcohol use if applicable.

The diagnosis of ET is based solely on clinical examination and

neurological history. Neuroimaging is not useful, and there are

no available biological markers or diagnostic tests that are specific

to ET. The evaluation of K.H.’s tremor should include laboratory analysis to rule out possible medical conditions associated

with tremor. If clinical signs suggest the possibility of hyperthyroidism, thyroid function tests should be performed. In patients

younger than 40 years of age who present with action tremor,

serum ceruloplasmin can be tested to evaluate for possible

Wilson disease.174

Treatment

CASE 57-6, QUESTION 2: What therapies are effective in

treating ET? How should K.H. be treated?

Patients with ET who have mild disability that does not cause

functional disability or social embarrassment can go without

treatment. Because K.H. is experiencing tremor that is interfering with her occupation and causing social embarrassment,

she should be considered for pharmacotherapy (Table 57-10).

It is important to note that although effective treatments exist,

tremor is rarely eliminated completely. Factors predicting lack of

response have not been readily identified.

Propranolol, a nonselective β-adrenergic receptor blocker,

or primidone, an anticonvulsant, are recommended as first-line

agents to treat ET.175,176 Propranolol is typically effective in doses

of at least 120 mg/day, with about 50% of patients having longlasting benefit.175 Long-acting propranolol is as effective as the

regular-release formulation. Other β1-selective blockers such as

atenolol and metoprolol have also been studied, but with mixed

findings.177 Propranolol has demonstrated greater efficacy than

theseβ1 selective agents, suggesting that blockade ofβ2 receptors

is of importance. β-Adrenergic receptor blockers with intrinsic

sympathomimetic activity, such as pindolol, appear ineffective in

ET.175 Caution should be exercised with propranolol in patients

with asthma, congestive heart failure, diabetes mellitus, and

atrioventricular block.

Several studies have compared propranolol and primidone in

ET,178,179 and they are considered to have similar efficacy.175,176

Primidone is metabolized to a phenobarbital-based metabolite;

however, phenobarbital is inferior to primidone in treating ET.180

Acute adverse effects of primidone include nausea, vomiting,

and ataxia, which can occur in up to one-fourth of patients, often

limiting its use.175 The long-term tolerability of primidone is very

good, however, and may actually be superior to propranolol.179

Primidone should be initiated at 12.5 mg/day and administered at

bedtime to reduce the occurrence of acute side effects. It can be

titrated gradually as tolerated up to 750 mg/day in divided doses,

although side effects become more common at doses greater

than 500 mg/day.175

Other agents that have demonstrated variable efficacy in

ET include gabapentin, pregabalin, topiramate, zonisamide,

levetiracetam, and benzodiazepines (specifically, alprazolam and

clonazepam).175,177 They are generally considered to be lessproven, second-line therapies, however. Adverse effects and

potential for abuse (specifically with benzodiazepines) should

be considered when an agent is selected.

If oral pharmacotherapy options for ET are not beneficial,

intramuscular injections of botulinum toxin A or surgical treatments can be used in selected patients.181 Targeted botulinum

toxin A injections can reduce hand, head, and voice tremor; however, they are associated with focal weakness of the adjacent

1385Parkinson Disease and Other Movement Disorders Chapter 57

TABLE 57-10

Pharmacotherapy for Essential Tremor

Drug Initial Dose Usual Therapeutic Dose Adverse Effects

β-Blockers

Propranolol 10 mg every day to BID 160–320 mg divided every day to BID Bradycardia, fatigue, hypotension, depression,

exercise intolerance

Atenolol 12.5–25 mg every day 50–150 mg every day Bradycardia, fatigue, hypotension, exercise

intolerance

Nadolol 40 mg every day 120–240 mg every day Bradycardia, fatigue, hypotension, exercise

intolerance

Anticonvulsants

Primidone 12.5 mg every day 50–750 mg divided every day to TID Sedation, fatigue, nausea, vomiting, ataxia,

dizziness, confusion, vertigo

Gabapentin 300 mg every day 1,200–3,600 mg divided TID Nausea, drowsiness, dizziness, unsteadiness

Topiramate 25 mg every day 200–400 mg divided BID Appetite suppression, weight loss, paresthesias,

concentration difficulties

Pregabalin 75 mg BID 75–300 mg divided BID Weight gain, dizziness, drowsiness

Benzodiazepines

Alprazolam 0.125 mg every day 0.75–3 mg divided TID Sedation, fatigue, potential for abuse

Clonazepam 0.25 mg every day 0.5–6 mg divided every day to BID Sedation, fatigue, ataxia, dizziness, impaired

cognition

Miscellaneous

Botulinum toxin A Varies by injection site: 50–100 units/arm for hand tremor;

40–400 units/neck for head tremor; 0.6–15 units/vocal cords for

voice tremor; retreat no sooner than every 3 months (extend as

long as possible)

Hand weakness (with wrist injection); dysphagia,

hoarseness, breathiness (with neck or vocal

cord injection)

BID, two times daily; TID, three times daily.

areas.175 Injections in the wrist can cause hand weakness, and

dysphagia, hoarseness, and breathiness can occur with injections

into the neck or vocal cords. The use of botulinum toxin injections in the United States is also limited by cost. Treatment should

occur with the lowest dose, and the interval should be as long

as possible between injections. DBS of the ventral intermediate

nucleus of the thalamus or unilateral thalamotomy is highly efficacious in reducing ET.176 Greater improvement in self-reported

measures of function and fewer adverse events make DBS the

preferred surgical option of the two.176,182

Because K.H. is otherwise healthy, she is a good candidate

for propranolol therapy. Propranolol can be initiated as needed

or on a scheduled basis depending on the degree of impairment

and desire of the patient. If the decision is made with K.H. to

use propranolol on an as-needed basis, she should begin with

one-half of a 20-mg tablet administered 30 minutes to 1 hour

before the desired effect. The dose can be increased from onehalf to two tablets. An example of a situation in which this may

occur is if she wants to avoid embarrassment with attending a

social activity or before certain tasks requiring manual dexterity at work. Given the degree of her impairment, she is probably a better candidate for chronic suppressive therapy with propranolol. In this situation, she can be prescribed 10 mg twice daily

and titrated every few days up to 120 to 360 mg/day in divided

doses.

KEY REFERENCES

A full list of references for this chapter can be found at http://

thepoint.lww.com/AT10e. Below are the key references for this

chapter, with the corresponding reference number in this chapter

found in parentheses after the reference.

Key References

Parkinson Disease

Miyasaki JM et al. Practice parameter: evaluation and treatment

of depression, psychosis, and dementia in Parkinson disease (an

evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.

2006;66:996. (18)

Miyasaki JM et al. Practice parameter: initiation of treatment

for Parkinson’s disease: an evidence-based review. Report of the

Quality Standards Subcommittee of the American Academy of

Neurology. Neurology. 2002;58:11. (24)

Morley JF, Hurtig HI. Current understanding and management of Parkinson disease: five new things. Neurology. 2010;

75(18 Suppl 1):S9. (10)

Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med. 2005;353:1021.

(12)

Pahwa R et al. Practice parameter: treatment of Parkinson

disease with motor fluctuations and dyskinesia (an evidencebased review): report of the Quality Standards Subcommittee

of the American Academy of Neurology. Neurology. 2006;66:983.

(66)

Suchowersky O et al. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review):

report of the Quality Standards Subcommittee of the American

Academy of Neurology. Neurology. 2006;66:968. (7)

Suchowersky O et al. Practice parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidencebased overview): report of the Quality Standards Subcommittee

1386Section 13 Neurologic Disorders

of the American Academy of Neurology. Neurology. 2006;66:976.

(17)

Zesiewicz TA et al. Practice parameter: treatment of nonmotor

symptoms of Parkinson disease: report of the Quality Standards

Subcommittee of the American Academy of Neurology. Neurology. 2010;74:924. (124)

Restless Leg Syndrome

Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update.

Chest. 2006;130:1596. (149)

Trenkwalder C et al. Treatment of restless legs syndrome: an

evidence-based review and implications for clinical practice. Mov

Disord. 2008;23:2267. (156)

Essential Tremor

Deuschl G et al. Treatment of patients with essential tremor.

Lancet Neurol. 2011;10:148. (175)

Zesiewicz TA et al. Practice parameter: therapies for essential

tremor. Report of the Quality Standards Subcommittee of the

American Academy of Neurology. Neurology. 2005;64:2008. (176)

Seizure Disorders 58

James W. McAuley, Rex S. Lott, and Brian K. Alldredge

CORE PRINCIPLES

CHAPTER CASES

1 Epilepsy is a disorder characterized by spontaneously recurring seizures. Seizures can

arise from a focal area of the brain (focal or partial seizures) or arise diffusely from both

brain hemispheres (primary generalized seizures).

Case 58-1 (Questions 1, 2)

2 The optimal choice of antiepileptic drug (AED) treatment is based on patient-specific

considerations including seizure type (or epilepsy syndrome, if defined), age, sex,

concomitant medical conditions and therapies, and AED adverse effects. Monotherapy

is preferred; polytherapy should be considered for patients with multiple seizure types

and/or when monotherapy (with 2 or 3 agents) fails at maximal tolerated doses.

Case 58-1 (Question 3),

Case 58-7 (Question 1),

Case 58-8 (Questions 1, 4),

Case 58-14 (Question 2)

3 Standard AEDs, such as carbamazepine, phenytoin, and valproate, are used commonly

for patients with newly diagnosed epilepsy. Newer AEDs (e.g., lacosamide,

lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, zonisamide) are

often initially approved for add-on therapy in patients with partial-onset seizures who

do not respond to other AEDs. Lamotrigine, oxcarbazepine, topiramate, and

felbamate are indicated for monotherapy.

Case 58-1 (Question 3),

Case 58-2 (Question 1),

Case 58-7 (Question 1)

4 Enzyme-inducing AEDs (carbamazepine, phenobarbital, phenytoin) increase the metabolism of many other drugs (e.g., warfarin, contraceptive hormones) and can influence

the concentrations of other AEDs and other AED metabolites (e.g., valproate effect on

carbamazepine epoxide). In addition, carbamazepine induces its own metabolism and

levels may decline during the first month of therapy despite excellent adherence.

Case 58-1 (Question 5),

Case 58-11 (Question 1),

Case 58-12 (Questions 1, 2),

Case 58-14 (Question 1)

5 Serious idiosyncratic adverse effects have been associated with most standard and

new AED and include carbamazepine-associated hematologic abnormalities;

lamotrigine-associated skin rash; valproate-induced hepatotoxicity; and

hypersensitivity syndrome seen with carbamazepine, phenobarbital, and phenytoin.

The role of routine laboratory monitoring for detection of these adverse effects is

controversial. Patients should know the signs or symptoms that should prompt them to

seek medical attention.

Case 58-1 (Question 4),

Case 58-2 (Question 1),

Case 58-8 (Questions 8, 9),

Case 58-13 (Questions 1, 2)

6 Unlike other AEDs, phenytoin displays capacity-limited pharmacokinetics at serum

concentrations that are clinically useful for epilepsy treatment. As a consequence,

phenytoin blood levels often change disproportionately to changes in dosage, and

time to steady-state varies significantly in individual patients based on the phenytoin

concentration.

Case 58-3 (Questions 2, 3)

7 Serum concentration monitoring can be useful for selected AEDs when there is a good

correlation between concentration and therapeutic or toxic responses. However,

clinical criteria (seizure control, medication tolerability) are the primary determinants of

the need for dosage adjustments.

Case 58-8 (Question 7)

8 The occurrence of seizure clusters (acute repetitive seizures) and status epilepticus

(prolonged or repeated seizures without recovery of consciousness) warrant emergent

AED therapy. Acute repetitive seizures are often treated by parents or caregivers with

rectal diazepam. Status epilepticus is a life-threatening emergency and should be

treated with intravenous lorazepam as initial therapy.

Case 58-9 (Question 1,

Case 58-15 (Questions 1–5)

1387

1388Section 13 Neurologic Disorders

Incidence, Prevalence, and

Epidemiology

Approximately 10% of the population will experience a seizure

at some time in their life. Up to 30% of all seizures are provoked by central nervous system (CNS) disorders or insults

(e.g., meningitis, trauma, tumors, and exposure to toxins); these

seizures may become recurrent and require chronic treatment

with antiepileptic drugs (AEDs). Reversible conditions such as

alcohol withdrawal, fever, and metabolic disturbances may provoke acute, isolated seizures. These seizures are not considered

to be epilepsy and usually do not require long-term AED therapy.

Approximately 1% of the general population has epilepsy.1

Terminology, Classification, and

Diagnosis of Epilepsies

CLASSIFICATION OF SEIZURES AND EPILEPSIES

A seizure is the “transient occurrence of signs and/or symptoms

due to abnormal excessive or synchronous neuronal activity in

the brain” (p. 471).2 These signs or symptoms “may include alterations of consciousness, motor, sensory, autonomic, or psychic

events” (p. 593).1 Epilepsy is a “disorder of the brain characterized by an enduring predisposition to generate epileptic seizures

and by the neurobiologic, cognitive, psychological and social

consequence of this condition” (p. 471).2 By definition, epilepsy

requires the occurrence of two or more seizures that are not

acutely provoked by other illnesses or conditions.3 A commonly

used classification scheme for epileptic seizures is shown in Table

58-1.4 Older terms such as “grand mal” and “petit mal” should

not be used, because their use may create confusion in the clinical

setting. For example, it is common for patients or caregivers to

identify any seizure other than a generalized tonic-clonic seizure

as a “petit mal” seizure. This labeling may result in the selection

of an inappropriate medication.

Generalized tonic-clonic seizures are common. The patient

loses consciousness and falls at the onset. Simultaneously, tonic

muscle spasms begin and may be accompanied by a cry that

results from air being forced through the larynx. Bilateral, repetitive clonic movements follow. After the clonic phase, patients

return to consciousness but remain lethargic and may be confused for varying periods of time (postictal state). Urinary

incontinence and tongue biting is common. Primary generalized tonic-clonic seizures affect both cerebral hemispheres from

the outset. Secondarily generalized tonic-clonic seizures begin

as either simple or complex partial seizures. The aura described

by some patients before a generalized tonic-clonic seizure represents an initial partial seizure that spreads to become a secondarily generalized seizure. Identification of secondarily generalized

tonic-clonic seizures is important because some AEDs are more

effective at controlling primary generalized seizures than secondarily generalized seizures. In general, partial seizures are often

more difficult to control with AEDs as compared to primary

generalized seizures.3,5,6

Absence seizures occur primarily in children and often remit

during puberty; affected patients may exhibit a second type of

seizure. Absence seizures consist of a brief loss of consciousness,

usually lasting several seconds. Simple (typical) absence seizures

are not accompanied by motor symptoms; automatisms, muscle

twitching, myoclonic jerking, or autonomic manifestations may

accompany atypical (complex) absence seizures. Although consciousness is lost, muscle tone is maintained and patients do not

fall during absence seizures. Patients are unaware of their surroundings and will have no recall of events during the seizure.

Consciousness returns immediately when the seizure ends, and

TABLE 58-1

Classification of Epileptic Seizures

Partial Seizure (Focal)

Simple Partial Seizures (Without Impairment of Consciousness)

Motor symptoms

Special sensory or somatosensory symptoms

Autonomic symptoms

Psychic symptoms

Complex Partial Seizures (With Impairment of Consciousness)

Progressing to impairment of consciousness

With no other features

With features as in simple partial seizures

With automatisms

With impaired consciousness at onset

With no other features

With features as in simple partial seizures

With automatisms

Partial Seizures That Evolve to Generalized Seizures

Simple partial seizures evolving to generalized seizures

Complex partial seizures evolving to generalized seizures

Simple partial seizures evolving to complex partial seizures to

generalized seizures

Generalized Seizures (Convulsive or Nonconvulsive)

Absence Seizures

Typical seizures (impaired consciousness only)

Atypical absence seizures

Myoclonic Seizures

Clonic Seizures

Tonic Seizures

Tonic-Clonic Seizures

Atonic (Astatic or Akinetic) Seizures

Unclassified Epileptic Seizures

All seizures that cannot be classified because of inadequate or

incomplete data and some that cannot be classified in previously

described categories

postictal confusion does not occur. Differentiation of atypical

absence seizures from complex partial seizures may be difficult if

only a second-hand account of the episodes is available; identification of a focal abnormality by an electroencephalogram (EEG)

often is necessary to identify complex partial seizures. This distinction is important for the proper selection of AED.

Simple partial (focal motor or sensory) seizures are localized

in a single cerebral hemisphere or portion of a hemisphere. Consciousness is not impaired during these events. Various motor,

sensory, or psychic manifestations may occur depending on the

area of the brain that is affected. A single part of the body may

twitch, or the patient may experience only an unusual sensory

experience.

Complex partial seizures result from the spread of focal

discharges to involve a larger area. Consciousness is impaired

and patients may exhibit complex but inappropriate behavior

(automatisms) such as lip smacking, picking at clothing, or aimless wandering. A period of brief postictal lethargy or confusion

is common.

In 2010, the International League Against Epilepsy recommended modifications to the traditional seizure classification scheme and terminology. While some of the terminology

remained unchanged, seizures limited to one hemisphere are

now termed “focal seizures” (instead of partial seizures) and the

formal distinction between complex partial and simple partial

seizures is eliminated.7 Since most of the existing literature on

1389Seizure Disorders Chapter 58

epilepsy makes use of the traditional seizure terminology, we

have retained the use of “partial,” “complex partial” and “simple

partial” for this chapter.

EPILEPSY SYNDROMES

Epilepsy can be classified based on seizure type as shown in Table

58-1. Epilepsy syndromes can be defined on the basis of seizure

type as well as cause (if known), precipitating factors, age of onset,

characteristic EEG patterns, severity, chronicity, family history,

and prognosis. Accurate diagnosis of epilepsy syndromes may

better guide clinicians regarding the need for drug therapy, the

choice of appropriate medication, and the likelihood of successful

treatment.1,5,6 Many epilepsy syndromes have been defined; a

complete listing is beyond the scope of this chapter. Several are

of interest with respect to pharmacotherapy and are described

in Table 58-2.6

Diagnosis

Optimal treatment of seizure disorders requires accurate classification (diagnosis) of seizure type and appropriate choice and

use of medications. Seizure classification may be straightforward

if an adequate history and description of the clinical seizure are

available. Physicians often do not observe patients’ seizures; thus,

family members, teachers, nurses, and others who have frequent

direct contact with patients should learn to observe accurately

and objectively describe and record these events. The onset, duration, and characteristics of a seizure should be described as completely as possible. Several aspects of the events surrounding

a seizure may be especially significant: the patient’s behavior

before the seizure (e.g., did the patient complain of feeling ill or

describe an unusual sensation?), deviation of the eyes or head

to one side or localization of convulsive activity to one portion

of the body, impaired consciousness, loss of continence, and the

TABLE 58-2

Selected Epilepsy Syndromes

Syndrome Seizure Patterns and Characteristics Preferred AED Therapy Comments

Juvenile myoclonic

epilepsy

Myoclonic seizures often precede

generalized tonic-clonic seizures.

Myoclonic and generalized

tonic-clonic episodes on awakening.

Absence seizures also common.

↓ sleep, fatigue, and alcohol

commonly precipitate seizures.

Valproate. Levetiracetam FDA-approved

as adjunct for myoclonic seizures.

Phenytoin possibly an adjunct to

valproate in resistant cases.

Carbamazepine reported to

exacerbate seizures in some patients.

5%–10% of all epilepsies; 85%–90%

response to valproate. Lifelong

therapy usually needed. High

relapse rate with attempts to

discontinue AED therapy.

Lennox-Gastaut

syndrome

Generalized seizures: atypical absence,

atonic/akinetic, myoclonic, and tonic

most common. Abnormal interictal

EEG with slow spike-wave pattern.

Cognitive dysfunction and mental

retardation. Status epilepticus

common.

Valproate and benzodiazepines may be

effective. Lamotrigine, rufinamide

and topiramate FDA-approved.

Felbamate also may be effective, but

potential hematologic toxicity limits

use. Poorly responsive to AED.

Oversedation with aggressive AED

trials may ↑ seizure frequency.

Tolerance to benzodiazepines

limits their usefulness.

Childhood absence

epilepsy

Typical absences often in clusters of

multiple seizures. Tonic-clonic

seizures in ∼40%. Onset usually

between ages 4 and 8 years. Significant

genetic component. EEG shows classic

3-Hz spike-and-wave pattern.

Ethosuximide or valproate. Lamotrigine

probably effective.

80%–90% response rate to AED

therapy. Good prognosis for

remission. Tonic-clonic seizures

may persist.

Reflex epilepsy Tonic-clonic seizures most common.

Induced by flicker or patterns

(photosensitivity) most commonly.

Reading also may precipitate partial

seizures affecting the jaw, which may

generalize. Some cases involve

precipitation of underlying seizures;

some seem primary.

AED specific to underlying seizures.

Avoidance of precipitating stimuli

when possible. Valproate usually

effective for cases of spontaneous

seizures precipitated by

photosensitivity.

Relatively rare; seizures may be

precipitated by television or

video games.

Temporal lobe

epilepsy

Complex partial seizures with

automatisms. Simple partial seizures

(auras) common; secondary

generalized seizures occur in 50%.

Carbamazepine, phenytoin, valproate,

gabapentin, lamotrigine, topiramate,

tiagabine, levetiracetam,

oxcarbazepine, zonisamide,

pregabalin, lacosamide.

Often incompletely controlled with

current AEDs. Emotional stress

may precipitate seizures;

psychiatric disorders seen with

temporal lobe epilepsy; surgical

resection can be effective when

patient is identified as a good

surgical candidate.

AED, antiepileptic drug; EEG, electroencephalogram; FDA, US Food and Drug Administration.

Source: Dreifuss FE. The epilepsies: clinical implications of the international classification. Epilepsia. 1990;31(Suppl 3):S3; Serratosa JM. Juvenile myoclonic epilepsy.

In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:491; Farrell K. Secondary generalized

epilepsy and Lennox-Gastaut syndrome. In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2001:525; Kotagal P. Complex partial seizures. In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2001:309; Berkovic SF et al. Absence seizures. In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2001:357; Zifkin BG et al. Epilepsy with reflex seizures. In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott Williams &

Wilkins; 2001:537.

1390Section 13 Neurologic Disorders

patient’s behavior after the seizure (e.g., was there any postictal

confusion?). In addition, it is helpful if the observer can record the

length of the event and how long it took for the patient to return

to baseline. The patient and caregivers should have a seizure calendar or diary to record events. Those who observe a seizure

should not try to label the seizure but should be encouraged to

describe the event fully and objectively.

Accurate seizure diagnosis and identification of the type of

epilepsy or epilepsy syndrome also depend on neurologic examination, medical history, and diagnostic techniques, such as EEG,

computed tomography (CT), and magnetic resonance imaging

(MRI). The EEG often is critical for identifying specific seizure

types. CT scanning may help assess newly diagnosed patients,

but MRI is preferred. MRI may locate brain lesions or anatomic

defects that are missed by conventional radiographs or CT scans.8

Treatment

Early control of epileptic seizures is important because it allows

normalization of patients’ lives and prevents acute physical harm

and long-term morbidity associated with recurrent seizures. In

addition, early control of tonic-clonic seizures is associated with a

reduced likelihood of seizure recurrence. Early control of epileptic seizures also correlates with successful discontinuation of

AED treatment after long-term seizure control.9–11

NONPHARMACOLOGIC TREATMENT OF EPILEPSY

Alternatives or adjuncts to pharmacotherapy may be helpful in

some patients. Surgery is an extremely effective treatment in

selected patients. Depending on the epilepsy syndrome and procedure performed, up to 90% of patients treated surgically may

improve or become seizurefree. A study of 80 patients with medically refractory temporal lobe epilepsy randomly assigned to

either surgery or continued medical treatment showed that after

1 year patients were more likely to be seizurefree after surgery.12

Surgery is advocated as early therapy for some patients with specific epilepsy syndromes, such as mesial temporal sclerosis. Early

surgical intervention may prevent or lessen neurologic deterioration and developmental delay.

Dietary modification may be used for patients who cannot tolerate AEDs or to treat seizures that are not completely responsive

to AEDs. In most circumstances, dietary modification consists

of a ketogenic diet. This low-carbohydrate, high-fat diet results

in persistent ketosis, which is believed to play a major role in

the therapeutic effect. Ketogenic diets seem to be most beneficial in children; they are also used as adjuncts to ongoing AED

treatment.13,14

The vagus nerve stimulator is an implantable device approved

for treatment of intractable partial seizures. This device uses electrodes attached around the left branch of the vagus nerve. The

electrodes are attached to a programmable stimulator that delivers stimuli on a regular cycling basis; patients can also use “on

demand” stimulation at the onset of seizures by swiping the

magnet over the subcutaneously implanted stimulator. Approximately 30% to 40% of patients who are so treated have a positive

response (50% reduction in seizures).15 The primary side effect

of this device is hoarseness during stimulation; infrequently, this

is accompanied by left vocal cord paralysis.

AVOIDANCE OF POTENTIAL SEIZURE PRECIPITANTS

It is impossible to generalize about environmental and lifestyle

precipitants of seizure activity in persons with epilepsy. Individual

patients or caregivers may identify specific circumstances such

as stress, sleep deprivation, acute illness, or ingestion of excessive

amounts of caffeine or alcohol, which may increase the likelihood

of a recurrent seizure event. Some women experience an increase

in the frequency and/or severity of seizures around the time of

menstruation or ovulation. Patients with epilepsy should avoid

activities that seem to precipitate seizures; as always, the goal is

complete seizure control with as little alteration in quality of life

as possible.

ANTIEPILEPTIC DRUG THERAPY

Pharmacotherapy is the mainstay of treatment for epilepsy.

Therefore, patient education regarding medications and consultation among health care professionals regarding the optimal use

of AEDs are essential to quality patient care. Optimal AED therapy completely controls seizures in approximately two-thirds of

patients.16,17 Optimization of drug therapy depends on several

factors, with the choice of appropriate AED, individualization of

dosing, and adherence being the most important.

For a narrated PowerPoint presentation of

mini case studies addressing multiple aspects

of AED therapy, go to http://thepoint.lww.

com/AT10e.

CHOICE OF ANTIEPILEPTIC DRUG

Many AEDs have a relatively narrow spectrum of efficacy against

selected seizure types; therefore, choice of appropriate drug therapy for a specific patient depends on an accurate diagnosis of

epilepsy. In addition, toxicity must be considered when selecting an AED. Preferred drugs for specific types of seizures and

common epileptic syndromes are listed in Tables 58-2 and 58-3.

Although certain drugs are preferred, the identification of the

most effective drug for a particular patient may be a process of

trial and error; several medication trials may be necessary before

success is achieved. The consensus method was used to analyze

expert opinion on treatment of three epilepsy syndromes and status epilepticus.18 The experts recommended monotherapy first,

followed by a second monotherapy agent if the first failed. If the

second monotherapy failed, the experts were not in agreement

on whether to try a third monotherapy agent or to combine two

therapies. The experts recommended epilepsy surgery evaluation after the third failed AED for patients with symptomatic

localization-related epilepsies.

To assess the evidence on efficacy, tolerability, and safety of

many of the new AEDs in treating children and adults with newonset and refractory partial and generalized epilepsies, a panel

evaluated the available evidence.19,20 They concluded that AED

choice depends on seizure and syndrome type; patient age; concomitant medications; and AED tolerability, safety, and efficacy.

The results of these two evidence-based assessments provide

guidelines for the use of newer AEDs in patients with new-onset

and refractory epilepsy.

THERAPEUTIC END POINTS

The individual patient’s response to AED treatment (i.e., seizure

frequency and severity, and symptoms of toxicity) must be the

major focus for therapy assessment. In general, the goal of AED

treatment is administration of sufficient medication to completely prevent seizures without producing significant toxicity.21

Realistically, this goal may be compromised for many patients;

it may not be possible to completely prevent seizures without

producing intolerable adverse effects. Thus, the therapeutic end

points achieved can vary among patients; optimization of AED

therapy for a specific person depends on tailoring therapy to the

patient’s needs and lifestyle. It is rarely optimal to administer

“standard” or “usual” doses of an AED to a patient or to adjust

doses to achieve a “therapeutic blood level” without considering

the effect of the dose or serum concentration on the patient’s

1391Seizure Disorders Chapter 58

TABLE 58-3

Antiepileptic Drugs Useful for Various Seizure Typesa

Primary Generalized

Tonic-Clonic

Secondarily Generalized

Tonic-Clonic

Simple or Complex

Partial Absence Myoclonic, Atonic/Akinetic

Most Effective With Least Toxicity

Valproate Carbamazepine Carbamazepine Ethosuximide Valproate

Carbamazepine Oxcarbazepine Oxcarbazepine Valproate Clonazepam

Lamotrigine Levetiracetam Levetiracetam Lamotrigineb Rufinamide (Lennox-Gastaut Syndrome)

Valproate Valproate (Topiramate)b Levetiracetam (Juvenile Myoclonic Epilepsy)

(Levetiracetam)b (Gabapentin)b Lamotrigine Lamotrigineb

(Oxcarbazepine)b Lamotrigine (Gabapentin)b (Topiramate)b

(Topiramate)b (Topiramate)b (Levetiracetam)b

(Zonisamide)b (Tiagabine)b (Topiramate)b

(Zonisamide)b (Tiagabine)b

(Levetiracetam)b (Pregabalin)b

(Pregabalin)b (Zonisamide)b

(Lacosamide)b (Lacosamide)b

Effective, but Often Poorly Tolerated or Cause Unacceptable Toxicity

Phenobarbital Phenobarbital Clorazepate Clonazepam (Felbamate)c

Primidone Primidone Phenobarbital

(Felbamate)c (Felbamate)c Primidone

Phenytoin Phenytoin (Felbamate)c

Phenytoin

Of Little Value

Ethosuximide Ethosuximide Ethosuximide Phenytoin

Carbamazepine

Phenobarbital

Primidone

Oxcarbazepine

Levetiracetam

Lacosamide

Rufinamide

Tiagabine

aDrugs are listed in general order of preference within each category. Recommendations by various authorities may differ, especially regarding the relative place of valproate

and the role of phenytoin as a first-line AED. The use of phenobarbital and primidone is now discouraged.

bThe place of gabapentin, lacosamide, rufinamide, lamotrigine, oxcarbazepine, levetiracetam, topiramate, tiagabine, pregabalin, and zonisamide is yet to be determined.

They are placed on this table only to indicate the types of seizures for which they appear to be effective. More clinical experience is needed before their roles as possible

primary AEDs are clarified.

cThe place of felbamate is yet to be determined. It is placed on this table only to indicate the types of seizures for which it appears to be effective. Felbamate has been

associated with aplastic anemia and hepatic failure; until a possible causative role is clarified, felbamate cannot be recommended for treatment of epilepsy unless all other,

potentially less toxic, treatment options have been exhausted.

Source: French JA et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment

Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252; French JA et al.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and

Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1261; Pellock JM. Efficacy and adverse

effects of antiepileptic drugs. Pediatr Clin North Am. 1989;36:435; Mattson RH et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and

secondarily generalized tonic-clonic seizures. N Engl J Med. 1985;313:145; Mattson RH et al. A comparison of valproate with carbamazepine for the treatment of complex

partial seizures and secondarily generalized tonic-clonic seizures in adults. The Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med.

1992;327:765; Fisch BJ et al. Generalized tonic-clonic seizures. In: Wyllie E et al, eds. The Treatment of Epilepsy: Principles and Practice. 3rd ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2001:369.

condition and quality of life. As with many conditions requiring chronic drug therapy, patient participation in developing and

evaluating a therapeutic plan is extremely important. Patients

should be educated regarding the expected positive and negative effects of their AED therapy, and they must be encouraged

to communicate with their health care provider regarding their

responses to prescribed AED.

SERUM DRUG CONCENTRATIONS

Relation to Dosage

For some AEDs, a good correlation exists between serum concentrations and both therapeutic response and toxicity. For these

agents, the wide availability of AED serum concentration determinations has had a significant impact on the treatment of seizure

disorders. The correlation between the administered maintenance dose of an AED and the resulting steady-state serum concentration is poor. Administration of “usual therapeutic doses,”

even when calculated on the basis of body weight, is equally likely

to produce subtherapeutic, therapeutic, or potentially intoxicating serum concentrations. Interindividual variation in hepatic

metabolic capacity probably accounts for most of this variability.

Relation to Clinical Response

For selected AEDs, proper use and interpretation of serum concentrations are important for optimizing treatment regimens in

epilepsy.22,23 An individual patient’s clinical response to AED

treatment must be the major focus for therapy assessment.

1392Section 13 Neurologic Disorders

Neither therapeutic effects nor toxic symptoms are “all or none”;

in most situations, there are gradations of efficacy and toxicity.

Dosage increases and titration to AED serum concentrations

within and occasionally above the “therapeutic range” may significantly improve therapeutic responses without producing significant toxicity.23 Individual patients often differ dramatically in

their response to a particular serum drug concentration; therefore, therapeutic serum concentrations should be considered

only as guidelines for treatment. Many patients’ condition may be

controlled with serum drug concentrations below the usual therapeutic range.24 In these patients, dosage adjustment to increase

the serum drug concentration is not warranted. In this case, it is

better to “treat the patient, not the level.”

Interestingly, a recent Cochrane Review found no evidence

that measuring AED concentrations routinely to inform dose

adjustments is superior to dose adjustments based on clinical

information.25 However, the authors do state that their review

does not exclude the possibility that AED serum concentration

might be useful in special situations or in selected patients.

Indications for Use

Measurement of serum drug concentrations may provide clinically useful information in the following situations:

 Uncontrolled seizures despite administration of greaterthan-average doses: Serum concentrations of AED may

help distinguish drug resistance from subtherapeutic drug

concentrations caused by malabsorption, nonadherence, or

rapid metabolism.

 Seizure recurrence in a patient whose seizures were previously controlled: This is often owing to nonadherence with

the prescribed medication regimen.

 Documentation of intoxication: In patients who exhibit

signs or symptoms of dose-related AED toxicity, documentation of the dose and serum concentration of the responsible drug is helpful.

 Assessment of patient adherence: Although monitoring

AED serum concentrations can be used to assess patient

adherence with therapy, conclusions must be based on comparisons with previous steady-state serum concentrations

that reflected reliable intake of a given dose of AED.

 Documentation of desired results from a dose change or

other therapeutic maneuver (e.g., administration of a loading dose): When patients are receiving multiple AEDs, it

is often appropriate to measure serum concentrations of

all drugs after a change in the dose of one agent because

changes to one drug frequently affect the pharmacokinetic

disposition of other drugs.

 When precise dosage changes are required: On occasion,

small changes in the dose of a drug (e.g., phenytoin) can

result in large changes in both the serum concentration and

clinical response. In addition, cautious titration of dosage

and serum concentration may be necessary to avoid intoxication. Knowledge of the serum drug concentration before

the dosage change may allow the clinician to select a more

appropriate new maintenance dose.

 During pregnancy, AED serum concentrations often

decline and dosage adjustments may be warranted to maintain adequate seizure protection. Free (unbound) concentrations should be monitored for highly protein-bound