| Medical TreatmentThe
goal is to find the drug or drugs that suppress all seizure activity
without side effects. Even for a single seizure, prophylactic treatment
with antiepileptic drugs delays the time to the next seizure,[1]
although most experts recommend treatment after a single seizure only
for patients in whom the likelihood of recurrent seizures is especially
high. The presence of abnormal EEG changes, abnormal neurologic
findings, a lesion on MRI, or a history of significant
brain injury increases the risk for recurrent seizures sufficiently to
consider treatment after only one seizure. If a seizure occurs in the
setting of an acute correctable metabolic or other provocation,
long-term treatment is not indicated.After
two unprovoked seizures, the risk for recurrence is 70%. Initiation of
treatment is typically indicated except in specific benign and
self-limited syndromes, such as febrile seizures and benign epilepsy
with centrotemporal spikes.Specific drugs are effective for specific types of seizures, and some drugs can worsen other types of seizures (Table 426-5).
Knowledge of individual drugs as they relate to age, sex, comorbid
conditions, drug interactions, sedation, tolerance, mood, and withdrawal
is critical in the drug selection process.Drugs
that cause enzyme induction (e.g., carbamazepine, phenytoin,
phenobarbital, oxcarbazepine, topiramate) or inhibition (e.g., valproic
acid) can be difficult to manage when additional medications are used
for independent conditions, such as oral contraceptives. For these
settings and in the elderly, gabapentin and levetiracetam are
particularly useful because they have no appreciable drug interactions.
The newer drugs are more expensive, whereas phenobarbital costs only
pennies per dose and is preferable in many undeveloped countries and for
individuals with limited resources.As
early as the 1980s, a randomized comparison study of carbamazepine,
phenytoin, primidone, and phenobarbital for newly diagnosed partial
seizures, with or without secondary generalization, found that all four
drugs had similar efficacies but that the side effects of primidone and
phenobarbital made carbamazepine and phenytoin preferable.[2]
In a more recent meta-analysis of randomized clinical trials of
antiepileptic drugs as monotherapy in newly diagnosed epilepsy, none of
the newer antiepileptic drugs showed more efficacy than the traditional
drugs, although tolerability was better in some situations. However,
methodologic concerns may limit the applicability of these data to
general treatment considerations. In trials comparing carbamazepine with
lamotrigine monotherapy, for example, efficacy was equivalent, but more
carbamazepine-treated patients withdrew from the trial because of side
effects.[3] In other randomized trials, valproate was as good as[4] or better than[5]
topiramate and carbamazepine. However, fetal exposure to valproate
increases the likelihood of lower cognitive function in three year olds
when compared with other maternal anti-seizure medications. The overall
data indicate that there is not indisputable advantage of any single
agent in terms of efficacy of monotherapy in patients with newly
diagnosed epilepsy, so side effects, toxicity profiles (Table 426-6),
and the type of seizure are of major importance in guiding therapy. For
example, carbamazepine, oxcarbazepine, phenytoin, topiramate,
lamotrigine, gabapentin, levetiracetam, and zonisamide could all be
considered for initial treatment of partial epilepsy, with lamotrigine
representing a potentially cost-effective alternative to carbamazepine.[6]
Final selection would depend on age, gender, weight, psychiatric
status, employment, concomitant medications, and pregnancy concerns
relevant to the individual. Similarly, treatment of absence seizures
would be equally appropriate with valproic acid, lamotrigine, and
ethosuximide, so the accompanying seizure types, gender, age, and other
aspects of the clinical setting would guide drug selection.Treatment
with the initial drug controls seizures completely in more than 50% of
patients with newly diagnosed epilepsy. After failure of the first
monotherapy, only 14 to 20% of patients with partial seizures will be
successfully controlled with any alternative single drug. In combination
therapy, drugs with differing mechanisms of action are used, but side
effects are additive, and selection of combinations is not
straightforward. Sometimes combining drugs with similar mechanisms is
facilitative. Unfortunately, after failing monotherapy trials, less than
10% of patients have complete control of seizures with dual therapy.Medical
intractability occurs more often in patients with frequent seizures,
multiple types of seizures, abnormal neurologic findings, a brain
lesion, onset in the first year of life, or abnormal EEG findings
consisting of either spike and slow wave activity or multifocal
abnormalities. However, the most valuable predictor of medical
intractability in epilepsy is the etiology. Patients with seizures
secondary to mesial temporal sclerosis associated with mesial temporal
lobe epilepsy or
developmental (migrational) substrates are most difficult to manage
medically; only 40 to 50% of such patients are controlled as compared
with a seizure-free rate of 65 to 80% in patients with newly diagnosed
epilepsy of vascular or neoplastic cause.Antiepileptic drugs and concomitant use of other drugs may alter serum levels. Antiepileptic drug levels (see Table 426-6)
can establish the optimal therapeutic ranges for the individual,
thereby allowing assessment of treatment failures as being caused by
noncompliance, drug interactions, or incorrect prescribing. Phenytoin,
carbamazepine, oxcarbazepine, topiramate, and phenobarbital induce
hepatic enzymes, which may necessitate increasing the dose of other
drugs. Similarly, enzyme inhibitors such as valproic acid or macrolide
antibiotics can cause toxic levels of antiepileptic drugs. Carbamazepine
induces the enzymes that metabolize it, so the initial dose needs to be
increased later. Valproic acid inhibits clearance of lamotrigine,
thereby allowing use of approximately half the dose of lamotrigine that
would otherwise be needed to achieve the same serum level.Treatment of Refractory EpilepsyWhen
seizures fail to respond to antiepileptic drug treatment, potential
causes to be considered include incorrect diagnosis, incorrect drug
selection, lack of compliance, factors that lower the seizure threshold,
factors that reduce medication effects because of enhanced metabolism
or reduced absorption, and factors that directly activate the CNS (Table 426-7).
However, an estimated 15% or more of patients with partial-onset
seizures are unresponsive to medical treatment, and resection of a
cerebral region identified to be the origin of intractable partial
seizures offers the possibility of cure. Removal of an epileptogenic
region requires accurate identification of the region, as well as
documentation of a lack of functional consequences after its removal.
Video EEG monitoring with seizure recording from scalp electrodes, MRI
protocols with special attention to areas commonly associated with
refractory seizures (e.g., the medial temporal and frontal lobes), and
functional neuroimaging, including PET (metabolism) and SPECT
(perfusion), are routinely used. Neuropsychological evaluation, both for
localizing areas
of dysfunction and for establishing the level of functional activity in
tissue being considered for possible resection, is an essential
component of the evaluation. Good performance on measures of verbal
memory, generally believed to rely on the dominant medial temporal lobe,
may be used as an indicator of excessive risk of memory loss from
contemplated resection of dominant medial temporal lobe structures when
seizures localize to that region. Sometimes, EEG localization of the
area of seizure onset requires implantation of intracranial or subdural
electrodes or grids, which are also used for electrical stimulation to
map cortical function in the nearby regions of the brain.Surgical InterventionsIn
a randomized trial, resective surgery for intractable medial temporal
lobe epilepsy achieved a 58% seizure-free rate at 1 year versus 8% in
the control group.[7]
Although 20% of patients relapse with long-term follow-up,
reintroduction of antiepileptic drugs can control the seizures in some
patients.When intractable epilepsy is
associated with multifocal seizures, when the onset of seizures occurs
in functionally critical brain regions, or when localization is not
possible, resection cannot be attempted. Alternative surgical
interventions, including corpus callosum section or multiple subpial
transection, may be of benefit. These usually palliative procedures
functionally disconnect epileptogenic tissue from other brain regions,
thereby preventing propagation of seizures and resulting in smaller,
partial events. Callosotomy severs the major interhemispheric commissure
and stops generalized seizures in most patients, but at the cost of
considerable morbidity. Multiple subpial transection involves vertical
cuts in the cortex to a depth of about 4 mm, placed 4 to 5 mm apart, in
the identified region or regions of seizure generation to sever the
horizontal connections that allow the seizure to propagate while
maintaining the vertical, functional columns.Electrical StimulationElectrical
stimulation is now used to treat medically refractory epilepsy when
surgery is not indicated. Programmed, intermittent stimulation of the
vagus nerve in the neck with implanted leads attached to a battery
placed subcutaneously in the upper part of the chest can reduce the
frequency of seizures in approximately a third of patients by about 30%.
Electrodes implanted to stimulate cortical epileptogenic locations are
under study.Management Issues in Women with EpilepsyHormonal
cycling, pregnancy, and the long-term effects of certain antiepileptic
drugs influence the management of epilepsy in women. Estrogen lowers the
seizure threshold, whereas progesterone raises it, and changes in
hormone levels during the menstrual cycle may aggravate seizures
perimenstrually, less often at midcycle. In many women these changes do
not cause difficulty with control of the seizure, but some women have
seizures more frequently or even only with their menses (i.e.,
catamenial epilepsy). Although levels of antiepileptic drugs may
fluctuate with the menstrual cycle, altering drug doses at mid or end
cycle is generally difficult. Catamenial epilepsy is sometimes improved
by the administration of an oral contraceptive pill; Depo-Provera may
also reduce perimenstrual seizures. Enzyme-inducing antiepileptic drugs,
particularly phenytoin, carbamazepine, phenobarbital, primidone, and
topiramate, reduce estrogen levels by enhancing its metabolism, so oral
contraceptives with higher doses of estrogen may be necessary, or
alternative methods of contraception may be preferable.Pregnancy
itself has no consistent effect on the frequency of seizures, and the
response varies not only among women but also among pregnancies in
individual women. Generalized tonic-clonic seizures during pregnancy may
pose a risk to the developing fetus. Whether complex partial seizures
have similar negative effects on fetal development is not known. Simple
partial seizures do not pose any risk unless they progress to a complex
partial or generalized tonic-clonic event.Although
most of the antiepileptic drugs double the risk (to 4 to 6%) of major
malformations in the developing fetus, it is usually important to
maintain an effective antiepileptic drug level for each patient during
pregnancy. Valproic acid is the most teratogenic of the commonly used
antiepileptic drugs, with a substantial risk for spina bifida; it should
be avoided in pregnancy and possibly in all women of childbearing age.
Carbamazepine is also associated with an increased risk for spina
bifida, but less so. The teratogenic effects of newer antiepileptic
drugs are still unclear. With use of a single drug at the lowest
possible dose, more than 90% of women with epilepsy have normal
pregnancies and deliver normal babies without complications.Most
antiepileptic drugs reach breast milk only in low concentrations, so
breast-feeding is possible. Occasionally, however, somnolence from
absorption of even small amounts of antiepileptic drugs by the nursing
infant may interrupt successful feeding.Women
of childbearing age and particularly women with epilepsy should
routinely take 1 to 3 mg of folate per day. Long-term bone loss in women
taking antiepileptic drugs, especially those that induce cytochrome
P-450, is treated prophylactically with supplemental calcium and vitamin
D.Epileptic SyndromesThe syndromic diagnosis of epilepsy (see Table 426-3)
uses the classification of the type or types of seizures, as well as
information about the setting in which seizures occur, the patient's
neurologic and cognitive status, age at onset, family history, and
results of diagnostic studies, including imaging. Selection of specific
drug treatment depends on the types of seizures present (see Table 426-5).
The need for lifelong treatment, the risk of genetic transmission, the
likelihood of concurrent neurologic diseases, the risk of comorbid
conditions, and the long-term prognosis are critical factors that can be
addressed only with knowledge of the specific epileptic syndrome.The
first issues in syndromic diagnosis are whether the epilepsy is related
to a localized brain region or is generalized and whether it has an
identified cause (symptomatic of or secondary to a detectable brain
lesion) or not (idiopathic). Sometimes epilepsy is presumed to be
symptomatic but no clear cause can be identified; these cases are called
cryptogenic. Thus, the syndromic classification of epilepsies first
divides syndromes into localization related versus generalized (see Table 426-3)
and into symptomatic versus idiopathic. Other variables are then used
to define the specific syndromes within these groups. Although most
generalized epilepsies are idiopathic (and genetic) and most
localization-related epilepsies are symptomatic with an identifiable
brain lesion or cause, idiopathic epilepsy syndromes can be associated
predominantly or exclusively with partial onset seizures (localizations
related), and symptomatic epilepsy syndromes can be associated
predominantly or exclusively with generalized seizures.Generalized Epileptic SyndromesBenign
neonatal convulsions, which occur in previously healthy newborns on
about day 5, may be partial or generalized tonic seizures. Mutations in
two potassium channel genes (KCNQ2, KCNQ3) have been associated
with this syndrome. Potassium channel regulation may be age dependent
and therefore account for the age-related appearance of the seizures.
The EEG recording is abnormal and shows rhythmic slow wave activity or
spiking with seizures. The seizures are refractory to treatment, are
recurrent over a brief interval, and disappear within a month. About 90%
of such infants subsequently have normal development, whereas 10% have
subsequent seizures in this idiopathic, generalized epileptic syndrome.In
generalized epilepsy with febrile seizures plus, febrile seizures occur
in combination with a variety of other nonfebrile types of seizures,
including myoclonic, absence, atonic, tonic-clonic, and partial
seizures. Mutations in at least four different ion channel genes,
including voltage-gated sodium channels (SCN1A, SCN2A, SCN3A) and GABA receptors (GABRG2), have been identified.In the syndrome of severe myoclonic epilepsy of infancy, which is also associated with various SCN1A mutations, myoclonic seizures are
associated with other types of seizures, including absence, atonic, and
partial seizures. The seizures are difficult to treat and are
associated with developmental and cognitive decline after 1 to 2 years
of normal development.Childhood absence
epilepsy begins in early to mid childhood, usually with autosomal
dominant inheritance, and is characterized by absence seizures, rarely
with other types of generalized seizures. It is self-limited in about
40% of cases. It occurs in the setting of otherwise normal brain
structure and function. The seizures are accompanied by a characteristic
3-Hz spike and wave EEG discharge, which appears in short bursts
between seizures and in continuous runs during seizures (see Fig. 426-2).
Earlier onset may be associated with a tendency to remit, whereas onset
after 12 years of age is more likely to be accompanied by generalized
tonic-clonic seizures and persist into adulthood.Juvenile
myoclonic epilepsy usually starts in the second decade with generalized
tonic-clonic and myoclonic seizures. Mutations in GABA receptors,
including GABRG1, can be found. Seizures typically occur in the
morning, immediately after awakening. A proportion of these patients
have had absence seizures as well. The EEG recording may be similar to
the 3-Hz spike-wave of absence epilepsy, but the spike-wave pattern can
be faster. The seizures are especially linked to sleep deprivation and
tend to appear in college students. Lifetime treatment is generally
needed.West's syndrome is a
catastrophic, usually secondary generalized epileptic syndrome that
appears before the age of 12 months and ceases by the age of 5 years,
often to be replaced by other symptomatic generalized epilepsy syndromes
such as Lennox-Gastaut (see later). Tuberous sclerosis (Chapter 444)
and hypoxia are among the common causes, but West's syndrome can also
be idiopathic. The syndrome comprises a triad of so-called infantile
spasms (synonymous terms include myoclonic spasms, jackknife
convulsions, salaam seizures), developmental arrest, and an EEG pattern
called hypsarrhythmia (a markedly abnormal EEG pattern with
high-amplitude slowing and superimposed multifocal spikes, polyspikes,
and spike and slow wave complexes). Associated abnormalities often
include developmental delay, porencephaly, atrophic lesions,
calcifications, and agenesis of the corpus callosum.Lennox-Gastaut
syndrome, a secondary or cryptogenic generalized epilepsy found in
children with mental retardation, is characterized by the occurrence of
multiple generalized types of seizures, including atypical absence,
generalized tonic-clonic, tonic, atonic, and partial seizures. The EEG
pattern is a spike-wave variation but slower than the 3 Hz associated
with absence seizures, more characteristically between 2 and 2.5 Hz. It
often appears after West's syndrome has resolved.Febrile
seizures are acute secondary seizures that are not considered epilepsy
because seizures occur only when provoked by fever. The seizures begin
after 6 months of age and generally do not continue beyond the age of 6
years. Usually, the febrile seizure diathesis is left untreated because
the prognosis is benign. When seizures occur in the setting of a
neurologic abnormality or are prolonged or complicated, the risk for
later epilepsy is increased.Localization-Related Epileptic SyndromesBenign
rolandic epilepsy, which is also called benign epilepsy with central
temporal spikes, is an age-related partial seizure disorder with onset
between 3 and 13 years of age; it is characterized by almost exclusively
nocturnal partial motor or sensory seizures with facial or oral onset
and with frequent secondary generalization. The family history is
positive for epilepsy diagnoses in nearly 50% of cases. The EEG
recording shows spiking in the central/temporal region. In some cases,
the disorder may not require treatment because it usually remits
spontaneously (97%) and is not associated with any known brain
abnormality.Autosomal dominant
nocturnal frontal lobe epilepsy is characterized by clusters of brief
seizures that occur during sleep and are manifested by turning prone,
vocalization, and violent thrashing lasting 10 seconds, followed by
immediate return to sleep. The syndrome is caused by mutations in genes
for neuronal nicotinic acetylcholine receptors (CHRNA4, CHRNB2);
the inheritance pattern appears to be autosomal dominant with variable
penetrance. Seizures begin in childhood and persist, but they are not
associated with other clinical manifestations or evidence of structural
or functional brain abnormalities.Lobar
epilepsies are epileptic syndromes that begin in the temporal,
parietal, occipital, and frontal lobes. Each of these lobes has
subdivisions and regions, which can result in different clinical
manifestations and EEG findings. Causes include neoplastic, traumatic,
developmental, infectious, and ischemic diseases. Clinical
characteristics are consistent with seizures originating in each
specific cortical location (see Table 426-2).Mesial Temporal Lobe EpilepsyMesial
temporal lobe epilepsy is the most common partial (lobar) epilepsy in
adults. It is characterized by recurrent simple and complex partial
seizures that originate in mesial temporal/limbic structures, as
documented by EEG seizure recordings obtained from implanted electrodes
placed in the medial temporal regions. Various components of the mesial
temporal limbic network (including the hippocampus, entorhinal cortex,
amygdala, neocortical areas of the frontal and temporal lobes, and
dorsal medial thalamus) are probably involved in the pathogenesis of
these seizures. Mesial temporal sclerosis, also called hippocampal
sclerosis, is characterized by neuronal loss and gliosis, mostly in the
CA1 and CA3 regions of the hippocampus, with mossy fiber reorganization
seen as sprouting of neuropeptide Y and dynorphin interneurons into the
inner third of the dentate molecular layer. Whether the neuronal loss is
secondary or primary and whether neuronal reorganization has a critical
role in the epileptogenic process are not known.The
seizures of mesial temporal lobe epilepsy begin at 5 to 15 years of
age. Seizures have mostly complex partial manifestations with altered
consciousness, typically beginning with an aura of a rising epigastric
sensation or a feeling of déjà vu, followed by oral and alimentary
automatisms and later by contralateral arm dystonia and ipsilateral arm
automatisms. The seizures are lengthy (lasting minutes), rarely
generalize, and typically occur three to five times a month. Auras
without following seizures are common. Up to 70% of patients have a risk
factor, such as lengthy and complicated seizures before the age of 4
years, frequently associated with fever or with encephalitis,
meningitis, or trauma. However, the characteristic seizures generally
begin some years later. Most cases are sporadic, but there are familial
forms of mesial temporal lobe epilepsy. Hippocampal atrophy and
increased hippocampal T2 signal are best seen on coronal MRI, and
widespread hypometabolism is seen in the temporal lobe on PET.
Material-specific (verbal or visual) memory impairment corresponds to
primary involvement of the dominant or nondominant hippocampus. EEG
recordings show temporal lobe spikes interictally (see Fig. 426-3), as well as rhythmic 4- to 7-Hz discharges over the appropriate temporal lobe during seizures (see Fig. 426-1).Less
than 40% of patients with newly diagnosed mesial temporal lobe epilepsy
will be controlled with medications, although familial cases are more
easily managed medically. Up to 80% of patients with medically
refractory seizures become seizure free, usually without medications,
after resection of the responsible anterior temporal lobe and
hippocampal structures.Status EpilepticusStatus
epilepticus is a medical emergency in which seizures occur continuously
or repeatedly without intervening resumption of consciousness. Although
the standard diagnostic criteria require a duration of 30 minutes, even
5 minutes of generalized tonic-clonic seizures cause hypoxia, lactic
acidosis, muscle breakdown, and CNS toxicity as a result of excessive
excitatory neurotransmitters, and longer durations cause progressively
more severe long-term morbidity and mortality. Immediate intervention
with parenteral agents to stop the seizures is mandatory. Prompt
attention to defining the cause of the status epilepticus must also be
given. Stabilization of airway and vascular status and initiation of
assessment of the diagnostic possibilities are immediately followed by
the use of intravenous benzodiazepines (e.g., lorazepam, 0.1 mg/kg given
at 2 mg/min).
Diazepam (10 mg intravenously) is an alternative. If seizures continue
for 10 to 15 minutes, intravenous phenytoin at 20 mg/kg (or fosphenytoin
in a similar phenytoin-equivalent dose) should be administered. If
seizures do not respond within an additional 15 minutes, barbiturates
(phenobarbital, 20 mg/kg intravenously) or a continuous drip of
midazolam (0.1 to 2 mg/kg/hr), pentobarbital (0.5 to 3 mg/kg/hr), or
propofol (2 to 4 mg/kg/hr) can be used. In refractory cases, the next
step is general anesthesia for 24 hours. |
-agonist), 10 mg three times daily.
Treatment is otherwise symptomatic. Diabetic amyotrophy and mononeuropathy
simplex usually improve or resolve spontaneously.
2-microglobulin.
