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Epilepsy in adults.

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NEUROLOGICAL PROGRESS
Epilepsy in Adults
Elson L. So, MD, and J. Kiffin Penry, M D
The past decade has seen advances in the management of patients with epilepsy. The development of practical
long-term electroencephalographic techniques, with or without simultaneous video recording, has increased the
accuracy of diagnosis of seizure types. The technique also provides clinicians and investigators with a method for
establishing the clinical efficacy of antiepileptic drugs and determining their therapeutic serum concentrations.
Computerized tomography has enhanced the identification of structural brain lesions. Most of the reported CT
abnormalities consist of diffuse and focal atrophies, mild ventricular dilatations, and porencephalies. CT has
detected tumors in 8 to 10% of the patients regardless of age or type of seizure involved. New concepts of antiepileptic drug therapy have developed from the recognition of pharmacological properties peculiar to each agent. Determination of serum antiepileptic drug levels has to be utilized to reduce the problem of pharmacokinetic variability from one patient to another and in the same patient at different times, so that dosage can be individualized
to achieve maximum therapeutic effects with least toxicity. Review of the literature on pregnancy in epileptic
women shows that a third to half experienced more seizures during gestation. Reduced serum levels of most antiepileptic drugs have recently been observed during gestation. Infants of epileptic women taking antiepileptic
drugs have a two to three times greater risk for congenital anomalies than infants of nonepileptic women. However,
with the exception of oxazolidinediones, evidence to date has not proved the teratogenicity of antiepileptic drugs.
The role of genetic factors and the effect of seizures during pregnancy have not been determined.
Modest progress has been made in epilepsy rehabilitation, but serious problems still remain. The unemployment
rate of persons with epilepsy is twice the national average. Half of those who are successfully employed did not
disclose their disorder at the time of employment. Several prognostic indicators have been reported, but the validity
of many of these indicators is questionable. For example, does shorter life expectancy apply to all subgroups, or does
it vary according to seizure type and cause? The life expectancy, treatment response, and probability of remission
in epileptic persons must be reevaluated after consistent applications of current methods of epilepsy management.
So EL, Penry JK: Epilepsy in adults. Ann Neurol '33-16, 1981
for Seizure Disorders
The first step in proper treatment of epilepsy consists
of correct identification of the type or types of seizure involved. Some antiepileptic drugs serve as the
agents of choice for certain kinds of seizures but may
aggravate other types [36, 79, 123, 1311. Also, the
cause of the seizure disorder is often suggested by
the kind of seizure [34, 63, 99, 1751.
Seizure type identification is based on the clinical
features of the epileptic attack and the electroencephalographic (EEG) abnormality. However, there are
several limitations in these two areas. The ictal event
is often inadequately reported by witnesses 1171 and
is rarely observed by the physician. It is also seldom
recorded during the routine EEG, which lasts only 20
to 30 minutes [14, 1811. Even multiple recordings
may fail to capture any ictal or interictal abnormality.
Furthermore, the patient is restricted to the laboratory environment. Paroxysmal abnormal discharges
have been shown to be influenced by biological cycles [148, 166, 1681 and ongoing activities [48, 57,
1501. A sleep tracing is difficult to obtain in some
patients, even after much coaxing and pharmacological sedation. Drugs could conceivably alter the tracing, and induced sleep frequently does not contain an
adequate duration of different stages of sleep for abnormalities to appear [87]. These handicaps had to be
From the Department of Neurology, Bowman Gray School of
Medicine, Winston-Salem, NC 27 103.
Received June 19, 1980, and in revised form July 28. Accepted for
publication Aug 4, 1980.
Most investigators arbitrarily use 20 years as the
lower age limit for adult epilepsy. This group includes patients who have epilepsy from childhood or
adolescence and those who develop postadolescent
epilepsy. The latter account for as many as 25 to 50%
of the epileptic patients reported in several large
series [62, 1081. Generally, prevalence rates of epilepsy seem to increase with age [61], probably due to
a decline in the crude death rate for epilepsy over the
last 30 years [91]. This review discusses some recent
advances in epilepsy research that have improved the
management or enhanced the understanding of
problems involving adult epileptic patients.
Development of Diagnostic. Aids
Address reprint requests to Dr So.
0364-5 134/81/010003-14$01.25 @ 1980 by the American Neurological Association
3
overcome by capabilities for practical documentation
of the actual seizure episodes and prolonged recording of the EEG. The value of synchronizing these
two variables was recognized 25 years ago, when
Schwabb et a1 [ 1531 used motion pictures to film patients while simultaneously recording their EEGs.
More practical techniques became available with the
advent of miniaturized electronic equipment and the
videotape recorder.
Prolonged E E G Recording
Development of telemetered EEG, by either radio transmission [15] or cable transmission [72], broadens the
use of EEG under a variety of circumstances. In
radiotelemetered EEG, usually only 4 to 8 channels
are available. The subject wears a plastic headband
that carries the transmitter with antenna. The EEG
signals received are recorded by either tape or polygraph. The former system has the advantage of simplified data collection and storage and greater flexibility for data editing. The ongoing transmission can
be displayed and monitored on an oscilloscope or a
video screen with the use of a waveform-to-TV reformatter.
The less frequently used cable-telemetered EEG
consists of a head-mounted EEG preamplifier and
multiplexer unit that is connected by a long cable to a
wall box. The EEG signals are relayed by wiring to
the EEG department. The multiplexer reduces the 16
signal lines to 1 to facilitate transmission through a
single twisted wire. A demultiplexer in the EEG department reconstructs the original EEG signals for
write-out. A “seizure button” can be incorporated
into the system so that patients with auras can push
the button to selectively record only the ictal events.
Wall boxes wired to the EEG department can be set
INSTRUMENTATION
AND TECHNIQUE.
up in different rooms in the ward to avoid patient
relocation whenever a recording is needed. A simpler
system [ 1461 has a small impedance-matching transformer clipped to the collar. The transformer receives the scalp electrodes and is directly connected
to a Mingograph machine by a 6 m cable.
Wearable cassette recorders have recently been
developed [73, 1501 for monitoring ambulatory patients outside the hospital. The results of their initial
applications to monitor absence seizures have been
promising. Table 1 compares the advantages and disadvantages of these major methods of prolonged
EEG recording.
Bowden, Gilliatt, and
Wilson [141 found that, with the use of prolonged
EEG recordings, the number of epileptic patients
showing abnormal discharges was doubled. The accuracy of seizure frequency determination is likewise
improved. When compared to the history given by a
patient’s mother and the results of a trained observer’s monitoring, long-term EEG recording has
been shown to give the most reliable estimates of seizure frequency [ 171. The technique has provided
clinicians and investigators with an objective method
of establishing both clinical efficacy and the therapeutic serum concentrations of antiepileptic drugs
[37, 73, 125, 145-147, 1741.
The effects of environmental factors [48],mental
activity [ 5 7 , 1501, and biological cycles [147, 148,
167, 1681 on the frequency of paroxysmal abnormal
discharges have also been studied. Some investigators [48, 57, 1501 have reported that situations
occupying the patients’ attention have an inhibitory
influence on paroxysmal discharges; on the other
hand, the frequency of discharges increased during
periods of inactivity. The use of telemetered EEG has
CLINICAL APPLICATIONS.
Table I . Comparison of Properties of the Major Techniques for Long-Term EEG Recording
Radio Telemetry
Cable Telemetry
Cassette Recorder
Use restricted to within hospital
Personnel required to monitor recording
Mostly 4 or 8 channels (16 channels has
been described [49])
Malfunctions can be detected by online monitor
Patient’s range of mobility averages
100 to 200 m
Minimal interference with patient’s activities by equipment
Likelihood of interference by commercial radio transmission
Simultaneous use with video recording
Dossible
Use restricted to within hospital
Personnel required to monitor recording
16 channels
Outpatient use possible
No personnel needed to monitor recording
4 o r 8 channels [I491
Malfunctions can be detected by personnel monitoring
Cable length is up to 8 m
Malfunctions will be undetected
Patient’s mobility is unrestricted
No interference
Minimal interference with patient’s activities by equipment
No interference
Simultaneous use with video recording
Dossible
Simultaneous use with video recording
not DossibIe
Patient’s activities hindered by cable
4 Annals of Neurology Vol 9 No 1 January 1981
also revealed that some patients have individual temporal patterns of fluctuation in the frequency of their
interictal discharges and seizure occurrences [ 124,
147, 1661. This knowledge permits manipulation of
the dose and time of antiepileptic drug intake to
achieve maximal suppression of seizure activity during periods of susceptibility [ 1471. Other applications
of long-term EEG include the study of psychiatric
disorders 158, 90, 130, 1781, monitoring of the comatose patient [ 161, and determination of the effect of
some sport activities on cerebral functions [ 140,
1841.
Simultaneous E E G and Video Recording
Video recording has become the most favored method for
documenting seizure episodes and other observable
clinical states. Unlike motion picture photography, it
can be monitored by closed-circuit T V screens and
reviewed immediately after recording. Playback allows repeated viewings of segments of the recording.
The tape is also reusable. These advantages of video
recording are attested to by its extensive applications
as a medium of instruction in institutions and as a
device for entertainment at home.
The number of cameras employed depends on the
number of views needed to give an adequate study;
usually a whole body and a close-up facial view are
necessary. A third camera can be placed over the
EEG machine to record simultaneous electrocerebral activity. A special-effects generator constructs
a composite picture of these multiple views. Telemetered EEG can be simultaneously recorded by
incorporating a waveform-to-TV reformatter. A T V
screen is used for on-line monitoring. The problem
of lighting is minimized by the use of low-light
monochrome cameras.
Long-term EEG and video recording are dealt with
in detailed, yet concise fashion by Porter et a1 [134].
INSTRUMENTATION AND TECHNIQUE.
SIMULTANEOUS APPLICATION.
The value of video
recording of epileptic attacks is enhanced by simultaneous EEG recording. Clinical manifestations of
different seizure types can be critically observed,
quantitated, and correlated with the EEG abnormality. Mith’this method Penry et a1 [ 1261found that the
likelihood of automatisms occurring during absence
seizures increases with the duration of the EEG discharge. Generalized spike-and-wave paroxysms lasting longer than 3 seconds are also more likely to produce observable impairment in behavior [53]. The
ictal automatisms were divided into two kinds:
preservative and d e novo automatisms [122]. Preservative automatisms were continuations of preictal
activities or behavior, usually at a slower rate and
an altered rhythm. D e novo automatisms consisted of
unconscious activities or behavior initiated either simultaneously with the ictus o r after its commencement. Lip smacking and chewing were commonly
noted with both complex partial seizures and absence
seizures [ 1261.
Complex partial seizures have also been analyzed
with simultaneous EEG and video recording. Escueta
et a1 [42] recognized three clinical phases in most of
the psychomotor seizure episodes they studied, each
having a distinct corresponding EEG abnormality.
During phase one the patient was motionless and unresponsive, and stared for an average of 10 seconds.
Phase two ensued with automatisms lasting 10 to
30 seconds. During phase three, which lasted
30 seconds to 12 minutes, the patient was still unresponsive and amnesic, and the automatisms were
semipurposeful. Lateralizing EEG discharges were
most often recorded in phase one. Automatisms occurred only with diffuse slow waves or low-voltage
fast rhythms. Videotape analyses also revealed features that distinguished the prolonged fugue state
of psychomotor status from that produced by petit
mal status [9]. The identification of these clinical
phenomena helps the clinician in formulating a more
accurate diagnosis.
Similarly, Kellaway et a1 [83] have characterized
the motor, autonomic, and behavioral phenomena associated with infantile spasms with prolonged polygraphic and video recordings [45, 831. The motor
activity is graphically monitored with surface electromyograms and accelerometers that detect movements of body parts. The technique enabled the investigators [69] to conduct a controlled study of
prednisone therapy in infantile spasms. Previous
studies, except for one, were uncontrolled and
wanting in objective criteria for evaluating drug effects [%I. The efficacy of the antiepileptic drugs
phensuximide and methsuximide was similarly assessed by comparing results of monitoring before and
after treatment [1331.
Simultaneous video recordings and stereoencephalography have been used to identify the primary seizure focus in complex partial seizures 1311.
The technique has also aided the selection of patients for anterior temporal lobectomy. According to
Delgado-Escueta [30], patients with localized 8 to 30
Hz rhythms in the medial temporal region preceding
their clinical attacks are good surgical candidates.
Computerized CraniaI Tomograpby
The symptomatic diagnosis of “epilepsy” o r “seizures” should compel the physician to look for its
etiological basis. This principle is particularly true
with seizures occurring during the first postnatal year
and in adulthood, the percentage of epilepsy with
identified causes being lowest for the age group 1 to
Neurological Progress: So and Penry: Epilepsy in Adults
5
Table 2.Incidence of Abnormalities Detected on CT Scan by Seizure Type
Series
Bogdanoff et al,
1975’ [131
Gastaut and
Gastaut, 1976’
(461
Caille et al, 1976
[2 11
Bachman et al,
1976‘ 161
Janz, 1977b 1771
Gastaut and
Gastaut, 1977b,d
L471
Scollo-Lavizzari et
al, 1977 11541
Zimmerman et al,
1977’ [1821
Carrera et al, 1977
[241
Ghazy et al, 1978
1501
Reisner et al, 1978
11411
Ratzka et al, 1978
[ 1381
McGahan et al,
1979 [I061
Lagenstein et al,
1979 [9Sl
Ladurner et al, 1979
1941
Generdized
TonicChic
Seizures
Partial Seizures
Partial
Elmentary
Partial
Complex
Secondary
Generalization
Total
Absence
Seizures
All ages
...
13 (?)
18 (?)
19 ( 3
50(35%)
...
All ages
25 (4%)
69 (66%)
84 (60%)
45 (64%)
I98 (63%)
20 (10%)
A11 ages
...
? (?)
? (?)
? (?)
66(46%)
3mo20 yr
20 yr and
above
All ages
23(32%)
14 (43%) 42 (27%)
...
97 (40%)
39 (82%) 66 (39%)
28 (3.5%)
? (?)
11-79 yr
59 (34%)
Patients’
Age
Infantile
Spasms
(West’s)
LennoxGastaut
Syndrome
Othersa
Total
...
...
50 (35%)
6 (100%)
42 (60%)
2 09
500 (55%)
...
...
...
...
66 (46%)
56 (31%)
1 (0%)
...
...
18
98 (30%)
44 (52%)
14905%)
...
...
...
4
250 (49%)
? (?)
? (?j
490 (63%)
2 1 (9%)
30 (77%)
94 (52%)
169
832 (50%)
16 (62%)
16 (19%)
...
32(40%)
...
...
...
0-40 vr
...
...
...
...
38 (47%)
...
38 (47%)
21-75 yr
...
22 (0%)
...
...
...
...
22 (0%)
8
99 (34%)
10-79 yr
40 (35%)
12 (58%)
5 (40%)
...
17 (52%)
3 (33%)
...
...
29
89 (42%)
3-15 yr
63 (83%)
65 (71%) 26 (31%)
...
91 (60%)
41 (49%)
...
...
33
228 (63%)
All ages
211 (48%)
98 (71%) 91 (61%)
5 2 (82%)
241(70%)
_..
...
...
...
452 (60%)
All ages
7 7 (38%)
12 (58%)
28 (32%)
17 (71%)
57(49%)
...
...
...
16
150 (40%)
Children
.
...
...
...
...
49 (41%)
19 (95%)
34 (91%)
43
145 (59%)
All ages
173 (29%)
...
35(62%)
..
...
...
...
208 (34%)
~~
Values are number of patients studied for each category and, in parentheses, percentage of patients with abnormalities.
*Consists o f mixed seizures or seizures not classifiable into categories shown in table.
bSeries with consecutive patients.
eChronic seizure patients only.
dContinuation and expansion of previous study r461.
... = none in series; ?
= not indicated in report.
19 years [62].Most identified causes of epilepsy consist of tumors, trauma, and vascular disorders of the
central nervous system 162, 801. Furthermore, an
epileptic seizure is one of the two most common
symptoms of brain tumors, being the initial symptom
in 40% of patients with brain tumors who experience
seizures [991.
There have been several studies on the yield of CT
in epileptic patients. Those with sufficient data for
comparison are presented in Table 2. The wide range
of total percentages of CT abnormalities (30 to 60%)
may be accounted for by differences in age group and
types of seizures represented. For example, the high
total rate of 5596 in the series of Gastaut and Gastaut
[46]could be due partly to their inclusion of 42 patients with Lennox-Gastaut syndrome, a condition
uniformly found to involve a high incidence of CT
abnormalities. The kind of CT equipment employed
and the use of intravenous contrast agents are seldom
mentioned in the studies. Use of the 160 x 160 matrix machine [ 1071 and dye-enhanced scans [ 15 l l are
6 Annals of Neurology Vol 9 No 1 January 1981
known to improve the yield of the procedure.
Referral patterns for CT and the interpretation of results may differ from one institution to another. Only
five series [13, 46, 47, 7 7 , 1821 studied consecutive
seizure patients, and another five [6, 22, 24, 106,
1831 reported using contrast agents in all or most of
the patients. With the exception of Bachman et a1 [ 6 ] ,
most investigators have reported that partial seizures
are more frequently associated with abnormal CT
findings than generalized tonic-clonic seizures. Three
times as many of the patients reported by Bachman
and co-workers had complex partial seizures as had
partial elementary seizures. The former seizure type
generally has a lower rate of associated abnormal C T
findings than the latter.
Most of the reported C T abnormalities consisted
of diffuse and focal atrophies, mild ventricular dilatations, and porencephalies. Tumors were detected in
8 to 10% of the patients regardless of age or type of
seizure involved, with t h e exception of the series reported by McGahan et al [lo61 and Cala and co-
workers 1221, which reported only 4% and 14%, respectively. In chronic epileptic patients, only 2 to 3%
had CT abnormalities of potential therapeutic importance [6, 741. Nevertheless, the demonstration of
a normal scan or a static process may still aid the
clinician in determining the cause and prognosis of
the disease. Factors that raised the likelihood of discovering a tumor include: (1) age above 20 years [13,
22, 26, 46, 94, 106, 114, 1831; (2) the presence of
abnormal neurological signs [13, 94, 1061; and (3)
partial seizures or generalized seizures with focal
components [52,77, 106, 114, 1541. CT also permits
early radiological diagnosis of tuberous sclerosis and
Sturge-Weber disease, even before the appearance of
characteristic calcifications on plain skull roentgenograms [821.
False-negative results with CT have often been encountered in the posterior fossa and parasellar regions [2, 29, 56, 67, 1181. Lesions in those areas,
however, had the lowest incidence of associated
epilepsy-2.5% and 5.796, respectively-compared
with 50% for supratentorial lesions [991.
Current Concepts of Antiepileptic Drug Therapy
Pharmacotherapy for epilepsy has made great gains
during the past 25 years. Increased knowledge about
old antiepileptic drugs (AEDs) has redefined their
usefulness and limitations. At the same time, new
drugs were introduced in a continuing effort to develop more effective medical therapy (Table 3). Indications for each antiepileptic agent based on seizure
type are being established [79, 131, 132, 1591. The
starting dose and the rate at which dosage is increased
depend on the likelihood of side effects developing.
Primidone, carbamazepine, clonazepam, and valproic
acid need to be raised gradually to maintenance level
to build tolerance for dose-related side effects. In
contrast, phenytoin and ethosuximide can be initiated at their average maintenance doses. A loading
dose can even be given for phenytoin. Further dose
increases and determination of serum levels, if necessary, should not be made until the expected steadystate is reached.
Half-lives of the primary antiepileptic drugs have
been determined for both adults and children (Table
3). It is necessary to know the half-life of each drug to
calculate the expected steady-state, to determine the
dose interval, and to estimate the duration of the
drug’s persistence in serum after discontinuation of
intake. The expected steady-state is 5 to 7 times the
half-life during constant dosing. The dose interval
should be kept to less than one half-life to avoid wide
fluctuations in serum concentrations. Hence, drugs
with half-lives longer than 24 hours may be given
once daily.
Determination of serum levels of antiepileptic
agents, mainly a research activity 15 years ago, has
become widely available to the clinician. Its use has
disclosed pharmacokinetic properties peculiar to
each drug. Knowledge of serum levels reduces the
problem of variability of drug absorption, distribution, and excretion from one patient to another and
at different times in the same patient. Previously, the
only guides to dose regulation or drug combinations
were the degree of seizure control or precipitation of
drug toxicity. Although this empirical method has
been effective in the management of some epileptic
patients, the use of serum level determinations increases the number of patients who become controlled and improves the degree of control in others
[18, 92, 132, 1601. It also identifies the responsible
agent in intoxicated patients on multiple drug therapy [191. Cases of poor compliance can be detected
[ 5 1, 1041. The effects of pathological conditions,
physiological states, and drug interactions can be
anticipated and confirmed with serum level determinations.
Multiple-drug therapy or crossing over to another
drug may be required in the following situations: (1)
when immediate seizure control is necessary; (2)
when seizure control is unsatisfactory at maximum
tolerated serum drug levels; o r (3) when toxicity restricts further dose increase.
These principles are presented as an introduction
to current concepts of antiepileptic drug therapy.
The interested reader is referred to recent articles
that discuss the subject in depth [70, 79, 123, 1591.
Epilepsy and Pregnancy
Approximately 0.3 to 0.7% of all pregnant women
have epilepsy [7, 120, 1631, and in these patients
the desirability of complete seizure control during
pregnancy must be balanced against the possible
teratogenicity of antiepileptic drugs. The main issues
posed by epilepsy in pregnancy are perhaps best examined in four separate parts: the effect of pregnancy
on the course of epilepsy, the effect of epilepsy on
the course and outcome of pregnancy, the effect of
antiepileptic medications on fetal development, and
the effect of these agents on the health of the neonate.
Effect of Pregnancy on the Course of Epilepsy
Most reports note an unpredictable increase in seizure frequency during gestation in one-third to half
of pregnant epileptic women [20, 851. Knight and
Rhind [85] observed in 59 patients that those with
frequent seizures before pregnancy were likely to
have more when pregnant. Earlier reports [20, 1711
speculated on the possible role of hematological
changes, fluid and electrolyte imbalances, acid-base
disorders, and hormonal influences. Lately, the in-
Neurological Progress: So and Penry: Epilepsy in Adults
7
Table 3. Primary Antiepileptic Drugs Currently in Most Common Use
Average Dailv
Maintenance Dose
(mdkg)
Y
Chemical
Class
Year
Introduced
Phenobarbital
(Luminal)
Barbiturate
1912
Phenytoin
(Dilantin)
Hydantoin
1938
Primidone
(My sol ine)
Barbiturate
1954
Ethosuximide
(Zarontin)
Succinimide
Carbamazepine
(Tegretol)
Generic
(Trade)
Name
Indications
Adults
Children
Generalized tonic-clonic seizures; all forms of partial seizures
Generalized tonic-clonic seizures; all forms of partial seizures
2-3
3-5h
3-5
4-7
10-25
10-25
1960
Generalized tonic-clonic seizures; all forms of partial seizures
Absence seizures
20-40
20-30
Dibenzoazepine
1974
All forms of partial seizures;
10-20
20-30
Clonazepam
(Clonopin)
Be nzod iazepine
1975
0.05-0.2
0.01-0.2
Valproic acid
(Depakene)
Branched-chain
carboxylic
acid
1978
30-60
30-60
~~~~
generalized tonic-clonic seizures
Myoclonic seizures; infantile
spasm; atonic seizures; absence
and akinetic seizures
Absence seizures; photosensitive
seizures; atonic seizures;
akinetic seizures; myoclonic
seizures; generalized tonicclonic seizures
~
"Total blood levels, free and protein bound.
bInfants, 8 rnglkg.
Source: Adapted from Penry and Newmark [123] and Pippenger et a1 [1271.
creased seizure frequency has been correlated with a
fall in serum phenytoin levels during pregnancy [8,
116, 1371. A reduction in serum level during gestation, and consequent increase in dose requirement, has also been noted with phenobarbital, carbamazepine, ethosuximide, and primidone [28, 40,
96, 97, 1191. After delivery, serum levels eventually
returned to the pregravid levels.
Physiological changes that accompany pregnancy
have been implicated for affecting absorption [1371,
biotransformation [28, 401, distribution [96], and
excretion [ 1161 of antiepileptic drugs. Several conclusions from these few studies were inferential, and
most observations were on phenytoin and phenobarbital. The degree of plasma protein binding of
phenytoin and carbamazepine during pregnancy is
apparently not an important factor since it did not
differ significantly from that in male and female
controls [28, 681. Other investigators [97, 1371
have found that the excretion of phenytoin and
its metabolite p-hydroxyphenylphenylhydantoin @H P P H ) is unchanged during pregnancy. Although
folic acid intake has been reported to lower the
8 Annals of Neurology
Vol 9 N o 1 January 1981
serum phenytoin level [121,169], none of the 23 patients in one study [28] were given folate supplements. Moreover, the fall in serum phenytoin
level may precede folate therapy, and the postpartum
rebound of serum phenytoin level may occur despite
continuation of folate therapy [40]. Of interest is
the observation by Ramsay of altered intestinal absorption as a cause of reduced serum drug levels
during pregnancy in 11 patients [136]. Urinary p H P P H content and half-lives of phenytoin from
intravenous administration were constant in these
patients, but a large amount of their oral dose was
recovered from stool.
The grave condition of status epilepticus during
pregnancy is, fortunately, rare [20, 55, 84, 85, 1051.
No single antiepileptic agent has been shown to be
exceptionally effective in controlling status epilepticus during pregnancy.
Effect of Epilepsy on the Course
and Outcome of Pregnancy
Information regarding the effect of epilepsy on
pregnancy is mostly derived from retrospective com-
Serum Half-Life
(hr)
Adults Children
Blood Levelsa
Effective
Toxic
96
+ 12
5 5 1 15
>40 pglml
24
+ 12
20 t 2
>20 pglml
12 + 6
...
>12 pglml
Most Common Side Effects
Sedation, paradoxical excitement, rash,
irritability and hyperactivity, especially in children
Skin eruptions, hypertrichosis, gingival
hyperplasia, coarsening of facial features, decreased blood folate level,
hypocalcemia, osteomalacia, lymphadenopathy, hepatitis, systemic
lupus erythematosus, fever
Same as phenobarbital
Drowsiness, ataxia, nystagmus, slurred speech
Nausea, vomiting, anorexia,
lethargy, headache, hiccups
Vertigo, drowsiness, nystagmus, diplopia, unsteadiness
Somnolence, confusion,
coma, hypotension
55+5
30?6
>I00 pglml
Nausea, skin rash, blood dyscrasias,
drowsiness, hiccups
17k7
1415
>8 pglml
Nausea, vomiting, anorexia, blood dyscrasias
32 1 13 2 3 1 10
>80 nglml
Sedation, drowsiness, ataxia, behavioral
problems, anorexia
1216
> 100 pglmi Nausea, vomiting, drowsiness, weight
1226
Most Common Toxic Signs
and Symptoms
Nystagmus, ataxia, slurred
speech, drowsiness, dlplopia, blurred vision
Same as phenobarbital
Ataxia, sedation
gain, transient alopecia, hypersalivation, diarrhea, thrombocytopenia, hepatic toxicity
parisons with unmatched control groups. The relative
contributions of the epileptic condition, of seizure
attacks, and of drug treatment have not been established .
Bjerkedal and Bahna [ 121found that the incidence
of vaginal hemorrhage and toxemia of pregnancy
among epileptic pregnant women was roughly twice
that of an unmatched control group. Discrepant results exist for the risk of intrapartum complications,
forceps delivery, cesarian section, and neonatal mortality [ l 2 , 43, 64, 78, 1641. O n the other hand, a
significantly higher rate of stillbirth has been noted
by all investigators [43, 112, 120, 1571 with the exception of Speidel and Meadow [164]. No difference was observed for the rate of spontaneous abortion [1641, and most studies [64, 112, 120, 1641 did
not find an increased risk of low-birth-weight infants.
Fedrick [431 has provided the only study that extensively matched its control group exactly for maternal age, parity, social class, area of residence, and
year and place of delivery-factors
which by themselves can influence the course and outcome of
pregnancy. She found that the risks for neonatal
death and premature delivery were not increased
in pregnancies of epileptic women. Only Fedrick’s
live-birth pregnancies have matched cohort groups.
Hence, the higher risk of stillbirths found by this
study was based on comparison with pregnancies in
the general population. Antepartum and intrapartum
complications were not evaluated.
Eflect of Antiepileptic Drugs on Fetal Development
Many studies [5, 12, 43, 59, 76, 88, 103, 112, 157,
163,1641 have shown that infants of epileptic women
taking antiepileptic medication have a 2 to 3 times
greater risk for congenital malformations than infants
of nonepileptic women. Several types of malformations have been described, but the most commonly
observed are cleft lip, cleft palate, and congenital
heart disease [5, 66, 761. The cause of the increased
risk is still undetermined. Some investigators [ 107,
1651 have reported a more frequent occurrence of
convulsive fits during the pregnancies of mothers
with malformed children, while others [ S , 43, 157,
1641 noted no difference. Studies comparing the incidence of malformations between infants of treated
Neurological Progress: So and Penry: Epilepsy in Adults
9
and untreated epileptic mothers have yielded
conflicting results [3, 76, 103, 110, 112, 157, 163,
1651. The comparability between the two samples of
epileptic mothers was not disclosed in most reports.
Moreover, most of these studies are based on small
numbers of patients. It has been estimated that close
to 2,000 births to epileptic women would have to be
investigated to obtain more conclusive results [ 3,
1101. There is also a need to determine the role of
genetics. In one series [157], the group of epileptic
parents themselves had more malformations than
nonepileptic parents. Although lacking in statistical
proof, there are reports of frequent occurrenceJ df
congenital anomalies among relatives of epileptic
persons [165, 1771. Dronamraju [38] noted that 15
to 20% of his patients with cleft lip, cleft palate, or
both have a first- or second-degree relative with epilepsy.
Good evidence incriminates the teratogenicity of
the oxazolidinediones (trimethadione and paramethadione). Twenty-four percent of the pregnancies
during which oxazolidinediones were taken terminated in spontaneous abortions, while 83% of the
remaining pregnancies resulted in the birth of a child
with at least one malformation [44]. Although other
antiepileptic agents were also taken during most of
these pregnancies, such a high rate of fetal loss and
serious malformation has been observed only with
the oxazolidinediones. Further, 7 of 8 fetuses exposed to oxazolidinediones alone were born with
anomalies [44].
In recent years, a miscellany of congenital defects
appearing in infants exposed to antiepileptic drugs
have been designated “fetal hydantoin syndrome”
[GO] and “fetal phenobarbital syndrome” [I 1, 1561.
The terminology directly incriminates these agents in
the absence of proof of their teratogenicity, as our
review has pointed out. There is considerable overlap
of the features of these syndromes, and some of the
infants reported were exposed to multiple drugs.
Effect of Antiepileptic Drugs on the Health
of the Neonate
Intrauterine exposure to phenytoin, barbiturates, and
trimethadione has been associated with both clinical
and subclinical coagulopathies, usually on the first
day of life [98, 162, 1731. The clotting abnormalities
are similar to those produced by vitamin K deficiency
and are reversed by vitamin K, administration [3 5 ,
1151. The pathogenetic mechanism is unknown.
Neonates exposed to barbiturates during late
pregnancy may develop restlessness, tremors, hyperreflexia, and vasomotor instability [331. These
symptoms begin 6 to 7 days after birth, in contrast to
the early onset of heroin-withdrawal syndrome in
neonates.
10 Annals of Neurology Vol 9 No 1 January 1981
If more than 30 mg of diazepam has been given to
parturients, respiratory depression, hypothermia,
and hypotonia may develop in most of their neonates
[271. Drowsiness may rarely occur in infants breast
fed by mothers taking more than 90 mg of phenobarbital per day [172]. The milk and serum concentrations of ethosuximide are roughly equal because of
minimal plasma protein binding [861, while the milk/
serum ratio is less than 1 for phenytoin [ l 111, valproic acid [ l l , and carbamazepine [1191. The estimated amount ingested from breast feeding is small
and appears to be insignificant.
M a nagement of the Pregnant Epileptic Pa tien t
Recent recommendations on the management of
pregnant epileptic patients have been formulated in
light of the dataalready discussed [76, 113, 155, 161,
1701.
1. Seizures should be as well controlled as possible
and dosages of antiepileptic medications stabilized
before pregnancy. Serum drug levels should be
monitored monthly and dosage adjusted accordingly
from the first trimester to 6 months postpartum, or
until pregravid levels have returned.
2. Epileptic women with the intention or potential
for childbearing should be counseled that infants of
epileptic women receiving antiepileptic agents have a
2 to 3 times greater risk (approximately 5 to 10%
rate of anomalies) for congenital malformations compared to infants of nonepileptic women. The cause of
the increased risk is still undetermined. Many of
these malformations are surgically correctable. Pregnancy need not be discouraged, and abortions need
not be routinely advised if pregnancy has occurred.
With the exception of oxazolidinediones, evidence to
date has not defined the teratogenicity of antiepileptic drugs. Discontinuation of these agents during
pregnancy is unwarranted in view of the possible
serious effects of repeated seizures on maternal and
fetal health. Nevertheless, only the minimum of
medications that maintains seizure control should be
used during pregnancy.
3. Women taking oxazolidinediones should receive
birth control measures. Alternative drugs should be
initiated before beginning a pregnancy, or during the
first trimester if the pregnancy is to progress. Such
patients should be given the option of abortion if
pregnancy occurs while they are taking oxazolidined iones.
4. Compared to unmatched control groups, epileptic persons receiving antiepileptic medications
have a higher risk for stillbirths. It may be reasonable
to advise closer prenatal checkups with fetal monitoring.
5. Neonates exposed in utero to antiepileptic
drugs should be examined for evidence of bleeding.
Coagulation studies should be performed immediately after birth and every 4 hours for 24 to 48 hours.
A prophylactic dose of 1 mg of phytonadione should
be given intramuscularly immediately after birth.
6. Mothers receiving antiepileptic agents need not
be discouraged from nursing their infants. Those receiving barbiturates should be informed of the small
possibility that their infants will develop drowsiness.
Progress in Epilepsy Rehabilitation
One of the most serious problems confronting many
adults with epilepsy is the denial of employment opportunities for which they are qualified. Assessment
of the magnitude of this problem by the Commission
for the Control of Epilepsy and Its Consequences revealed that the unemployment rate among persons
with epilepsy is twice the national average [128].
Underemployment is even more prevalent. Half of
those who are successfully employed did not disclose
their disorder at the time of employment.
Initiatives have been taken to improve the occupational status of adult epileptics. The Developmental
Disabilities Services and Facilities Construction Act
[135], passed in 1970, for the first time specifically
declared epilepsy a priority area for habilitation and
rehabilitation. In 1975, the Commission for the
Control of Epilepsy and Its Consequences was
created by law (PL-94-63) to investigate all aspects of
epilepsy and recommend appropriate actions directed to the problems identified. Job development
and job placement services for persons with epilepsy
were emphasized in its proposals. However, vocational training and rehabilitation programs must be
complemented with an effort to rectify the social
stigmata that epileptic persons suffer. In a survey of
state vocational rehabilitation agencies, 80% of the
directors indicated that a negative attitude toward
epileptic clients is a major barrier to rehabilitation
[75], notwithstanding a trend of improvement in
public attitudes toward epilepsy for the past 30 years
[251. Factors intrinsic to the epileptic person, such as
motivation, intelligence, social skills, and psychological status, also determine employment success or
failure [32, 54, 1441.
A parallel advancement in other aspects of the
epileptic person’s life is also occurring. Although decisions concerning participation in athletics should be
individualized, the epileptic person need no longer
be strictly barred from any sport, including contact
and collision sports, if his seizures are well controlled
[102]. Group life insurance plans are now available to
epileptic persons through the Epilepsy Foundation of
America (EFA), while group health insurance plans
are available through EFA and group employee plans
[ 1291. Individual life and health insurance are avail-
able from commercial firms, at a considerably higher
premium, to a limited number of persons with epilepsy depending on the type of seizure and related
medical history [4 11. Policies regarding driving
privileges for the epileptic person vary from state to
state [ 1001. Some regulations arbitrarily restrict the
licensing of epileptic persons. There is a need for
more data on the driving performance of epileptic
persons and the relative accident risks accompanying
different types of seizures. Licensing guidelines
based on these data can then be formulated and standardized.
Medical Prognosis of Adult-Onset Epilepsy
The prognosis of adult-onset seizure disorders depends in part upon the underlying cause or causes of
the seizures. Brain tumors have been found in 10 to
16% [139, 158, 1761 of patients presenting with
their first seizure at or after the age of 20 years. A
later series [89], which extended the lower age limit
to 1 7 years, discovered brain tumors in 7.7% of 216
patients. An even wider range (2% [152] to 36%
[lSO]) of tumor occurrence rates exists for seizure
disorders developing after age 35, with a mean of 10
to 15% reported by most authors [ l o , 65, 80, 1791.
These series are not epidemiological surveys and
hence suffer biases in sample selection. There is a
disparity among the studies in the age distributions of
patients. Some investigators have excluded patients
with acute metabolic illnesses causing seizures [ 101,
1521, posttraumatic epilepsies [ 1391, o r brain tumors
[7 1, 1011, and those with neurological abnormalities
prior to seizure onset [lo, 1801. Approximately
one-third to half of seizures beginning after age 50
years have been attributed to cerebral vascular diseases or hypertension. However, the clinical criteria
for this diagnosis may have varied from one center to
another. Interestingly, no cause could be established
in as many as half of the cases of adult-onset seizures
[lo, 23, 39, 80, 89, 152, 158, 1761.
While the life expectancy of epileptic persons in
general is shorter than that of the overall population
[ 1421, it is not known whether this applies to all subgroups according to seizure type and age. Claims
have been made in uncontrolled studies [117, 1791
that late-onset epilepsy does not influence life expectancy. However, when unselected epileptic persons in Rochester, Minnesota, were compared with
matched controls, those with epilepsy diagnosed
from age 20 to 59 years had poorer survival [62].
Although the lag between onset and diagnosis of
epilepsy is more than two years in 30% of the cases,
this observation is probably still representative of
adult-onset epilepsy, considering the large number of
patients surveyed and the wide range of ages affected. It is not known whether deaths in the age
Neurological Progress: So and Penry: Epilepsy in Adults
11
group 20 to 59 occurred mainly among persons with
symptomatic or those with idiopathic epilepsy. The
same study and its continuation [4] observed that remission rates with and without antiepileptic medications generally declined as age at diagnosis increased
beyond the first decade. This lends support to an earlier report [81] that showed higher recurrence rates
following antiepileptic drug withdrawal for epilepsy
beginning after age 30. Claims to the contrary
abound [ 1421, but they originate mostly from
smaller, nonlongitudinal studies with short follow-up
intervals. Distinction is seldom made between patients who have single o r a few seizures secondary to
acute reversible disorders and true epileptic patients
who are at risk for recurrent seizures.
Some unfavorable prognostic indicators of response to treatment that Kuhl et al [89]identified in
their patients with adult-onset epilepsy are complex
partial seizure type, long duration of illness, and high
frequency of seizures prior to treatment. These factors have likewise been recognized in the general
epileptic population, in addition to other poor prognostic indicators such as the presence of a history of
grand ma1 status epilepticus, multiple seizure types,
or a persistently abnormal EEG [ 1421.
The current principles of diagnosis and management of epilepsy must be widely utilized for 5 to 10
years before we can appraise their benefits in terms
of patients who have been completely controlled
without chronic toxicity and completely rehabilitated
with achievement of education, employment, and recreation. Before the advent of blood level monitoring,
the achievement of complete seizure control for a
minimum of 2 years (2-year terminal remission rates)
for different antiepileptic drugs had been reported as
fairly constant for six decades [143]. The essential
corollary to the availability of any new antiepileptic
medication, however, is its proper application after
correct identification of the seizure type or types involved. Mere prescription of antiepileptic drugs will
not result in adequate treatment. Compliance has to
be constantly ascertained and adequacy of dose repeatedly verified by serum level determination as
necessary.
We thank Ms Linda Morton for preparing the manuscript.
~~~
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