J Epilepsy 1988;1:173-195

© 1988 Demos Publications

Myoclonic, Tonic, and Atonic Seizures in Children:

Clinical and Electroencephalographic Features

Gregory L. Holmes

Tonic, atonic, and myoclonic seizures are among the most difficult seizures to
classify, diagnose, and treat in children. In this review, syndromes associated
with childhood tonic, atonic, and myoclonic seizures are reviewed with particular
attention to the clinical manifestations, EEG findings, and management. Key
Words: Epilepsy--Tonic seizures--Atonic seizures--Myoclonus.

The t a x o n o m y of myoclonic, tonic, and atonic
seizures is one of the most controversial and con-
fusing problems in pediatric epileptology. Myoclo-
nus, in particular, represents a particularly difficult
problem in classification. Clinicians have struggled
with the concept of myoclonus in an effort to define it
properly, to differentiate it from other m o v e m e n t dis-
orders, and to elucidate its pathophysiology (1-7).
No c o m m o n etiological, anatomical, or physiological
features bind all types of myoclonus. Myoclonus can
arise from m a n y areas of the central nervous system,
and the condition has been reported in association
with lesions of the cortex, cerebellum, brainstem, and
spinal cord. Likewise, multiple etiological agents can
lead to myoclonus. As can be seen in Table 1, the etio-
logies of myoclonus are quite diverse and vary con-
siderably in significance. Myoclonus may be a totally
normal p h e n o m e n o n , such as hypnic jerks or sleep
starts. Conversely, myoclonus may be associated
with virtually any severe insult to the brain, w h e t h e r
toxic, metabolic, infectious, traumatic, or degenera-
tive. Likewise, the pathophysiology of myoclonus
varies; some types of myoclonus are nonepileptic
p h e n o m e n a and are classified as movement disorders
From the Department of Neurology, Harvard Medical
School and The Children's Hospital, Boston, MA, U.S.A.
Address correspondence and reprint requests to Dr. G.
L. Holmes at Clinical Neurophysiology Laboratory, The
Children's Hospital, 300 Longwood Avenue, Boston, MA
02115, U.S.A.
similar to chorea, tics, athetosis, or tremors, whereas
other types of myoclonus are epileptic p h e n o m e n a
(8). Without EEG monitoring it may be very difficult
to differentiate epileptic from nonepileptic myoclonus.
In this review, only epileptic myoclonus is discussed.
In the International Classification of Seizures,
myoclonic seizures are classified as a generalized sei-
zure disorder (9). Myoclonic seizures may be of the
primary seizure type or a c o m p o n e n t of an epileptic
syndrome (Table 2). For example, myoclonic seizures
are the primary seizures in cryptogenic myoclonic
epilepsy of early childhood and infantile spasms,
whereas in the Lennox-Gastaut s y n d r o m e (LGS)
myoclonic seizures are just one of many seizure
types.
Unlike myoclonus, tonic and atonic seizures are
somewhat easier to diagnose and differentiate from
nonepileptic events. Furthermore, both tonic and
atonic seizures rarely occur as the isolated sole
seizure types and are usually seen in association with
other types of seizures.
Clinical Features of Myoclonic, Tonic,
and Atonic Seizures
Some authors combine myoclonic, tonic, and atonic
seizures together u n d e r the rubric " m i n o r motor sei-
zures" in order to distinguish seizures with less
motor involvement from generalized tonic-clonic
seizures. However, even though the seizures some-
times are difficult to differentiate from one another,

j EPILEPSY, VOL. 1, NO. 4, 1988 173

G. L HOLMES
Table 1. Classification of myoclonus they are classified as distinct seizure types in the
Nonepileptic myoclonus International Classification of Epileptic Seizure (9).
Physiological myoclonus
Sleep starts
Benign awake myoclonus
Pathophysiological myoclonus Myoclonic Seizures
Hyperexplexia (startle disease)
Shuddering attacks In epileptic myoclonus, the seizures are character-
Periodic movements of sleep (sleep myoclonus) ized by sudden, brief (<350 ms), shock-like contrac-
Restless leg syndrome tions that may be generalized or confined to the face
Benign neonatal sleep myoclonus and trunk or to one or more extremities, or even to
Benign myoclonus of early infancy individual muscles or groups of muscles (7). Myoclo-
Benign familial polymyoclonus nic seizures result in short bursts of synchronized
Segmental myoclonus electromyographic (EMG) activity, which often in-
Brain stem
volves simultaneous activation of agonist and antago-
Opsoclonus
Palatal myoclonus nist muscles.
Spinal cord Massive, generalized myoclonic jerks are usually
easily diagnosed. However, subtle myoclonic seizures
Epileptic myoclonus may resemble tics, chorea, or tremors. Differentiating
Infections
myoclonus from tics may be difficult. In children, tics
Subacute sclerosing panencephalitis (SSPE)
Jakob-Creutzfeldt disease involve primarily the head, neck, and shoulders, and
Encephalitis consist of complex movements such as facial grim-
Congenital brain anomalies acing, eye blinking or rolling, head nodding or turn-
Toxins ing, and shrugging of the shoulders. Tics can usually
Systemic diseases be suppressed, at least temporarily, by an effort of
Uremia will, whereas myoclonus cannot. In chorea, the move-
Hepatic insufficiency ments occur randomly, usually in multiple muscle
Others groups, whereas myoclonus is usually characterized
Postanoxic by repetitive, stereotyped movements affecting the
Component of familial progressive neurological disease same muscle groups. Myoclonus does not have the
Progressive myoclonic epilepsy with Lafora's bodies
characteristic continuous flow of movements that is
Progressive myoclonic epilepsy without Lafora's
bodies so distinctive in chorea. Tremors can usually be
Dyssnergia cerebellaris myoclonia (Ramsay-Hunt) differentiated from myoclonus by the smooth to-and-
Metabolic disorders fro movements compared with myoclonus, which is
Ceroid lipofuscinosis more abrupt and has distinct intervals between each
Juvenile form of Gaucher's disease movement.
Sialidosis (cherry red spot-myoclonus syndrome)
Gangliosidoses including GM2, GM1
Mitochondrial syndromes
Myoclonus and ragged red fibers (MERRF) Tonic Seizures
Mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke-like episodes (MELAS) These seizures are characterized by periods of
tonic contraction of muscle groups accompanied by
Primary epileptic myoclonus altered consciousness. While tonic seizures may be
Generalized epileptic myoclonus of early childhood
brief, lasting only seconds, they are invariably longer
Symptomatic myoclonic epilepsy
Cryptogenic myoclonic epilepsy than myoclonic seizures. At times, however, it maybe
Juvenile myoclonic epilepsy of Janz difficult to distinguish myoclonic seizures from brief
Epilepsia partialis continua tonic seizures, since absolute criteria regarding maxi-
Focal cortical myoclonus mum duration of a myoclonic seizure have yet to be
As component of other seizure types established. Like myoclonic seizures, EMG activity is
Absence with myoclonic component dramatically increased in tonic seizures.
Eyelid myoclonic seizures with absences Gastaut and colleagues (10) divided tonic seizures
Component of generalized tonic-clonic seizures into four types: axial, axorhizomelic, global, and
Centrencephalic myoclonic-astatic petit real asymmetrical. Axial tonic seizures begin with a tonic
Lennox-Gastaut syndrome contraction of the neck muscles, leading to fixation of

174 ] EPILEPSY, VOL. 1, NO. 4, 1988

 MYOCLONIC, TONIC, AND ATONIC SEIZURES IN CHILDREN

the head in an erect position, widely o p e n e d eyes,

and jaw clenching or m o u t h opening. Contraction of
the respiratory and abdominal muscles follows, and
tO this may lead to a high-pitched cry and brief periods
e of apnea. Tonic axorhizomelic seizures begin with a
o o o oO 0 sequence similar to the axial type, but then the tonic
contractions extend to the proximal musculature of
cr the u p p e r limbs, elevating the shoulders and abduct-
ing the arms. In global tonic seizures, the tonic con-
0 0
v "=
tractions extend to the periphery of the limbs. The
arms are pulled upward to a semiflexed position in
front of the head, and the fists are clenched, produc-
o r" r- "~
~._~ ing a b o d y position similar to that of a child defending
.--= o L; ~ o ~3 ._9o
himself against a facial blow. Involvement of the
lower extremities can also occur, leading to falls if the
NN N ~"
child is in a standing position. Asymmetrical tonic
seizures vary from a slight rotation of the head to a
C~
tonic contraction of all the musculature of one side of
the body. Occasionally, tonic seizures terminate with
a clonic phase.
o ~No~ In a study of epileptic falls in children, Ikeno et al.
•= .= = -= (11) described two types of tonic seizures. The first
¢-5 ~ ~ ~.~ type, termed the "tonic type," was characterized by
excessive flexion or extension of fingers, forced flex-
ion of hand joints, jaw protrusion, shoulder elevation,
~0 0
,
0 0 0
u p p e r arm abduction, and tonic flexion of the trunk.
,. ~ - ~ "~
This hypertonic state continued unchanged even
m mm~ u~ after the patient fell down. The second type, termed
"flexor spasms," was differentiated from the tonic
type by the different distribution of hypertonicity. It
was characterized by forward flexion of the head,
0 elevation of shoulders, abduction of the u p p e r arms
in which the arms are flung outward and forward, and
flexion of the thighs at the hip. Ur~like what was seen
0'~ ~ D DDZ in the tonic type, fingers, hand joints, and elbows
remained neither tonic nor atonic: The flexor spasms
were n o t e d by the authors to resemble infantile
0
spasms.
o
Egli et al. (12) described tonic d r o p seizures as
O
~0 O "~xial spasms." They consisted of a uniform pattern
.<
of m o v e m e n t consisting of a moderate flexion of the
hips, u p p e r trunk, and the head lasting 0.5-0.8 s. The
arms were almost always abducted, elevated, and in a
v v ¢'~
semiflexed position. The fall was provoked by the
O O ~, ~.
•-0 "-O o rapidity and violence of the flexion in the hips.
r~
o
The period of impaired consciousness during tonic
~ o H 0 0 "~. O seizures has an average duration of around 10 s and
D .. ~3 . . "~ 0
u
o ranges from a few seconds to a minute. Postictal
(D
impairment, if present, is usually brief.
¢~ 0 "~ 0 -~- 0 r~ On occasion, breath-holding attacks in children
may be difficult to differentiate from tonic seizures (7,
13-15). The usual clinical sequence in breath-
e~- ~
~
~.~O
O ~"
I~
O
~,.~
M 0
O L~ holding attacks is crying--frequently after sustaining
o O
a mild head injury--followed by breath-holding,

j EPILEPSY, VOL 1, NO. 4, 1988 17S

G. L HOLMES
cyanosis, and loss of consciousness. With the onset of
unconsciousness, the child loses muscle tone and
remains limp until normal breathing is restored. The
child regains composure rapidly, and the marked
lethargy and confusion seen after a generalized tonic
or tonic-clonic seizure usually does not occur. How-
ever, if apnea results in significant hypoxia, opistho-
tonic posturing or generalized tonic-clonic seizures
may ensue. A history of attacks always associated
with crying is the key to the diagnosis. In addition,
the apnea and usually the cyanosis occur before any
alteration in consciousness.
Atonic Seizures
Atonic (astatic) seizures, or drop attacks, are char-
acterized by a sudden loss of muscle tone. They
begin suddenly, without warning, and cause the
patient, if standing, to fall quickly to the floor. Since
there may be total lack of tone, the child has no means
to protect himself and injuries often occur. The attack
may be fragmentary and lead to dropping of the head
with slackening of the jaw or dropping of a limb. In
atonic seizures, there should be a loss of EMG activity.
Consciousness is impaired during the fall, although
the patient may regain alertness immediately upon hit-
ting the floor. Atonic attacks are frequently associated
with myoclonic jerks either before, during, or after
the atonic seizure (12,16). This combination has
been described as myoclonic-astatic seizures (see
below).
Atonic seizures are rare (11,12). The majority of
children with drop attacks will have myoclonic or
tonic seizures (11). To accurately distinguish atonic
seizures from myoclonic and tonic seizures, EMG
monitoring would be necessary. In atonic seizures
there is a decrease in EMG activity compared to in-
creased activity in myoclonic and tonic seizures.
Syncope in children may be confused with atonic
seizures (7,13). Syncope is usually precipitated by
events such as blood drawing, systemic illness, or
standing in a warm room for several hours. Unlike
atonic seizures, the loss of consciousness in syncope
tends to be gradual. The child often feels light-
headed and dizzy and may have visual impairment.
This is followed by loss of consciousness, with the
patient falling to the floor. The fall is slow and rarely
as violent as during myoclonic, atonic, or tonic sei-
zures. Syncope may, on occasion, be followed by a
brief tonic or tonic-clonic seizure. The physician
should be aware that occult cardiac arrhythmias may
present as unexplained syncope (7,17-19).
176 ] EPILEPSY, VOL 1, ~I0. 4, 1988
EEG Features of Myoclonic, Tonic,
and A t o n i c S e i z u r e s
Tonic Seizures
The EEG ictal manifestations of tonic seizures usu-
ally consist of bilateral synchronous spikes of 10-25
Hz of medium to high voltage with a frontal accentua-
tion (Fig. 1). Simple flattening or desynchronization
may also be present. Occasional spike-and-wave activ-
ity (Fig. 2) or diffuse slow activity may occur during a
tonic seizure (20).
Atonic Seizures
Atonic seizures are usually associated with rhyth-
mic spike-and-wave complexes varying from slow, 1-
2-Hz activity to more rapid, irregular spike- or multi-
ple spike-and-wave activity (20,21).
Myoclonic Seizures
Myoclonic seizures are usually associated with
generalized spike-and-wave activity. The frequency
and morphology of the spike-and-wave activity differ
considerably among the various myoclonic syn-
dromes.
Syndromes Associated with Myoclonic,
Tonic, and Atonic Seizures
There are a number of clearly delineated syn-
dromes associated with myoclonic, tonic, and atonic
seizures. Some of the syndromes are characterized
by one seizure type, such as infantile spasms, whereas
others, such as LGS, are associated with mixed sei-
zures. Proper identification of these syndromes is
important, since this often helps the clinician deter-
mine inheritance patterns, choose appropriate anti-
epileptic drugs, and predict outcome. However, these
syndromes are not distinct entities, and clinical heter-
ogeneity is the rule rather than the exception.
Infantile Spasms
Infantile spasms are a unique, and frequently ma-
lignant, epileptic syndrome confined to infants. The
characteristic features of this syndrome are tonic or
myoclonic seizures, hypsarrhythmic EEGs, and men-
tal retardation. The triad of infantile spasms, a hypsar-
rhythmic EEG, and mental retardation is referred to
as West's syndrome. Although the seizures are usu-
ally resistant to conventional antiepileptic drugs

Fp1-F3
"',-.F3-C3
- " - ' - " ~ I sec. ~ ~f'G'~%/x''-'-~
..
Figure 1. Rapid spikes during tonic seizure during sleep in 8-year-old girl
(AEDs) and most of the affected children will remain
retarded, there is some evidence that early cessation
of the spasms is of prognostic significance (22-25),
and, therefore, early diagnosis and treatment may be
important.
Epidemiology
The incidence of infantile spasms has been estimated
at 0.24-0.60/1,000 live births (24,26,27). In recent
epidemiological surveys of childhood epilepsy, infan-
tile spasms made up 1.4-3.9% of the total seizure
types (28-30). Despite improving obstetrical and
perinatal care, there has been no significant decrease
in infantile spasms during the past two decades (26).
Most studies have demonstrated a moderate excess
of infantile spasms in boys in comparison to girls (27).
The onset of infantile spasms is during the first 2
years of life. The peak age of onset is between 4 and 6
months of age. Approximately 90% of infantile
spasms begins before 12 months of age (31). It is rare
MYOCLONIC TONIC AND ATONIC SEIZURES IN CHILDREN
~,e~,~r,*',.-~'~/~h~yi~f~.~
~
v"~¢,~,~*,' "
"---'-'--- -
TONIC Sz
for them to begin during the first-2 weeks of life or
after 18 months.
Clinical Features
Infantile spasms may vary considerably in their clin-
ical manifestations. In a study of 5,042 spasms moni-
tored polygraphically in 24 infants, Kellaway and
associates (32) classified infantile spasms into three
major groups: flexor types, extensor types, and mixed
flexor-extensor types. Flexor spasms consist of flexion
of the neck, trunk, arms, and legs. Spasms of the mus-
cles of the upper limbs result either in adduction of
the arms in a.self-hugging motion or in adduction of
the arms to either side of the head with the arms
flexed at the elbow. Extensor spasms consist of a pre-
dominance of extensor muscle contractions producing
abrupt extension of the neck and trunk with extensor
adduction of the arms, legs, or both. Mixed flexor-
extensor spasms include flexion of the neck, trunk,
and arms, and extension of the legs or flexion of the
j EPILEPSY, VOL 1, NO. 4, 1988 177
G. L HOLMES
ASLEEP
Figure 2. Rapid spikes and spike-and-wave activity during tonic seizure during sleep in 11-year-old girl
legs and extension of the arms, with varying degrees
of flexion of the neck and trunk. Occasionally, asym-
metrical spasms occur and consist of the maintenance
of a "fencing" posture. Most spasms last longer than
350 ms and would therefore be better described as
tonic rather than myoclonic seizures.
Infantile spasms are frequently associated with eye
deviation or nystagmus. Eye movements may precede
the onset of the actual spasms by days or weeks or, in
the patient with spasms, may occur independently of
the muscular contractions. Akinesia and impaired
responsiveness sometimes follows spasms and lasts
as long as 90 s. At times akinesia can occur without a
preceding motor spasm. Infantile spasms may be
associated with autonomic dysfunction characterized
by pallor, flushing, sweating, pupillary dilation, lacri-
mation, and changes in respiration and heart rate
(33,34). Variability of the type of infantile spasms
occurs frequently, with the majority of patients hav-
ing more than one seizure type.
178 J EPILEPSY, VOL 1, NO. 4, 1988
ARMS U P
Infantile spasms frequently occur in clusters, and
the intensity and frequency of the spasms in each
cluster may increase to a peak before decreasing
progressively. The seizures are very brief, and single
seizures may be missed by the casual observer. The
number of seizures per cluster varies considerably,
with some having as many as 160 seizures. The num-
ber of clusters per day also varies, with some patients
having up to 60 clusters a day. Clusters frequently
occur after awakening. The number of infantile
spasms occurring at night is similar to the number
occurring during the day (34). Crying or irritability
during or after a flurry of spasms is commonly
observed.
Infantile spasms are frequently associated with
mental retardation. Lacy and Penry (34), in a review
of the literature, found that only 10% of patients were
developmentally normal at the time of diagnosis of
the infantile spasms. Patients with identifiable causes
of symptomatic infantile spasms have a higher inci-
 MYOCLONIC, TONIC, AND ATONIC SEIZURES IN CHILDREN
Figure 3. Hypsarrhythmia in 6-month-old with infantile spasms.
dence of retardation than those with idiopathic causes
(33).
Neurological abnormalities on physical examina-
tion are also commonly reported• Lacy and Penry
(34) reported that 70% of patients with infantile
spasms have abnormal neurological examinations.
Children with identifiable etiologies for the spasms
are much more likely to have neurological impair-
ment than those in the idiopathic group (31,33.). Lom-
broso (33) found that 99% of patients with identifiable
etiologies for the infantile spasms had abnormal phys-
ical examinations, versus 20% of the patients with
cryptogenic causes for the infantile spasms.
EEG
Infantile spasms are usually associated with mark-
edly abnormal EEGs. The most commonly found
EEG pattern is hypsarrhythmia (Fig. 3) (27,31,34).
Variations of hypsarrhythmia include hypsarrhythmia
with interhemispheric synchrony, hypsarrhythmia
with a consistent focus of abnormal discharge, hypsar-
rhythmia with episodes of attenuation, and hypsar-
rhythmia consisting primarily of high-voltage slow
activity with few sharp waves or spikes (35). During
sleep, especially rapid-eye-movement (REM) sleep,
there may be a marked reduction or total disappear-
ance of the hypsarrhythmia pattern (35). Although a
hypsarrhythmic or modified hypsarrhythmic pattern
is the most common type of interictal abnormality seen
in infantile spasms, this pattern may not be present in
some patients with infantile spasms (27). Some pa-
tients with infantile spasms do not have hypsar-
rhythmia early in the course of the disorder but go on
to develop the pattern. Although hypsarrhythmia is
primarily associated with infantile spasms, it occurs
in other disorders as well. Baird and Borofsky (36)
reported that of 80 patients with hypsarrhythmia,
only 51 had infantile spasms; 20 had other types of
seizures, such as generalized or focal seizures; 9 had
no history of a seizure disorder. In a consecutive
] EPILEPSY, VOL 1, NO. 4, 1988 179
G L HOLMES
series of infants with seizures of a type other than
infantile spasms, Jeavons and Bower (31) found that
4% had hypsarrhythmia or modified hypsarrhythmia.
The ictal EEG changes during infantile spasms are
variable. While Kellaway and colleagues (32) found
11 different types of ictal EEG patterns that accom-
panied the clinical seizures, a marked generalized
attenuation of electrical activity was a feature of 72%
of the seizures. There was not a close correlation be-
tween ictal EEG abnormalities and clinical seizure
type.
Differential Diagnosis
In the child with flexor or extensor spasms there is
usually no difficulty in making the diagnosis. The
biggest error is not considering the possibility and
dismissing the spasms as bouts of colic or other non-
epileptic phenomena.
The one disorder that may be confused with infantile
spasms is benign myoclonus of early infancy (37). In
this disorder, infants have clusters of tonic or myoclo-
nic movements. Unlike infants with infantile spasms,
these children are normal neurologically and devel-
opmentally and have normal EEGs. The movements
cease by 18 months of age.
Etiology
On the basis of past history, physical examination,
and laboratory studies, cases of infantile spasms have
been conventionally classified into those in which
there is no apparent preceding neurological disorder
or identified etiological factor (idiopathic) and those
in which a pre-existing, presumptively responsible
pathological event or disorder is demonstrated (symp-
tomatic cases). Patients with idiopathic infantile
spasms have been further divided into those children
who were neurologically and developmentally nor-
mal prior to their first infantile spasms (cryptogenic)
and those who, for unknown reasons, were impaired
prior to the first infantile spasm (doubtful).
The number of patients with symptomatic: versus
idiopathic infantile spasms varies considerably in
different studies. In selected series, the percentage of
symptomatic cases accounts for the vast majority of
the cases (26,27,38-41). Improving radiological tech-
niques has reduced the number of idiopathic cases. In
three recent studies, the percentage of idiopathic
cases was reported to be 9% by Matsumoto et al. (41),
10% by Singeret al. (22), and 14% by Riikonen (23).
No single factor has been identified as a fundamen-
tal etiological abnormality in this disease. Table 2 lists
etiological agents associated with infantile spasms.
180 ] EPILEPSY, VOL. 1, NO. 4, 1988
Some of the common causes of infantile spasms will
be briefly discussed.
Hypoxic-ischemic encephalopathies. One of the most
common etiologies of infantile spasms is hypoxic-
ischemic encephalopathy (23,27,31,42). Prenatal
causes of hypoxic-ische mic encephalopathy are most
common, although it can also occur at birth or post-
natally (43). Infants with hypoxic-ischemic enceph-
alopathy often have seizures prior to the onset of the
infantile spasms.
Congenital infections. Congenital infections have
been reported in infantile spasms. Cytomegalovirus
(CMV) (44,45), toxoplasmosis (42), rubella (23,46),
and herpes simplex (23) have all been reported in in-
fantile spasms, as have postnatal meningitis and
encephalitis (23,42). New virological methods such as
radioimmunoassay, enzyme-linked immunosorbent,
and enzyme-labeled antigen may be used to diagnose
congenital infections (24).
Brain anomalies. Congenital abnormalities of the
central nervous system are important causes of infant-
ile spasms. The most frequent gross abnormalities
are hydrocephalus and microcephalus (27), but other
reported abnormalities include porencephaly (23,27),
lissencephaly (23,47), hydranencephaly (48), cerebral
neoplasms (49,50), polymicrogyria (23,47), neuronal
heterotopias (51), .myelomeningocele (23), and agen-
esis of the corpus callosum (52).
An important congenital brain anomaly, Aicardi's
syndrome, consists of agenesis of the corpus callo-
sum, infantile spasms, and multiple ocular abnormal-
ities. Aicardi's syndrome is seen primarily in girls
(53,54).
Tuberous sclerosis. Infantile spasms and tuberous
sclerosis often occur together. In three large series of
cases of patients with tuberous sclerosis, 42% of the
patients had a history of infantile spasms (55-58).
Conversely, in reports of cases of infantile spasms,
the frequency of patients with tuberous sclerosis has
varied from 4 to 25% (23,33,40,42,58).
Immunization~ Whether there is an association be-
tween immunizations and infantile spasms has been
the subject of considerable debate among physicians
and lawyers. Most of the reports of the association
of vaccines with infantile spasms have been based on
anecdotal reports. The vaccine most frequently impli-
cated has been the diphtheria-pertussis-tetanus (DPT)
vaccine. Of the three agents, pertussis has raised the
most concern (31,59,60).

Fukuyama and co-workers (61) evaluated the role
of pertussis, smallpox, Japanese encephalitis, and
poliomyelitis vaccines in the etiology of infantile
spasms. Using strict criteria for a causal relationship,
the authors found that less than 5% of their cases met
the requirements. The authors concluded that this
small number could easily be explained as occurring
by chance. The British National Childhood Encepha-
lopathy Study (NCES) evaluated the risk of seizures
following immunizations (DPT and diphtheria-teta-
nus) (27,62). The analysis of the NCES was carried
out by a case-control method whereby two control
subjects matched for age, sex, and area of residence
were selected for each case of infantile spasms. The
timing of the immunization was then compared in the
two groups. There was no significant difference in
incidence of infantile spasms between the children
that had received immunizations and the controls.
Hirtz and colleagues (63) studied the relationship
of immunizations to seizures in 2,766 children regis-
tered in the National Collaborative Perinatal Project.
In 39 children (1.4%), the seizures occurred within
2 weeks of an immunization. All but one of the sei-
zures were associated with fever, and in no cases
did infantile spasms develop. Melchior (64) com-
pared the age of onset of infantile spasms in two
groups of children. The first group consisted of chil-
dren who received DPT vaccinations at 5, 6, and 15
months; the second group received the pertussis
vaccine at ages 5 weeks, 9 weeks, and 10 months, and
diphtheria-tetanus-polio vaccine at 5, 6, and 15 months
of age. The author suggested that if a causal relation-
ship existed between pertussis vaccination and infan-
tile spasms, the age of onset of infantile spasms
should be lower in the second group. In fact, he
demonstrated that the age distributions were very
similar.
It remains possible that in a small number of
patients, especially in cases in which a striking neuro-
logical reaction occurs within 24 h after the immuni-
zation, a causal relationship exists between immuni-
zation and infantile spasms. It is also possible that in
some cases the vaccine acts in conjunction with other
unidentified factors to precipitate the clinical onset of
symptoms in children already predisposed to the
disease (27,62).
Genetics. The majority of patients with the dis-
orders described above do not develop infantile
spasms. The fact that some infants have infantile
spasms while others with similar brain disturbances
do not suggests that genetic factors may be impor-
tant. Although in families of children with infantile
spasms the incidence of epilepsy and infantile spasms
MYOCLONIC TONIC AND ATONIC SEIZURES IN CHILDREN
in other family members is low, it is higher than in the
normal population (34,65). Family studies support a
multifactorial model involving a polygenic determi-
nation of susceptibility to infantile spasms but requir-
ing environmental factors such as hypoxia-ischemia
to precipitate seizures (65).
Treatment
While adrenocorticotropic hormone (ACTH) and
corticosteroids have been the primary drugs used in
the treatment of infantile spasms for over 30 years
(66), no control studies comparing ACTH therapy
with placebo have been performed. Because of the
devastating nature of infantile spasms and the evi-
dence that ACTH is helpful, it is unlikely that such a
study will ever be performed. Although ACTH is
currently the most frequently used drug in the treat-
ment of infantile spasms (67), corticosteroids such as
hydrocortisone (27), prednisone/prednisolone (31,
68,69), and dexamethasone (31) have been used. In
addition to steroids, AEDs that have been successful
in the treatment of infantile spasms include nitraze-
pare (27,34,70-72), valproic acid (73,74), clonazepam
(34,75), clobazam (76,77), and diazepam (78).
Although the prevailing view is that ACTH is more
effective than corticosteroids in stopping infantile
spasms (34,67), this has not been substantiated in
prospective studies. Lombroso (33) compared ACTH
with oral steroids and other modes of treatment in
infants with infantile spasms. When the children
were evaluated after 10 months, there were no statis-
tical differences between the groups, although there
was a general trend favoring AC~H. Hrachovy and
colleagues (68) compared ACTH (given in a dose of
20-30 units/day) to prednisone (given in a dose of 2
mg/kg/day). No major difference between the effec-
tiveness of ACTH and prednisone was found. The
authors also found that patients who fail to respond to
ACTH may respond to prednisone and vice versa.
The effects of ACTH and other therapies on long-
term outcome remain controversial. For example,
several authors have found no differences in develop-
mental outcome between patients who did and did
not receive treatment (42,79,80). For the large
number of infants who exhibit pre-existing brain
damage, it is highly unlikely that any form of therapy
would significantly influence the long-range out-
come in terms of mental and motor development. The
important question is whether the type of treatment
for infantile spasms in children who were normal
before the onset of the spasms or who have a cryp-
togenic cause of the spasms alters outcome. Lombroso
(33) did long-term assessments (6 years after diagno-
j EPILEPSY, VOL 1, NO. 4, 1988 181
G. L. HOLMES
sis) on infants with cryptogenic infantile spasms who
received ACTH, oral steroids, or other AEDs. The
group that received ACTH had a lower incidence of
seizures and better psychomotor development than
infants treated with oral steroids or other agents.
The most advantageous dosage of ACTH has yet to
be established. Riikonen (23) compared the efficacy
of three daily dosages of ACTH: 20-40 International
Units (IU), 80 IU, or 120-160 IU. In this series the
large dosages did not have a better effect on spasms,
hypsarrhythmic EEGs, relapse rate, or later mental
development than the small dosages.
The length of time a child should be treated with
ACTH or corticosteroids has not been established.
The response to ACTH is sometimes very dramatic,
with cessation of seizures and marked improvement
of the EEG within a few days. Hrachovy and
associates (68) found that 12 of 16 patients (75%)
who responded to prednisone or ACTH did so in 2
weeks. These authors then tapered and discontinued
the medication over I week. The other four patients
who responded required a 6-week course of therapy.
Of the responders, 31% (5 of 16) relapsed. Other
studies have also demonstrated significant relapse
rates in patients who initially responded to ACTH
(23,81). Because of this high relapse rate, some
authors have recommended longer treatment peri-
ods (23,82). There is no firm evidence that longer
treatment periods improve the remission rate (68).
When relapses occur, the child may respond well to a
second course of ACTH therapy (24).
Singer and co-workers (22) suggested that early
treatment of infantile spasms with ACTH is necessary
to prevent psychomotor retardation. Nineteen pa-
tients with normal developmental and neurological
examinations and normal neuroradiological studies
prior to the infantile spasms were treated with ACTH.
Eight of nine (89%) children started on ACTH within
1 month of treatment were normal in follow-up,
whereas all 10 infants who were treated after I month
were abnormal. Lerman and Kivity (82) also reported
that patients with idiopathic infantile spasms treated
within I month of onset of infantile spasms with ACTH
had better outcomes than those in whom treatment
was delayed. Riikonen (23,24) reported that the effect
of ACTH was better when the first treatment course
was started without delay. However, in the NCES, the
prognosis in children diagnosed and treated with ste-
roids within I month of the onset of seizures was no
better, with regard to developmental and neurological
status, than in those children in whom a nonsteroid
drug was started (27). Other authors have also not
found a relationship between time of diagnosis and
treatment and outcome (27,69).
182 ] EPILEPSY, VOL. 1, NO. 4, 1988
The mechanisms of action of ACTH and adrenal
corticosteroids in the treatment of infantile spasms
have not been established (83,84). The fact that some
studies demonstrate better results with ACTH than
corticosteroids has led to the hypothesis that ACTH
may exert its action by means other than stimulating
the adrenal cortex, such as by acting directly on the
brain (83,85). Farwell et al. (83) treated eight infants
with infantile spasms with prednisone (2 mg/kg/day)
for 2 weeks. Six patients continued to have seizures,
and ACTH (40 IU/day) was added to the prednisone
regimen. Serum prednisone and cortisol were mea-
sured at a number of points during treatment. In in-
fants receiving prednisone and then prednisone plus
ACTH, serum cortisol was suppressed to about one-
quarter of baseline levels and remained suppressed
during ACTH administration. Despite this suppres-
sion of cortisol levels, ACTH had a beneficial effect,
suggesting that ACTH can act without stimulating
endogenous cortisol production.
It is known that ACTH is distributed in the brain in
areas outside the pituitary. Whereas reactive cell
bodies containing ACTH are found only in the hypo-
thalamus, dense axonal networks containing ACTH
are widely distributed to other brain areas (86-88).
This widespread distribution has led to speculation
that ACTH acts as a central nervous system neuro-
transmitter or neuromodulator (89). A direct effect
on the brain would also explain why some authors
report better results with doses of ACTH higher than
necessary to maximally stimulate the adrenal gland
(22,27,82). ACTH may have otherwidespread effects
as well. For example, Izumi and Fukuyama (90)
found that ACTH therapy suppressed T4 levels, and
they suggested that the benefit of this mode of
therapy might be dependent in part on the suppres-
sion of thyroid hormone.
The side-effects of ACTH are numerous, and some
appear to be dose-dependent (91). Steroid therapy is
invariably associated with cushingoid obesity. In
addition, growth retardation, development of ache,
and severe irritability may ensue. Infrequently, ste-
roids may aggravate clinical spasms. Riikonen and
Donner (91) reported pronounced side-effects with
the use of ACTH in 37% of 162 children with infan-
tile spasms. In this series, children received up to 160
IU of ACTH daily. Side-effects were higher (43%)
with high doses of ACTH (120-160 IU/day) than
with doses of 20-40 IU/day (35%). Complications
included infection, arterial hypertension, osteoporo-
sis, hypokalemic alkalosis, and other electrolyte dis-
turbances. The synthetic analogs of ACTH cause
more side-effects than the nonsynthetic ones (91).
Infections should be excluded before starting ACTH

Table 3. Etiological agents associated zoith infantile spasms
Prenatal
Congenital Acquired
Cerebral anomalies Hypoxia-ischemia
Hydrocephalus Congenital infection
Microcephaly
Hydranencephaly
Schizencephaly
Polymicrogyria
Sturge-Weber
Incontinentia pigmenti
Tuberous sclerosis
Neurofibromatosis
Down's syndrome
Aicardi's syndrome
treatment. Because white blood counts are elevated
by cortisol-induced leukocytosis and neutrophilia,
infections may be more difficult to recognize follow-
ing the start of ACTH therapy. Another problem that
may be encountered during immunosuppressive ther-
apy is infection caused by uncommon micro-organ-
isms. ACTH may activate a latent CMV infection or
render a child susceptible to a new infection, or an
infection may become aggravated and even persis-
tent (24,91).
ACTH therapy should be avoided in children with
congenital or symptomatic, acquired CMV infection.
Children with a proven history of congenital CMV
infection (virus isolated in the urine before the age of
2-3 weeks) and children suspected to have a congeni-
tal infection because of their clinical symptoms should
preferably be treated with AEDs other than ACTH
(24). Children with meningoencephalitis or pneu-
monitis or with other clinical manifestations of a
possible CMV infection should be tested for CMV
infection. If antibody titers rise to fourfold or'greater,
CMV infection must be highly suspected, and ACTH
therapy should not be given or it should be inter-
rupted. It is recommended by Riikonen (24) that
CMV titers be obtained before starting ACTH.
Infants treated with ACTH may develop adreno-
cortical insufficiency (92). In a study of 10 infants
treated with 80 IU during weeks 1-3, 40 IU during
weeks 4-5, and tapering during week 6, Perheentupa
et al. (92) found subnormal cortisol excretion I and 2
weeks after treatment. The basal concentrations of
serum cortisol of one-third of the patients and post-
MYOCLONIC, TONIC, AND ATONIC SEIZURES IN CHILDREN
Perinatal Postnatal
Birth trauma Metabolic
Hypoxia-ischemia Maple syrup urine disease
Phenylketonuria
Nonketotic hyperglycinemia
Urea cycle defects
Leigh's syndrome
Pyridoxine dependency
Hypoglycemia
Lysosomal storage disease
Intracranial hemorrhage
Hypoxia-ischemia
Encephalitis
Meningitis
Immunization
Trauma
ACTH challenge of cortisol concentrations of two-
thirds of the patients were subnormal. Some infants
are therefore at risk for adrenal insufficiency follow-
ing ACTH therapy.
Prognosis
Infantile spasms is one of the most devastating sei-
zure disorders to affect infants. The poor prognosis
has been confirmed in virtually all follow-up studies.
A significant number of infants will demonstrate psy-
chomotor retardation and continue to have seizures.
Children who continue to have seizures may develop
LGS (93). In some children, it appears that the
infantile spasms are replaced by tonic axial spasms
(12). Some children continue to have seizures that
are very similar to infantile spasms. Ikeno et al. (11)
labeled these types of seizures as flexor spasms and
reported them in children as old as 14 years of age.
A summary of selected studies on long-term prog-
nosis in infantile spasms is given in Table 3, although
the studies are difficult to compare because of dif-
ferences in lengths of follow-up and criteria by which
the patient's status is judged. Since a large number of
patients have neurological impairment prior to the
onset of the spasms, it is not surprising that the prog-
nosis is so poor. In all likelihood the patients would
have had similar neurological outcomes regardless of
the infantile spasms.
Prognosis is directly related to etiology. Crypto-
] EPILEPSY, VOL 1, NO. 4, 1988 183
G. L. HOLMES
genic cases have significantly better prognoses than
symptomatic cases. Patients who are classified as
doubtful usually have outcomes similar to the symp-
tomatic cases (27). In view of the clear evidence for
the better outcomes of cryptogenic cases, classifica-
tion with respect to antecedent factors appears to be
one of the most important prognostic indicators.
A prognostic factor related to etiology is neurological
status prior to the onset of infantile spasms. Children
with normal neurological examinations and normal
development have a much better prognosis than in-
fants with developmental delay and abnormal neuro-
logical examinations (31,34). An additional poor
prognostic sign reported by some authors is early
onset (before 6 months of age) (23,80,94,95). Age of
onset appears to be directly related to etiology, since
the onset of the spasms is at a younger age in chil-
dren with symptomatic etiologies than with children
with cryptogenic etiologies (33). The occurrence of
other types of seizures in addition to infantile spasms
has been found to be associated with a poor progno-
sis by some authors (41,80,95).
Cryptogenie Myoclonic Epilepsy of
Early Childhood
Cryptogenic myoclonic epilepsy of early child-
hood consists of those cases in which the children
have no prior history of brain damage (21,96,97).
However, other types of seizures, especially febrile
seizures, may precede the myoclonic seizures. The
age of onset is between 6 months and 5 years (21,96).
The myoclonic seizures are often associated with
other types of seizures, such as generalized tonic-
clonic seizures, atonic seizures, partial seizures, and
atypical absence seizures (21,96,97). While McBride
(97) reported that tonic seizures occurred in her pa-
tients, Aicardi (21) states that tonic seizures are rare
in this disorder. In fact, Aicardi uses the presence of
tonic seizures to differentiate children with LGS from
cryptogenic myoclonic epilepsy.
The incidence of early cryptogenic or idiopathic
myoclonic epilepsy is difficult to assess because the
syndrome is often not distinguished from other types
of myoclonic epilepsy (21). It is likely that the dis-
order is underrecognized (97). Genetic factors may
play a role in the etiology (21,98).
The course of the disorder is difficult to predict,
since there is a considerable amount of variability in
outcome. The course of cryptogenic myoclonic epi-
lepsy is variable. In a series of 55 patients, Aicardi
(21,96) reported that 27 had been seizure-free for a
184 ] EPILEPSY, VOL. 1, NO. 4, 1988
minimum of I year after a mean follow-up of 6 years,
3 months. Twenty children had an IQ of 80 or more;
35 had some degree of mental impairment, but only 6
had an IQ of less than 50. Those children who had no
seizures prior to the onset of myoclonic seizures had a
significantly better outlook than the remainder of the
patients. Jeavons (99) found that the mental outlook
was favorable in the group of children with crypto-
genic myoclonic epilepsy of childhood but that sei-
zures often recurred when treatment was discontinued.
Lombroso and Erba (100) also reported that crypto-
genic myoclonic epilepsy was a benign form of epi-
lepsy.
However, some authors (101,102) divide crypto-
genic myoclonic epilepsy into benign and severe
forms. According to Dravet et al. (103), the benign
type has an early onset (under 24 months of age) and
myoclonic seizures are the only type of seizures
except for occasional febrile seizures. The severe
form typically starts before age 10 months with gen-
eralized or unilateral seizures often triggered by
fever (104). The seizures are often prolonged and
occur frequently. Myoclonic seizures appear most
commonly during the second part of the second year
of life and are associated with generalized tonic-
clonic seizures, partial complex seizures, and atypi-
cal absence seizures (21). The EEG demonstrates
generalized bursts of irregular spike-and-wave activi-
tyofthe fast (>2.5-Hz) variety (6,21). Photic stimula-
tion frequently elicits bursts of spike-and-wave or
multiple spike-and-wave activity.
The outlook for the severe form of cryptogenic
myoclonic epilepsy is poor, both for seizures and for
mental development, which stops progressing dur-
ing the second year of life. Of the 42 patients re-
ported by Dravet et al. (104), four died and all sur-
vivors were mentally retarded after the age of 3 years.
According to Dravet et al. (104), this form is well
individualized and completely different from LGS.
While there are undoubtedly several types of cryp-
togenic myoclonic epilepsy, it is very difficult to
confidently place an individual patient into one of
these categories. It is clear that the myoclonic epilep-
sies of early childhood constitute a heterogeneous
group with many possible outcomes.
Table 4 lists some of the differentiating features in
the myoclonic epilepsies.
Symptomatic Myoclonic Epilepsies
of Early Childhood
Symptomatic myoclonic epilepsies have their onset
between a few months and 3-4 years of age in

Table 4. Long-term prognosis of infantile spasms: clinical state on follow-up
Intelligence
Number of Epilepsy Normal
patients (%) (%)
150 55 21
25 44 16
205 43 15
104 56 22
267 26 30
286 31 --
patients who have psychomotor retardation and
symptoms of chronic organic brain damage such as
cerebral palsy (21). Aicardi and Chevrie (105) found
the mean age of onset of myoclonic seizures to be 22
months of age, with the youngest infant 4 months old
at the time of the first seizure. The myoclonic sei-
zures may be the only seizure type, or they may be
associated with clonic or tonic-clonic generalized or
partial seizures. Absence and tonic seizures are
usually not observed (21). Prognosis is usually poor,
and mental retardation is the rule.
Centrencephalic Myoclonic-Astatic Petit Mal
Doose and colleagues (106) described a group of
51 children with myoclonic and astatic seizures, often
in combination with absence seizures, generalized
tonic-clonic seizures, and tonic seizures. In this syn-
drome, astatic seizures (defined as the inability to
stand) occur suddenly, without warning, and the
child collapses onto the floor as if his legs have been
pulled from under him. No apparent loss of con-
sciousness accompanies these seizures. At times the
astatic seizures are so short that only a brief nodding
of the head and slight flexion of the knees is seen.
Based on the clinical description of these seizures, it
appears that they are atonic in type. The myoclonic
seizures in this disorder are characterized by symmet-
rical jerking of the arms and shoulders with siihultan-
eous nodding of the head. Some myoclonic jerks are
violent, with the arms flung upward, and some are so
mild that they are easier to feel than see. A combina-
tion of myoclonic and astatic seizures has frequently
been observed. In these children, the loss of postural
tone is immediately preceded by myoclonic jerks,
hence the term myoclonic-astatic seizures.
The onset of the disorder takes place between the
first and fifth year of age and occurs in boys more fre-
quently than girls. The EEG pattern consists of bilat-
erally synchronous, regular or irregular, 2-3-Hz
MYOCLONIC, TONIC, AND ATONIC SEIZURES IN CHILDREN
Neurological
Retarded abnormality Died
(%) (%) (%) References
79 47 22 80
84 -- -- 95
85 -- -- 42
78 56 16 41
70 29 6 27
-- 32 11 33
spike-and-wave activity, whereas the background
activity exhibits an excess of monomorphic theta
activity.
With few exceptions, the mental and motor devel-
opment of the children is normal before the onset of
the illness. However, the prognosis is generally un-
favorable, and most patients develop dementia. Ab-
sence status is reported to play a role in the patho-
genesis of the dementia (107).
In 40% of the patients, seizures were reported in
close family members of the proband (siblings, parents,
parents" siblings, grandparents), with seizures in the
first 5 years of life being particularly frequent (26% of
the cases). Seizures occurred in 12.6% of the siblings
and in 7.1% of the parents. In addition, 46% of the
siblings and 14% of the parents had abnormal EEGs.
Combining the EEG and clinical findings, the authors
found clear indication of seizures or seizure suscep-
tibility in 34 families (68% of the total).
Although Doose and colleagues ~rgue that this is a
distinct syndrome, it is unclear whether the syndrome
differs significantly from LGS or cryptogenic myoclon-
ic epilepsy of early childhood. In a study of epilep-
tic falls in children with LGS, Ikeno et al. (11) found
that 25% of the seizures responsible for the falls were
of the myoclonic-atonic type. In a series of eight chil-
dren with cryptogenic myoclonic epilepsy of early
childhood, McBride (97) reported that five patients
had myoclonic-astatic seizures.
Myoclonic Jerks with Absence Seizures
Myoclonic seizures often occur as a component of
an absence seizure (108). In a study of 426 typical
absence seizures and 500 atypical absence seizures
studied in 54 children using simultaneous EEG fre-
quency modulation radiotelemetry and videotape
monitoring, Holmes and colleagues found myoclonic
jerks in 13% of typical absence seizures and 12% of
atypical absence seizures. Myoclonus was never seen
j EPILEPSY, VOL. 1, NO. 4, 1988 185
G. L HOLMES

-~./__.i ...___ ,

Figure 4. Generalized3-Hz spike-and-wave activity in 16-year-old girl with typical absence seizures.

as the initial manifestation in typical absence seizures or by watching a television screen .has also been
but was occasionally seen as the first manifestation of reported (110). - -
." ~ • .
atypical absence seizures. In this study, absence sei-
zures were classified by EEG criteria. Seizures with a
luvenile Myoclonic Epilepsy of Janz~
generalized, regular, symmetrical spike-and-wave
discharge were classified as typical absence seizures . M y o c l o n i c seizures in children may occur as a"
(Fig. 4) whereas absence seizures with slow (~2.5 • componen t of juvenile myoclon!c e p i l e p s y 6 f Janz
Hz), irregular~ o r asymmetrical spike-and, wave dis- ..- (benign juven!le my.oclon!c ep!lepsy) (111,112). The
charge were classified as atypical absence seizures . syndrome is named• after Janz, who described a fam-
(Fig. 5) . . . . . . . ....... ilial-disorder of myoclonic, epilepsy associated with
Jeavons (99) has described a syndrome of eyelid ,.:. i :an excellent prognosis in patients who were otherwise
myoclonus with absence seizures, a type of epilepsy ~; mentally a n d neurologically normal. Janz initially
characterized b y rhythmic jerking of the eyelids with termed the syndrome "impulsive petit mal" to indi-
upward deviation of the eyes. The attacks follow eye cate that the myoclonic jerks are a type of minor sei-
closure. Some, but not all, patients have photosen- zure (113,114).
sitivity (99,109). The patients usually also have typi- The myoclonic seizures are usually mild to mod-
cal absence seizures. The EEG pattern associated erate in intensity and involve the neck, shoulders,
with eyelid jerks is irregular, 3-Hz spike-and-wave and arms. The movements involve an entire extrem-
complexes. Induction of seizures by slowly blinking ity or body part rather than an isolated muscle con-

186 ] EPILEPSY, VOL 1, NO. 4, 1988

 MYOCLONIC, TONIC, AND ATONIC SEIZURES IN CHILDREN
-rFT-' ; 1 1] I 1 I I I r ' I T f - I 1 1 1 I I ._. 1 1 I I I I , I ~ . _ 11 I I I I I I ~ I I w , I , I I ,_~ I I I I I , I ' 1 - ' = ' 1 I I ' 1 I I I I ~ . r l | | 1 I I I-F~I I I 1 I, l*rr'd | I I 1 1 I I I'1-~ 1 I I I I I I I _ ' - I 1 I 1 I I I I .dI --

<..~/\, . : u~' ,I ., ~ ~ ~,':~. ~!j&~ a "-,~--¢~

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= ~l.
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Fp 1-F7 ,Vf~'\4r" I : ~ 'ks~'t,[gt~'J"dd""A"i v " Y ' , ~ 2 " ~ / ' ~ " " - - " " ~ " ~
-'-'r'~W";ii

t ~ - t S - - ~ ~ ' ~ / ~ .,~, tg! .M,. 1,11fk~,"-,~,[\, At,g..,. t"~'t~'t.w, p',,.uWWg--','.<~",..'W'Xr.~.~.',,~.',~"

--/ ',l "7 t ':7 t - - "-

--'I--'EK6
NO CLINICAL SIGNS

Figure 5. Slow spike-and-wave activity in lO-year-old boy with atypical absence seizures.

traction (114). They can occur either singularly or when the patient is fatigued. They are typically
repetitively and may cause the patient to drop objects. aggravated by sleep deprivation.
They are generally bilateral although sometimes The vast majority of patients with this syndrome
they are asymmetric with changing left-right accen- have tonic-clonic or clonic-tonic-clonic seizures
tuation. Rarely, the jerks may involve the legs and (111,112). Only 2 of 43 of Delgado-Escueta and En-
cause the patient to fall to the ground. More com- rile-Bascal's patients were free of these seizure types.
monly they are quite mild, and the patient may attrib- In a series of 12 patients reported by Asconape and
ute them to nervousness or clumsiness (111). Occa- Penry (111), 83% had generalized tonic-clonic sei-
sionally, however, the jerks become more severe and zures. Although there are cases in which the myo-
the patient develops a chorea-like picture of violent clonic and generalized tonic-clonic seizures begin
jerks in rapid succession. Myoclonic status, a state in simultaneously, and others where the generalized
which the patient has myoclonic jerks every few tonic-clonic seizures occur before the onset of the
seconds or in salvos of three to five jerks, can occur. myoclonic seizures, in the large majority of cases the
Although consciousness is preserved, the patient is myoclonic jerks precede the onset of the generalized
often incapacitated by the continuous myoclonic tonic-clonic seizures (114). Like the myoclonic
jerks. The myoclonic seizures usually are confined seizures, these seizures often occur shortly after a-
to several hours after awakening from a night's sleep wakening or during early morning sleep. At times
or nap. In some patients they may continue all day, patients will have a series of myoclonic seizures cul-
albeit at a lesser frequency. The seizures may minating in a generalized seizure. Some patients will
increase in frequency again at the end of the day have several days of an increasing number of myoclo-

J EPILEPSY, VOL 1, NO. 4, 1988 187

G. L. HOLMES
~P4-O2
Fpl
FS-T4 '~'
T4-T6
"--'-T6- 02 " ~
~T5 -01
-~EKG
NO CLINICAL SIGNS
Figure6. Rapid, 6-Hz spike-and-wave activity in 16-year-old boy with benign myoclonic epilepsy of Jan~
nic seizures, followed by generalized tonic-clonic
seizures.
Absence seizures also occur in a substantial number
of patients. Janz (114) and Delgado-Escueta and
Enrile-Bascal (112) reported that 10% and 40% of pa-
tients, respectively, also had absences, usually in
association with tonic-clonic or clonic-tonic-clonic
seizures. As with other seizure types, these often
occur shortly after awakening.
The disorder begins in childhood, with the onset in
the second decade in most patients (111). In a study
of 43 patients, the average age of seizure onset was
13.6 years, with a range of 8-24 years of age (112). The
general findings of the physical and neurological
examinations in these patients are usually normal. In
addition, normal intelligence is the rule. A positive
family history of epilepsy is commonly obtained. The
mode of inheritance appears to be polygenic, with
females having a lower threshold than males (112).
188 J EPILEPSY, VOI. 1, NO. 4, 1988
~ .- ~
50uV. [
1 SEC.~
/1
EEG. The interictal EEG in this disorder is re-
ported to be distinctive and easily distinguished from
other forms of generalized epilepsies. The character-
istic feature of the EEG is the fast (3.5-6-Hz) spike-
and-wave and multiple spike-and-wave complexes
(Fig. 6). This pattern contrasts with the 2.5--3-Hz
spike-and-wave complexes seen in classic absence
and the slow (1.5-2.5-Hz) spike-and-wave complexes
of LGS. During myoclonic seizures, the ictal EEG con-
sists of 10- to 16-Hz rapid spikes, followed by irregular
slow waves. Photosensitivity may activate the epilep-
tiform discharges (111). If the diagnosis is suspected
and the awake EEG is normal, it is imperative that a
sleep-deprived EEG be obtained, since this may be
the only time the abnormality is present.
Valproic acid therapy is very effective in this dis-
order (111,112). In the series of 43 patients reported
by Delgado-Escueta and Enrile-Bascal (112), 86%
were either seizure-free or satisfactorily controlled

either on valproic acid alone or in combination with
other AEDs. In the study by Asconape and Penry
(111), 73% had either complete control or a marked
reduction in seizure frequency with valproic acid
monotherapy.
Although seizures in patients with juvenile myo-
clonic epilepsy of Janz may be easily controlled with
valproic acid, attempts to withdraw the drug after pa-
tients have been seizure-free for a period of time are
usually not successful. Only rarely do the seizures
remit spontaneously, and 90% of patients relapse
after withdrawal of AEDs (112).
Focal Cortical Myoclonus
Focal cortical myoclonus consists of single arrhy-
thmic jerks involving, with variable frequency,
groups of muscles, a limb, or one side of the body
(115). Focal cortical myoclonus may resemble focal
clonic seizures, which consist of a series of rhythmic
jerks, or epilepsia partialis continua, which consist of
rhythmic or irregular jerking movements persisting
for hours or years. Clinically, the manifestations
merge into one another and likely represent a spec-
trum (116).
Focal cortical myoclonus is a rare seizure pattern
(115,117). Kuzniecky et al. (115) reported four
patients with the onset of focal myoclonus in child-
hood in whom two patients had pathological evidence
of rolandic cortical dysplasia. The ictal EEG manifes-
tations of the disorder were also focal.
Lennox-Gastaut Syndrome
In 1939, Gibbs and co-workers (118) described the
EEG findings of slow, rhythmical, spike-and-wave
discharges as being different from the more rapid
3-Hz spike-and-wave discharges seen in petit mal sei-
zures. The authors designated this slow spike-and-
wave pattern as the "petit mal variant." Subsequently,
Lennox and colleagues (119,120) observed that pa-
tients with this EEG pattern were different from pa-
tients who had the more rapid 3-Hz spike-and-wave
discharges, in that their ictal symptoms were atypical,
they were frequently retarded, and their seizures
were intractable to AEDs. Gastaut and associates
(121) further expanded this clinical description and
emphasized that this slow spike-and-wave pattern on
the EEG was found in patients who were clinically
distinguishable from those with the "petit mal" pat-
tern. Patients with the slow spike-and-wave pattern
had a high incidence of intellectual impairment, had
MYOCLONIG TONIC, AND ATONIC SEIZURES IN CHILDREN
seizure types other than absence seizures, and fre-
quently had intractable seizures. Detailed descrip-
tions of the clinical and EEG features of this pattern
led to the common use of the eponym "Lennox" or
"Lennox-Gastaut'" syndrome for this EEG pattern
and the associated clinical features (121-124).
In addition to being termed petit mal variant, the
Lennox syndrome, and the Lennox-Gastaut syn-
drome, this disorder has also been described as astatic
seizures, epileptic encephalopathy with diffuse spike-
and-wave discharges, myoclonic-astatic petit mal,
and the minor motor seizure syndrome (7,106,125).
It is likely that the syndrome is not a homogeneous
entity but probably consists of several overlapping
complexes (98,105,124,125). Whether these terms all
apply to the same syndrome is controversial. For this
review, LGS will be operationally defined as having
the following characteristics: (a) a slow spike-and-
wave EEG pattern during a portion of the awake-state
EEG and (b) intractable seizures of various types.
Epidemiology
The incidence of LGS is not known. This probably
reflects the lack of a uniform definition of the dis-
order. As noted by Aicardi (124), the incidence of LGS
has been estimated at from 3 to 11% of the epilepsies
of childhood.
Clinical Features
The child with LGS has a mixture of seizure types.
The most frequently occurring are tonic seizures, ton-
ic-clonic seizures, myoclonic seizures, atypical ab-
sence seizures, and "head drops," which represent a
form of atonic, tonic, or myoclonic.seizure (12,16,94,
122,123,124).
Tonic seizures are one of the most frequently occur-
ring seizure types in this syndrome (10,21,94,124,126).
They are typically activated by sleep and may occur
repetitively throughout the night. They are much
more frequent during non-REM sleep than during
wakefulness and do not occur during REM sleep (21).
In LGS, tonic seizures are usually brief, lasting from a
few seconds to 1 min, with an average duration of
about 10 s. The seizures may throw the patient off
balance and cause many of the falls observed in chil-
dren with this syndrome. Eyelid retraction, staring,
mydriasis, and apnea are commonly associated and
may be the most prominent features (124). During
tonic seizures, the patient is unconscious, although
arousal from light sleep may occur. Since tonic
seizures are often very brief, they often go undetected.
While atonic seizures commonly occur in this syn-
j EPILEPSY, VOL. 1, NO. 4, 1988 189
G. L HOLMES

drome, they are usually less frequent than tonic and nitive abilities occur in LGS patients and are, to some
myoclonic seizures. Most atonic seizures are quite degree, correlated with the intensity of EEG abnor-
brief, lasting 1-4 s. In the briefest attacks, patients malities. In addition to cognitive difficulties, behav-
may show only head drops or sagging at the knees ioral problems--from hyperactivity with aggressivity
(21). If a fall ensues, the patient typically picks him- to frank psychotic and autistic behavior--are very
self up immediately and resumes what he was doing. common in LGS. In addition to mental retardation
The seizures are so brief that it is difficult to deter- and behavioral problems, neurological abnormalities
mine if consciousness is lost. have been reported in 30-88% of the patients with
Many children with drop attacks will have myoclo- LGS (16,42,123).
nic or tonic seizures. In a study of 48 drop attacks in
15 children with LGS (11), only 4% of the seizures EEG
were of the atonic type. As noted earlier, it may be
The sine qua non of the EEG findings in LGS is the
very difficult to differentiate myoclonic from atonic
slow spike-and-wave discharge. The slow spike-and-
seizures, since both are very brief and may have few
wave or sharp-and-slow-wave complexes consist of
differentiating features. In selected patients with LGS,
generalized discharges occurring at a frequency of
myoclonic seizures are a prominent feature. In some
1.5-2.5 Hz (Fig. 5). The morphology, amplitude, and
patients, they are very prominent, and some investi-
repetition rate may vary from burst to burst as well as
gators have described a myoclonic variant of LGS
during a single paroxysmal burst of spike-and-wave
(124). activity. Transient and shifting asymmetries of the
Atypical absence seizures and generalized tonic-
discharge frequently occur. The area of maximum
clonic seizures are seen in over half of the patients voltage, while variable, is usually frontal or temporal
wth LGS (16,123,125). Generalized tonic-clonic sei-
in location. Although sleep increases the frequency
zures usually cause the most concern to parents and
of the discharges, hyperventilation and photic stimu-
are often the seizure type to precipitate hospitaliza-
lation rarely activate these discharges.
tion. Atypical absence seizures are generally longer
During non-REM sleep, slow spike-and-wave dis-
than typical absence seizures and have a higher asso-
charges may be replaced by multiple-spike-and-wave
ciation with changes in postural tone and myoclonic
discharges, whereas in REM sleep the paroxysmal
jerks (7). activity decreases markedly. Runs of 10-Hz rhythms,
Patients with LGS typically have very frequent sei-
the so-called grand mal discharges of Gibbs and
zures. Markand (123) found that 60% of his patients
Gibbs, are one of the most characteristic features of
had seizures daily, whereas Papini and colleagues
the sleep tracings of LGS (128).
(127), in a longitudinal study of 16 patients with LGS,
The background activity is usually abnormally
found the mean daily frequency of seizures to range
slow. Sleep spindles, vertex activity, and K-com-
from 9 to 70. Some children with this syndrome have
plexes are often poorly recognizable because of the
hundreds of seizures daily.
frequent occurrence of generalized paroxysms.
Seizure frequency may vary considerably during
As noted above, the typical EEG manifestations of
the course of a day. Papini and co-workers (127)
tonic seizures is the occurrence of fast rhythm dis-
found that seizure frequency was highest during
charges of 10-20 Hz with progressively increasing
drowsiness and inactivity. In addition, in many of the
amplitude, at times followed by a few slow waves or
patients there is a weekly or monthly periodicity in
spike-and-wave discharges. In atonic seizures, the
seizure frequency unrelated to AED therapy. This
EEG pattern is most frequently a fast, recruiting dis-
makes it very difficult to assess efficacy of AEDs.
charge, but bursts of slow spike-and-wave complexes
Mental retardation is present before onset of the
or large-amplitude, 10-Hz discharges are sometimes
seizures in 20-60% of patients (124). In these pa-
recorded. The EEG correlate of myoclonic seizures
tients, bilateral or focal neurological signs are often
consists of bursts of arrhythmical multiple spike-and-
present, as are abnormal computed tomography or
wave or irregular spike-and-wave activity. Atypical
magnetic resonance imaging scans. Some patients
absence seizures are associated with slow (K2.5 Hz),
with idiopathic or cryptogenic etiologies of their sei-
often asymmetrical, and irregular spike-and-wave
zures have normal IQ scores or normal developmental
activity (108).
histories prior to the onset of their seizures. The
proportion of retarded patients increases with age be-
Etiology
cause of the deterioration that often occurs in LGS
(124). According to Aicardi (124), a few patients es- Like infantile spasms, the etiology of LGS may be
cape mental retardation. Marked fluctuations in cog- idiopathic (cryptogenic), arising de novo in a pre-

190 ] EPILEPSY, VOL 1, NO. 4, 1988

 MYOCLONIC, TONIG AND ATONIC SEIZURES IN CHILDREN
Table 5. Etiological factors associated zoith the Lennox-Gastaut syndrome
Prenatal Perinatal Postnatal

Congenital brain anomalies Hypoxia-ischemia Encephalitis

Tuberous sclerosis Intracranial hemorrhage Meningitis
Prematurity Postimmunization
Prenatal trauma Acute hemiplegia
Eclampsia Status epilepticus
Infection (cytomegalic inclusion Head injury
disease, toxoplasmosis) Intracranial hemorrhage
Anoxic encephalopathy
Hypoglycemia
Progressive degenerative or metabolic disease [ceroid
lipofuscinosis, gangliosidoses, subacute sclerosing
panencephalitis (SSPE), nonketotic hyperglycin-
emia]

viously well child, or symptomatic of a definable etio-
logy. Etiologies have been identified in 30-66% of
patients (16,42,123) (Table 5). Whereas the majority
of patients with LGS have a static disease, degenera-
tive disorders have been associated with the syn-
drome (124). For example, neuronal ceroid lipofus-
cinosis may present as LGS (129).
The role of genetic factors in this syndrome is con-
troversial. Although many children with LGS have
acquired the disease, genetic susceptibility may still
play a role. For example, only a few patients with
hypoxic-ischemic encephalopathies develop LGS.
Genetic factors may influence which of these chil-
dren develop seizures. Chevrie and Aicardi (94) and
Gastaut and co-workers (121) found a positive family
history in 2.5% and 14% of their series of children
with the syndrome, respectively. In addition, LGS
may be part of the clinical presentation of an in-
herited disorder, such as tuberous sclerosis (16,42).
Treatment
Treatment of LGS is one of the most difficult tasks
the physician has to face. Complete seizure control is
rarely achieved. Because of the intractable nature of
the seizures and their mixed types, there is a tendency
to place the child on numerous AEDs. This polyphar-
maceutical approach rarely results in good seizure
control and usually causes toxic reactions--fatigue,
nausea, and ataxia--from the cumulative effects of
the drugs.
Table 6 lists the AEDs of choice in different seizure
types in LGS. Valproic acid and the benzodiazepines
are probably the most effective AEDs used in this syn-
drome (7).
Ketogenic diet The ketogenic diet is an accepted
therapeutic modality for the treatment of intractable
seizures in childhood (130,131). Although the diet
may be helpful in other seizure types, it has primar-
ily been used in the treatment of infantile spasms,
atypical absence seizures, myoclonic seizures, tonic
seizures, and atonic seizures. A medium-chain tri-
glyceride (MCT) regimen may be used instead of the
conventional ketogenic diet (132,133). The MCT
treatment has the advantage of providing more car-
bohydrate and protein, but gastrointestinal side-

Table 6. Antiepileptic drugs of choice in different seizure types in the

Lemwx-Gastaut syndrome
Generalized Atypical
tonic-clonic Tonic Myoclonic absence

Carbamazepine Phenytoin Valproic acid Valproicacid

Phenytoin Carbamazepine Clonazepam Ethosuximide
Valproic acid Valproic acid Steroids Acetazolamide
Phenobarbital Phenobarbital Ketogenic diet Clonazepam
Ketogenic diet
Steroids

] EPILEPSY, VOI_. 1, NO. 4, 1988 191

G. L HOLMES
effects, including cramping and diarrhea, are more
c o m m o n and may preclude the chronic use of MCT.
Corpus callosotomy. Corpus callosotomy may also
be useful in the treatment of patients with LGS (134-
137). Generalized tonic-clonic and atonie seizures
may be significantly reduced in patients undergoing
an anterior two-thirds corpus callosotomy (134). How-
ever, total control of seizures is quite rare following
the procedure, which does carry a risk for morbidity
or mortality (134,136). In addition, patients with
mental retardation do not do as weU as patients with
normal IQ scores (134,136).
Prognosis. The p o o r prognosis in this s y n d r o m e
has been noted by n u m e r o u s authors (42,94,124). Al-
though the natural course of the disorder is for a de-
creasing frequency of atonic, myoclonic, and atypical
absence seizures with increasing age, often there is an
increase in generalized tonic-clonic seizures and an
emergence of partial seizures (125). Only a few
children u n d e r g o remission. Gastaut et al. (121)
found that 80% of patients with the syndrome con-
tinued to have seizures into adulthood, whereas
Schneider and associates (16) reported that approxi-
mately two-thirds of their patients had seizures resis-
tant to AEDs. In a study of 123 patients with LGS
followed for a minimum of 5 years, Kurokawa and co-
workers (42) found that nearly 66% continued to
have seizures.
Mental difficulties tend to increase with the pass-
ing of time. However, a few patients escape mental
retardation despite very frequent seizures and re-
peated episodes of nonconvulsive status epilepticus.
In a series reported by Aicardi (124), 11 of 120
patients had a normal IQ (>90) at the end of follow-
up, and 65 (54%) had an IQ of less than 51. The rela-
tionship between the seizures, the EEG abnormalities,
and the mental deterioration is unclear. The deter-
ioration that accompanies LGS differs from what is
seen with progressive degenerative central nervous
system disorders in that it is self-limited and may
even improve once the active period of the epilepsy is
over. The mechanism of mental deterioration is not
understood (124).
The prognosis of LGS is poor because of the combi-
nation of intractable epilepsy, mental retardation,
and, often, behavioral problems. Very few patients
can eventually live an i n d e p e n d e n t life. Additional
problems stem from the use of high-dosage drug
therapy, which is probably responsible in part for the
marked slowness seen in LGS patients (124). In most
cases of LGS, the course fluctuates between bad
periods, often with nonconvulsive or tonic status and
192 J EPILEPSY, VOL. 1, NO. 4, 1988
diminution of awareness, and good periods, during
which seizures are rare or cease altogether, with the
EEG sometimes normalizing. Such a fluctuating
course makes assessment of therapy extremely diffi-
cult.
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