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Epilepsia 4O Suppl.
IO):S57-S64, 1999
Lippincott Williams Wilkins, Philadelphia
nternational
League
Against
Epilepsy
Forced Normalization: Clinical and Therapeutic Relevance
E. S .
Krishnamoorthy and
M. R.
Trimble
Institute o
Neurology,
London United Kingdom
Summary: The phenomenon of forced normalization and its
clinical counterpart, alternative psychoses, is discussed. The
historical origins are briefly noted before the clinical presenta-
tion, and some associated clinical findings are given. The main
part of the article is dev oted to the literature on chemical and
electrical kindling, in an attempt to provide some heuristic
model to understand the antithetical relationship between sei-
zures and behavior disorders. We conclude
that
the use
of
the
kindling model may provide further insights in to these phe-
nomena, particularly taking into account such key neurotrans-
mitters as glutamate, dopamine, and GABA. Key Words:
Forced normalization-A lternative psychoses-Mecha-
nisms-Kindling-Neurotransmitters.
The phenomeno n of forced norm alization and its clini-
cal counterpart, alternative psychoses, has been in the
literature for half a century, although many neurologists
have not com e across the concepts embedd ed within the
terms, and even those who know of the subject often
claim to have se en no clinical cases. The c oncept is older
than that introduced by Landolt. What Landolt brought to
it was a rather specific scientific approach and also in-
vestigations with the electroencephalogram.
There was a considerable body of literature in the
nineteenth century that suggested an increased associa-
tion between epilepsy and psychiatric disorder
(1).
In
that literature, a number of authors noted that the course
of epilepsy could suddenly change and the seizures
somehow be replaced by a behavioral disorder. These
patterns were sometimes referred to as transformed epi-
lepsy or epileptic equivalents. This led to a literature
implying that in some people, even in the absence of a
seizure, an acute behaviour disorder could be a manifes-
tation of epilepsy, albeit,
a
masked one. Here the idea
was that the pattern of the beh avior, with its acute onset,
and abrupt offset, with conside rable agitation in between,
resembled that of a paroxysm of epilepsy. It was the
German and French authors who wrote most ab out this,
particularly by Samt
2 , 3 ) ,
Fairet (4-6), and Morel (7).
The general proposition that there was an increased
association between epilepsy and psychopathology un-
derwent a change in the early part of this century, with a
number of authors reporting a low frequency of seizures
Address correspondence and reprint requests
to
Dr. M. R. Trimble
at
Institute of Neurology, Queen Square, London WClN 3BG, U.K.
in patients with schizophrenia and only a few cases in
which epilepsy and schizophrenia were noted to be co-
morbid conditions. Impressed by these data and by the
differing brain patho logies noted in epilepsy and schizo-
phrenia, von M eduna formulated a hypothesis that in the
former there was hyperfunct ion of the gl ial cel ls ,
whereas in the latter there was hypofunction
8).
He
looked for evidence of an antagonism between the two
disorders, and was encouraged by a report of Nyiro and
Jablonsky
(9),
who noted that the prognosis for epilepsy
was better when it was combined with schizophrenia
than when it presented alone. The developm ent of con-
vulsive therapy by von Meduna was therefore, logically
based, upon these observations 8).
Lando lt, in a series of papers (10-12), describe d the
results of serial EEG investigations in patients who had
psychotic episodes, some of whom had epilepsy.
In
de-
fining the EEG during psychotic episodes of epilepsy, he
noted three different types. The first was the postparox-
ysmal tw ilight state; this essentia lly referred to a postic-
tal psychosis. Second, there was the petit ma1 status of
Lenno x, essentially n oncon vulsive status. It was his third
type, however, that was the most innovative. These were
the productive psychotic episodes with forced normal-
ization in the EEG. Landolt noted:
These cases reveal an unmistakable correlation between
the course of the psychotic process and the changes in the
EEG, in that the EEG focus which
is
active before the
twilight state dissolves during this twilight state, and often
so completely that the record is normalised.
He went on to say f orced normalisation is the phenom-
enon characterised by the fact that, with the occurrence
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FORCED
NORMALIZATION s59
one side. Fewer stimuli are therefore required to kindle
structures on the co ntralateral side (2 1,22 ). Interestingly,
once this transfer effect has occurred, the ability of the
original site to induce a motor seizure after stimulation is
impaired (23,24). This ability to inhibit seizure develop-
ment persists even after the secondary focus has been
ablated.
Pharmacologic kindling
A number of pharmacologic compounds have been
shown to produc e behav ioral responses, all of which can-
not be explained on the basis of their documented phar-
macologic effects. The propensity of amphetamines to
produce chronic effects on behavior, particularly para-
noid psychoses, is well known. It has also been reported
that even after a long abstinence, amphetamine users
experience reactivation of paranoid ideation with expo-
sure to the drug. (25)
Post and co-workers (26,27) have shown that a num-
ber of behavioral responses and an increased suscepti-
bility to convulsions can be produced in animals with the
administration of cocaine and lidocaine (a no nstimulant
local anesthetic with n o am ine potentiation). They have
also shown that selective activation of the limbic struc-
tures occurs during lidocaine-induced seizures and that
this resembles the limbic activation that occurs during
electrical kindling. It has been postulated that the end
point for pharmacologic kindling may be a particular
form
of affective expression or behavior, unlike electri-
cal kindling that terminates in a motor seizure (19).
Another finding in these experimental models has
been that a degree of behavioral sensitization and con-
ditioning exists. Post and co-workers (2 6,28) have shown
that repeated administration of dopamine agonists and
stimulants in sm all doses produces an increasing behav-
ioral response, which might last for weeks and on occa-
sion becomes relatively permanent. Furthermore, it has
been shown that the response is conditionable and can be
replicated with saline administration in a sensitized ani-
mal. A certain degree of cross-sensitization is also
known to o ccur, to stimulants, to dopamine agonists, and
to stressors such as tail pinch, shock, and starvation (29).
There appears to be a psychological component related
to conditioning of kindled behavior that can be modified
by stress. It has been postulated that dopaminergic sys-
tems and neurohormones have important roles
in
the
modulation of changes (19).
Models of antagonism between seizures
and psychosis
Although electrical kindling has gained acceptance as
a useful model for understanding epilepsy, it has also
been postulated that pharmacologic kindling and behav-
ioral sensitization may well be a useful m odel to under-
stand the development of psychosis in human epilepsy.
Both electrical and pharmacologic kindling have been
used in attempts to develop models of the antagonism
between epilepsy and psychosis that seems to exist, at
least in a proportion of patients. Arguably, the most fre-
quently cited study in this regard is that of Stevens and
Livermore (30), who developed an interesting model for
psychosis using electrical and pharmacologic mean s. The
working hypothesis was that dopamine release
in
the
striatum was regulated by presynaptic and postsynaptic
receptors in the caudate nucleus and nucleus accumbens
and by y aminobutyric acid (GABA) in the substantia
nigra and ventral tegmental area (VT A). Thus, an injec-
tion of a GABA antagonist (bicuculline) into the sub-
stantia nigra and ventral tegmental area of cats did not
lead to a motor convulsion end point but a n umber of the
animals showed a behavioral k indled response. Previ-
ously docile and friendly animals became fearful and
withdrawn and showed waxy flexibility and hiding be-
havior. Stevens and Livermore then proceded to electri-
cally stimulate the VTA and found that although the
motor response was brief and limited to the period
of
stimulation, the animals tended to develop the character-
istic behavioral response as described earlier. However,
two cats with prior 6-hydroxydopamine lesions of the
catecholaminergic pathways did not develop this behav-
ioral change in response to local bicuculline or daily
electrical stimulation of the VTA but demonstrated pro-
nounced afterdischarges or EEG spike propagation dur-
ing the k indling procedure.
Two weeks after completion of kindling, the animals
were given haloperidol, pimozide, GABA, and 6-OHDA .
Only haloperidol and pimozide administration resulted in
a significant decrease of isolating and fearful behavior,
the other two drugs having little or no effect on behavior
or the EEG . The au thors also noted during these experi-
ments that apomorphine 1 mgkg given before the be-
havioral kindling produced a characteristic response-
marked fear, searching, hiding, and stereotyped lateral
head moyem ents unaccompanied by an EEG change. On
the other hand, after kindling, a sm aller dose of apomor-
phine produced a similar behavioral response accompa-
nied by striking high-voltage spindled activity in the
nucleus accumbens on the kindled side and contralateral
circling. This they interpreted as indirect evidence of
altered postsynaptic function in the dopam ine receptors
associated with behavioral kindling. Arguably, the most
interesting finding with respect to the antagonism be-
tween epilepsy and behavior in this study was that they
demonstrated the seizure-inhibiting role of the catechol-
aminergic system, which is opposite to the convulsant
effects of dopamine-blocking neuroleptics.
It can therefore be postulated that stimulation
of
the
CA system would be consistent with a clinical state
of
exacerbation of psychosis and reduction of seizure ex-
pression. On the other hand, an increase
in
seizure ex-
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FORCED
NORMALIZATION S61
stimulus for the induction of kindling. Some support for
this comes from studies on removed human epilepto-
genic tissue in which GABA and excitatory amino acid
(EAA) receptor changes have been found (34).
Kindling secondary epileptogenesis and psychoses
The development of epileptiform activity in areas of
the
CNS
hat receive synaptic input from the epileptic
focus, the development of secondary foci, is called sec-
ondary epileptogenesis. Although this phenomenon
could explain the development of psychopathology in
epilepsy, its very existence has remained controversial.
The presence of secondary foci in many patients, al-
though a clear-cut primary focus like a tumor exists, and
the development of secondary and bilateral foci years
after the primary focus was first detected support its
occurrence 35,36) .
There is no convincing hypothesis to explain how kin-
dling might lead to secondary epileptogenesis. An alter-
nate mechanism that has been proposed is the phenom-
enon of long-term potentiation (LTP). LTP is the en-
hancement of synaptic activity after high-frequency
stimulation of an afferent pathway. The enhancement of
synaptic efficacy is specific to the input that has been
tetanized (it is homosynaptic), and therefore the postsyn-
aptic neurons respond to other stimuli normally (for re-
view see ref. 37). The development of secondary epilep-
togenesis through the kindling process, using LTP
mechanisms, is, however, based on the assumptions that
(a) the high-frequency stimulus used in LTP is similar to
the epileptiform activity in the primary focus and (b)
only synapses that have been repeatedly activated as a
result of epileptiform activity
in
the primary focus should
be affected (34).It is noteworthy that during the kindling
process a secondary focus often develops contralateral to
the primary focus and that this is consistent with the
aforementioned hypothesis.
Although LTP is a possible explanation for the devel-
opment of secondary epileptogenesis, there is some evi-
dence against the LTP hypothesis (for review see ref.
38). Moreover, there are other mechanisms that do not
involve change in synaptic efficacy, e.g., the modulation
of intrinsic membrane properties (39j, that may also ex-
plain the transmission of epileptiform activity to other
parts of the CNS.
Although secondary epileptogenesis may develop
through the kindling process, through LTP, or other
means, to be of relevance to the forced normalization
issue we must have evidence to show that it leads to the
neurochemical changes associated with psychosis.
It has been repeatedly demonstrated in the experimen-
tal models discussed earlier that dopamine agonists re-
duce epileptiform activity and exacerbate behavioral dis-
order, whereas dopamine antagonists increase epilepti-
form activity but reduce the latter. Various studies have
demonstrated abnormalities in interictal behaviour in
kindled animals. Stevens and Livermore
(301,
in their
frequently cited study discussed in some detail earlier,
demonstrated that kindling of the VTA in cats produced
electrophysiologic change that correlated with behavior-
al change. They postulated that because stimulation of
the VTA resulted
in
increased dopamine release
in
the
limbic system and neocortex, kindling in the VTA might
result in potentiation of dopamine transmission. If psy-
chosis in patients with epilepsy, at least to a significant
extent, were a manifestation of enhanced dopamine
transmission, then spread of seizure activity to the VTA
may well explain the development of psychosis through
secondary epileptogenesis. It has also been suggested
that increased dopamine interictally may result
in
corti-
cal inhibition, demonstrated as hypometabolism in PET
studies of psychosis and epilepsy with psychosis.
It is possible to envision a role for secondary epilep-
togenesis in the development of psychopathology in pa-
tients with epilepsy. If a new site of epileptic activity
were to develop distant to the original focus that led to
seizure expression, and if that site was one in which
seizures were poorly expressed, this may well lead to
inhibition of epileptic activity in the primary focus (as
has been demonstrated in kindling) and a behavioral ex-
pression may then predominate (40).
NEUROTRANSMITTERS AND
FORCED NORMALIZATION
When one considers various neurobiological sub-
strates that may mediate an antagonistic relationship be-
tween seizures and behavior, leading to forced normal-
ization and alternative psychoses, neurotransmitters
known to have a role in the two processes (seizures and
mental disorders) emerge as the most likely candidates.
Much of the evidence in this regard has emerged from
animal studies of kindling and electroconvulsive seizures
(ECSj (for review see ref. 41).
ECT
(the presumed
equivalent of ECS in humans) may well give us some
anique insights into this biologic antagonism. However,
its use in research is limited by complex ethical consid-
erations. Although some evidence is available from hu-
man studies (for review see ref. 42), most of the evidence
on the
CNS
hanges it produces comes from animal stud-
ies using
ECS
When the data are collated, however, the
possibility of an antagonistic relationship at the level of
the substrate between seizures and psychopathology be-
comes perceptible.
It is apparent that some neurotransmitters are more
likely than others to play
in
role in the development of
forced normalization and alternative psychoses of epi-
lepsy. Dopamine, glutamate, and GABA are clearly im-
portant.
Dopamine is an obvious candidate and has been linked
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S62
E.
S.
KRISHNAMOORTHY AND M . R . TRIMBLE
TABLE
1. Relationship between
seizures
and psychosis
Tentative
Neurotransmitter Seizure s Psych osis relationship
Dopa min e Anticonvulsant Propsychotic
Antagonism
Glutamate
Proconvulsant ?Antipsychotic
Antagonism
Peptides Unclear
Unclear Unclear
Norepinephrine Unclear Unclear
Unclear
Serotonin
?Proconvulsant ?Propsychotic
Unclear
GABA Anticonvulsant Propsychotic
Antagonism
with the development of psychosis for many years.
Trimble (43) pointed out that antipsychotics are dopa-
mine antagonists but are known to provoke seizures. On
the other hand, dopam ine agonists increase the intensity
of psychotic symptoms or can precipitate a psychosis.
We discussed earlier the phenomenon of pharmacologic
kindling and the role played by the catecholaminergic
system. There, too, this antagonism between seizures and
psychosis mediated by the catacholaminergic pathways
was apparent. It can therefore be postulated that dopa-
mine may have a significant role in mediating forced
normalization. It has been postulated that enhanced glu-
taminergic excitation is a po tential epileptogenic mecha-
nism, particularly with respect to the role of the
N -
methyl-D-aspartate glutamate (NMDA) receptor (44).
Both electrical kindling and LTP appear to involve acti-
vation of the excitatory amino acid (probably glutamin-
ergic) pathways involving NMDA receptors. In schizo-
phrenia, on the other hand, an endogen ous antagonist at
the NMDA receptor, N-acetyl-aspartyl-glutamate, ap-
pears to have enhanced activity in the frontal cortex and
hippocampal formation. Interestingly, this hypothesized
dysfunction of glutaminergic transmission interdigitates
with the traditional dopamine hypothesis of schizophre-
nia. Presynap tic D, receptors on corticostriatal and lim-
bic glutaminergic terminals provide a negative regulation
of glutamate release. Neuroleptic blockade of these pre-
synaptic receptors may thereby enhance glutaminergic
input to the caudate and putamen and to other forebrain
regions receiving dopaminergic innervation (45).
Loss of GABA inhibition has been a considered a
potential epileptogenic factor. However, it has become
apparent that modulation of inhibition is a normal brain
mechanism. Therefore, although there appears
to
be an
alteration in functional inhibition in some brain regions
and in some m odels of epilepsy, these changes are com-
plex and often subtle (44). Interestingly, AEDs that in-
crease GABA levels are associated with the developm ent
of a psychopathologic state in up to
10
of patients,
characterized by m ood changes, ag itation, and even psy-
chotic symptoms of a paranoid nature (46). It has been
suggested that when functional psychoses are considered
as a continuum of disorders ranging from schizophrenia
to affective psychoses, the same underlying defect, i.e.,
GABergic
preponderance/glutaminergic
deficit, may be
responsible. Moreover, it has been proposed that a
num-
ber of antipsychotics and antidepressants exert
their
therapeutic effects by weakening GABergic inhibitory
activity or by potentiation of counterbalancing neuro-
transmission in the brain, and that a mechanism similar
to kindling, leading to long-lasting reduction of GABer-
gic inhibition in the brain, may be involved in several
treatments of psychoses (47). Therefore, at the level
of
neurotransmitters, there appears to be an antagonism that
correlates with that between epilepsy an d functiona l psy-
choses. Alterations in the balance of glutaminergic and
GABA ergic activity may w ell cause seizures or psycho-
sis to predominate at different times, and dopamine,
with
its comp lex interactio ns, may well play an imp ortant role
in modulating this mechanism.
THE ROLE OF AEDS IN FORCED
NORMALIZATION
The commonest AED reported
in
the literature has
been ethosuximide, although
it
is reasonable to say
that
almost all AEDs have at some time been anecdotally
reported to provoke these effects. However, some AEDs
may be more relevant than others. Certainly there has
been an upsurge in the reporting of cases of alternative
psychoses and forced normalization in the past decade
with the introduction of new AEDs. These prescriptions
essentially have been given as add-on therapy to patients
who have not responded to standard AE D therapy. They
are patients wh o have reg ular seizures, usually focal, and
usually limbic-related. This population, with a suscepti-
bility in any case to develop psychopathology, also
seems to possess a susceptibility to the Landolt phenom-
enon (48). More extensive reviews are available else-
where but, of the newer agents, psychosis and affective
disorder have been reported with most of them. Included
are felbamate, lamotrigine, tiagabine, topiramate, viga-
batrin, and zonisamide (46).
The frequency of the reporting of psychiatric disorder
in these chronic cases varies, perhaps up to
5
for psy-
chosis and
10-15
for affective disorder. However, the
number of patients in whom a forced normalization is
related
to
this is unclear because most patients are
not
having continuous E EG monitoring. Alternative psycho-
ses, however, are clearly described. In the series de-
scribed by Tho mas et al. (49), of a group of patients who
developed psychosis as a treatment-emergent effect
of
vigaba trin, 64 of the popula tion becam e seizure-free.
Of these, most had total supp ression of seizures, and
in
a
subgroup the psychosis followed suppression of seizures
for a long interval, followed by a cluster of seizures and
a classical postictal psychosis. It is not yet clear if any
particular chemical class of drugs is interlinked with
these problems, although studies to date suggest that
GABergic drugs may be particularly involved.
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FORCED NORMALIZ4TION S6
A further problem to be resolved is the differences
between prescribing these drugs in monotherapy as op-
posed to polytherapy (almost all the cases reported have
been when the drugs have been given as add-on). The
extent to which these problems may occur in patients, for
example, with less severe forms of epilepsy who can be
managed with monotherapy, is unclear.
MAKING
THE
DIAGNOSIS
One of the difficulties that has impeded research into
the Landolt phenomenon and even prevented it from be-
ing diagnosed clinically is the absence of clear, agreed-
on
diagnostic criteria. Therefore, with the exception of
the pioneering studies of Landolt, research into this phe-
nomenon has been confined to retrospective studies at
best and most often to case reports. There are several
problems here. For example, should the EEG necessarily
be completely normal for this diagnosis to be made, or
should relative normalization also be included? What is
the relationship between normalization of the EEG and
suppression of seizures? Is alternative psychosis the ex-
pression of forced normalization, a variant, or is it unre-
lated? Should this condition be considered only when
there is a clinical presentation with psychotic symptoms,
or is alternative psychoses a ubiquitous term to de-
scribe behavioral disorder with normalization of the
EEG? These questions were actually posed by Landolt,
Janz, and Tellenbach, with no clear consensus.
To improve our understanding of this condition and
promote research into it, we suggest a broader approach
with inclusion of cases who show a decrease of seizure
frequency, with both relative and complete normalization
of the EEG. The term alternative psychoses suggested by
Tellenbach is, from the available evidence, a broad term
to include several behavioral disorders, and can present
as, e.g., a delirium, psychotic disorder, affective disorder,
or hysteria (16). In clinical practice, we would like to
suggest that criteria of the kind we propose herein are
applied.
CONCLUSIONS
Forced normalization and its clinical counterpart, al-
ternative psychosis, have been repeatedly observed and
reported by many interested physicians. The sad fact is
that this fascinating phenomenon is often ignored and
remains poorly understood, especially because it repre-
sents one of the many difficulties encountered in treating
patients with epilepsy. Although the goal of treatment is
to render patients seizure-free, there clearly are some
patients in whom seizure control seems to provoke al-
ternative expressions of
CNS
dysfunction, behavioral
disorders becoming paramount. We are beginning to
identify some groups of patients who may be more sus-
ceptible to this. These are patients with chronic epilepsy,
probably but certainly not exclusively focal epilepsy at a
TABLE 2
Proposed criteria
f o r
forced normalization
Primary (essential) criteria
EEG and imaging
characterized by one or more of the following:
1
Established diagnosis of epilepsy based on clinical history,
2 .
Presence of a behavioral disturbance of acutelsubacute onset
Psychosis w ith thought disorder, delusi ons, hallucinations
Significant mood change, hypomanidmania
or
depression
Anxiety with depersonalization, derealization
Hysteria: motor, sensory, abasia
3A. Reduction in the total number of spikes counted in a 60-min
awake EEG recording with a 16-channel machine, using
standard 10 20 electrode placement, by over 50 compared
to a similar recording performed during a normal state of
behavior,
OR
3B. Report of complete cessation of seizures for at least 1 week,
corroborated by a relative or carer
Supportive criteria
regimen
disturbance in the past, from close relative
or
carer, or general
practitioner, or documentation of this in hospital records with
or without EEG evidence. This may
or
may not be linked with
an anticonvulsant drug
Primary criteria I , 2 and 3A
OR
Primary criteria
1, 2,
and 3B and one supportive criterion
Recent change (within 30 days) of pharmacotherapeutic
Report
of
similar episodes of seizure cessation and behavioral
To make the diagnosis:
limbic site, patients with some previous disposition to
develop behavioral problems, and possibly those treated
with drugs with certain chemical actions.
Although we do not clearly understand the mecha-
nisms of the development of forced normalization, we
have chosen here to concentrate
on
the fascinating phe-
nomena of kindling. Although it is true that kindling was
introduced as a biologic model to understand epileptic
seizures, it seems that the CNS changes that accompany
the development of kindling would form a potential
mechanism for the phenomenon of aIternative psychosis
as seen in patients. In particular, we have emphasized the
way that electrical and chemical kindling interact with
each other and how the processes can seem, from the
point of view of behavioral expression, to be antagonis-
tic. We have also attempted to show how key neurotrans-
mitters that are associated not only with epilepsy and
functional psychoses but also with AEDS, such as glu-
tamate, GABA, and dopamine, may be interlinked with
this process.
We have not reviewed the literature on stress-related
changes of such transmitters here. However, clinically
the development of the behavioral disorder may be her-
alded by sleep deprivation and be precipitated by a social
crisis 15,16). This helps to bring together the psycho-
logical and the neurologic aspects of the Landolt phe-
nomenon into a psychobiologic unit, as indeed Landolt,
Janz, and Tellenbach first suggested. Landolts careful
observations lead us to review many of our existing clini-
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S64
E. S. KRISHNAMOORTHY AND
M .
R. TRIMBLE
cal and biologic understandings of epilepsy, which surely
must be mistaken in our present state
of
knowledge and
which perpetually remind us that seizures are not the
same as e pilepsy.
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