Epilepsia, 4O(Suppl.

IO):S57-S64, 1999
Lippincott Williams & Wilkins, Philadelphia
0 International League Against Epilepsy

Forced Normalization: Clinical and Therapeutic Relevance

E. S. Krishnamoorthy and M. R. Trimble
Institute of 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 presentation, and some associated clinical findings are given. The main
part of the article is devoted 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 into these phenomena, particularly taking into account such key neurotransmitters as glutamate, dopamine, and GABA. Key Words:
Forced normalization-Alternative
psychoses-Mecha-

The phenomenon of forced normalization and its clinical counterpart, alternative psychoses, has been in the
literature for half a century, although many neurologists
have not come across the concepts embedded within the
terms, and even those who know of the subject often
claim to have seen no clinical cases. The concept is older
than that introduced by Landolt. What Landolt brought to
it was a rather specific scientific approach and also investigations with the electroencephalogram.
There was a considerable body of literature in the
nineteenth century that suggested an increased association 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 epilepsy 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 manifestation of epilepsy, albeit, a masked one. Here the idea
was that the pattern of the behavior, with its acute onset,
and abrupt offset, with considerable agitation in between,
resembled that of a paroxysm of epilepsy. It was the
German and French authors who wrote most about 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 underwent a change in the early part of this century, with a
number of authors reporting a low frequency of seizures

in patients with schizophrenia and only a few cases in

which epilepsy and schizophrenia were noted to be comorbid conditions. Impressed by these data and by the
differing brain pathologies noted in epilepsy and schizophrenia, von Meduna formulated a hypothesis that in the
former there was hyperfunction of the glial cells,
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 development of convulsive therapy by von Meduna was therefore, logically
based, upon these observations (8).
Landolt, in a series of papers (10-12), described the
results of serial EEG investigations in patients who had
psychotic episodes, some of whom had epilepsy. In defining the EEG during psychotic episodes of epilepsy, he
noted three different types. The first was the postparoxysmal twilight state; this essentially referred to a postictal psychosis. Second, there was the petit ma1 status of
Lennox, essentially nonconvulsive status. It was his third
type, however, that was the most innovative. These were
the productive psychotic episodes with forced normalization in the EEG. Landolt noted:

nisms-Kindling-Neurotransmitters.

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 forced normalisation is the phenomenon characterised by the fact that, with the occurrence

Address correspondence and reprint requests to Dr. M. R. Trimble at

Institute of Neurology, Queen Square, London WClN 3BG, U.K.

s57

S58

E. S. KRISHNAMOORTHY AND M . R. TRIMBLE

of psychotic states, the EEG becomes more normal, or

entirely normal, as compared with previous and subsequent EEG findings.

FORCED NORMALIZATION SINCE THE TIME

OF LANDOLT
It should be emphasized that many of Landolts cases
(but not all) were provoked by the administration of a
new antiepileptic drug (AED). Ethosuximide was recently released, and several patients in his series were
described who developed a forced normalization and
productive psychosis with this drug. Several other series
have been written up over the years (for review see ref.
13), usually involving the precipitation of a psychosis
with the cessation of seizures after either a change in
dose of drug or the initiation of a new drug. It has become apparent that the clinical presentation of forced
normalization is polymorphic. Wolf (14) described one
of the largest series. The psychopathology varied from
paranoid hallucinatory states to anxiety and also to conversion phenomena. The final presenting picture may
well relate to some underlying predisposition. This appears to be borne out to some extent in more recent
studies with new AEDs (see below). The psychoses usually occur in the setting of clear consciousness, and usually can be terminated by an epileptic seizure. In the
older literature there was some debate as to whether or
not ECT is more effective than an endogenous seizure;
the consensus of opinion was that the latter was the more
efficacious.
Forced normalization and its counterpart, alternative
psychosis, so termed by Tellenbach (15) to avoid the
necessity of doing an EEG to define these states, occurs
with both generalized and focal epilepsies, although in
recent years more patients with a focal, particularly a
temporal lobe focus, for their epilepsy have been the
defined population.

MECHANISMS OF FORCED NORMALIZATION

The neurobiological processes that underlie forced
normalization and alternative psychoses of epilepsy are
poorly understood. Knowledge of these mechanisms will
greatly help in understanding the interesting relationship
between epilepsy and behavior, and has potential to influence the treatment of both epilepsy and mental illness.
Wolf ( 16) has proposed several possible mechanisms
of forced normalization. These include a true biologic
antagonism between seizures and psychoses; continuing
epileptic status in the limbic system; propagation of epileptiform discharges along unusual pathways; a role
played by the reticular activating system (RAS) and its
interactions with hippocampal structures; a role of AEDs
in influencing underlying metabolic processes or increasing activation, leading to sleep withdrawal and psychoses; reactions of the healthy parts of the brain against the
Epilepsia, Vol. 40, Suppl. 10, 1999

epileptic focus of illness and the entire psychosocial consequences of that reaction; and inability of patients with
epilepsy to adjust socially to the sudden loss. Wolfs own
view appears to be that in paradoxical normalization (the
term he prefers) the epilepsy is still active but subcortical
and restricted and, at the same time, inhibitory processes
are active. The latter lead to insomnia, hypervigilance,
and dysphoria. At this point the psychosis is impending,
but its development depends on several other factors,
including the risk factors for psychosis, past psychotic
experiences, premorbid personality, social competence,
and the general life situation of the patient.

THE KINDLING PARADIGM

The phenomenon of kindling was discovered by
Alonso-DeFlorida and Delgado (17) but was first systematically investigated by Goddard et al. (18). It was
observed that repeated (daily) brief, high-frequency
trains of electrical pulses to limbic and cortical areas
produce a change in response to the stimulus, such that
the latter elicits a motor convulsion that outlasts the
stimulus train. Thus, when a current of low amplitude but
high pulse frequency is applied to the amygdala, a region
of great susceptibility, there is a gradual stepwise progression of behavioral and EEG responses that finally
culminate in a full motor seizure. The convulsive sensitization is long-lasting and sufficient limbic stimulation
can result in the creation of a spontaneous seizure disorder. The phenomenon has been demonstrated in a wide
range of species, including primates, and has become a
major experimental model for epilepsy ( 1 9,20). Because
the mechanism involves the spread of seizure activity
from the site of stimulation to other areas of the central
nervous system, it is a potential mechanism to explain
the evolution of psychosis in patients with epilepsy.

EXPERIMENTAL MODELS
Electrical kindling
Kindling results in a progressive behavioral sequence
that follows the EEG changes. This behavioral sequence
is remarkably species-specific and replicable and includes behavioral arrest or relapses, repetitive stereotyped automatic movements, and the development of
tonic-clonic movements until a full tonic-clonic seizure
occurs. A discrete gradient of neural susceptibility exists
within parts of the limbic system, i.e., the amygdala,
pyriform cortex, and olfactory bulb providing the most
robust response, neocortical areas requiring higher afterdischarges to provoke a response, and areas of the posterior neocortex appear impervious to kindling. In general, the cerebral cortex is far more resistant than limbic
areas (18,2 1,22).
An important finding is that excitation of the contralateral amygdala follows the kindling of the amygdala on

FORCED NORMALIZATION

one side. Fewer stimuli are therefore required to kindle

structures on the contralateral side (21,22). 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 development persists even after the secondary focus has been
ablated.

Pharmacologic kindling
A number of pharmacologic compounds have been
shown to produce behavioral responses, all of which cannot be explained on the basis of their documented pharmacologic effects. The propensity of amphetamines to
produce chronic effects on behavior, particularly paranoid psychoses, is well known. It has also been reported
that even after a long abstinence, amphetamine users
experience reactivation of paranoid ideation with exposure to the drug. (25)
Post and co-workers (26,27) have shown that a number of behavioral responses and an increased susceptibility to convulsions can be produced in animals with the
administration of cocaine and lidocaine (a nonstimulant
local anesthetic with no amine potentiation). They have
also shown that selective activation of the limbic structures 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 electrical kindling that terminates in a motor seizure (19).
Another finding in these experimental models has
been that a degree of behavioral sensitization and conditioning exists. Post and co-workers (26,28) have shown
that repeated administration of dopamine agonists and
stimulants in small doses produces an increasing behavioral response, which might last for weeks and on occasion becomes relatively permanent. Furthermore, it has
been shown that the response is conditionable and can be
replicated with saline administration in a sensitized animal. A certain degree of cross-sensitization is also
known to occur, 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 systems 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 behavioral sensitization may well be a useful model to understand the development of psychosis in human epilepsy.
Both electrical and pharmacologic kindling have been

s59

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 frequently cited study in this regard is that of Stevens and
Livermore (30), who developed an interesting model for
psychosis using electrical and pharmacologic means. 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 (VTA). Thus, an injection of a GABA antagonist (bicuculline) into the substantia nigra and ventral tegmental area of cats did not
lead to a motor convulsion end point but a number of the
animals showed a behavioral kindled response. Previously docile and friendly animals became fearful and
withdrawn and showed waxy flexibility and hiding behavior. Stevens and Livermore then proceded to electrically 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 characteristic behavioral response as described earlier. However,
two cats with prior 6-hydroxydopamine lesions of the
catecholaminergic pathways did not develop this behavioral change in response to local bicuculline or daily
electrical stimulation of the VTA but demonstrated pronounced afterdischarges or EEG spike propagation during the kindling 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 authors also noted during these experiments that apomorphine 1 mgkg given before the behavioral kindling produced a characteristic responsemarked fear, searching, hiding, and stereotyped lateral
head moyements unaccompanied by an EEG change. On
the other hand, after kindling, a smaller dose of apomorphine produced a similar behavioral response accompanied 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 dopamine receptors
associated with behavioral kindling. Arguably, the most
interesting finding with respect to the antagonism between epilepsy and behavior in this study was that they
demonstrated the seizure-inhibiting role of the catecholaminergic 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 expression. On the other hand, an increase in seizure exEpileusia, Vol. 40, Suppl. 10, 1999

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E. S. KRISHNAMOORTHY AND M . R. TRIMBLE

pression would indicate a reduction in CA and a waning

of psychosis ( 19).
Sat0 and colleagues, in a series of experiments, have
devised elegant experimental models to tease out complex relationships between seizures and psychosis. Sat0
et al. (31) compared groups of cats and determined their
susceptibility to amygdaloid kindling. In their experimental group were animals that were pretreated with
dopamine agonists, cocaine and apomorphine, which
showed the characteristic behavioral responses of stereotypy and catalepsy. They then divided this group into
two, those that received haloperidol and those that received no other medication. The control group did not
receive any pretreatment. It was found that the untreated
control group required about 20 stimulations before convulsions resulted. On the other hand, animals in the experimental group that received pretreatment with both
dopamine agonists and haloperidol, needed only 10
stimulations, and the group that received pretreatment
with agonists but not haloperidol, required 40 stimulations before they progressed to a convulsion. These findings suggest that the progress of amygdaloid kindling to
a generalized seizure can be suppressed by the dopamine
receptor agonism brought about by pretreatment with
cocaine and amphetamine (dopamine agonists) and facilitated by dopamine receptor antagonism induced by
neuroleptics (haloperidol). These findings, taken with the
other data, also suggest that there are clear differences
between the mechanisms of electrical kindling and those
of pharmacologic kindling, and provide evidence to further the theory that whereas the end point of the former
is a convulsion, the latter may be behavioral responses.
In another experiment (32), five groups of cats had
amygdaloid kindling induced by daily electrical stimulation in the left amygdala. The five groups were a
chronic cocaine pretreatment group, a chronic methamphetamine (MAP) pretreatment group, two treatment
groups, one with pimozide and the other with haloperidol
given during the period of kindling, and a drug-free control group. The number of stimulations required for the
development of convulsions was significantly greater in
the two chronic pretreatment groups and significantly
less in the two treatment groups compared to the control
group. All animals in the chronic cocaine and MAP pretreatment groups developed hemiconvulsions instead of
symmetrical generalized convulsions and lateralized interictal discharges in the stimulated hemisphere. On rekindling to the right amygdala, seizure development was
significantly suppressed compared to the control group.
In the two chronic pretreatment groups, chronic administration of cocaine or MAP was followed by enhancement of behavioral responses to cocaine, MAP, and apomorphine. The authors postulated that the association of
such sensitization with impairment of the electrical kindling process suggests that dopamine receptor sensitivity

is an important factor in these responses. In what was

probably the most interesting report in this series (33),
Sat0 and colleagues pretreated all the animals in the experimental group with MAP and then subjected them to
amygdaloid kindling while leaving the controls untouched except for retests. The experimental groups received a standardized dose of MAP, and after a period of
30 min while they were showing maximal stereotypy
were subjected to amygdala kindling. If they failed to
progress to a convulsion, the effect of pimozide was
examined. A dose of the neuroleptic was administered
150 min before receiving further MAP and the amygdala
was stimulated 30 min later. It was found that an enhancement of the behavioral response to MAP could be
elicited in the kindled group but not in controls. Stereotypic behavioral responses were also significantly augmented 3 days after reaching the kindling end point (persisting until day 10) compared to the response before
kindling. Autonomic manifestations to MAP were also
more common in the kindled group. Perhaps the most
significant finding was that after the administration of a
standardized dose of MAP, followed by kindling after 30
min, four of the six cats failed to produce a generalized
convulsion. However, with the administration of pimozide they all progressed to a generalized convulsion.
These experimental models suggest that the neuroanatomic and neurophysiologic bases of electrically kindled
seizures, pharmacologically kindled seizures, and
kindled behavior differ and that these mechanisms are
antagonistic. Moreover, the expression of electrically
kindled seizures is modified by neurochemicals which
themselves can kindle behavioral changes and which can
inhibit the expression of seizures, a form of antagonism.
For a review of these experimental models see ref. 19.

KINDLING, EPILEPSY, AND

BEHAVIORAL DISORDER
The process of kindling involves the spread of seizure
activity from the site of stimulation to other areas of the
CNS. It has therefore been postulated that it may be a
potential mechanism by which focal epilepsy might lead
to a more generalized effect on behavior and psychosis.
It appears likely that for a kindling effect to lead to a
psychosis, the neuronal activity within an epileptic focus
would have to be similar to the type of stimulus that
normally induces kindling. Both in brains of human beings with intractable epilepsy and in animals in whom
seizures have been induced experimentally, removed
brain tissue has shown evoked depolarization shifts and
burst discharges. It is therefore conceivable that if kindling were a relevant mechanism for epilepsy, recurrent
seizure activity in one area might well spread to other
areas that receive synaptic input from it. Thus neuronal
activity within the epileptic focus may approximate a

FORCED NORMALIZATION

stimulus for the induction of kindling. Some support for

this comes from studies on removed human epileptogenic 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 that receive synaptic input from the epileptic
focus, the development of secondary foci, is called secondary 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, although 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 kindling might lead to secondary epileptogenesis. An alternate mechanism that has been proposed is the phenomenon of long-term potentiation (LTP). LTP is the enhancement 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 postsynaptic neurons respond to other stimuli normally (for review see ref. 37). The development of secondary epileptogenesis 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 development of secondary epileptogenesis, there is some evidence 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 explain 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 experimental models discussed earlier that dopamine agonists reduce epileptiform activity and exacerbate behavioral disorder, whereas dopamine antagonists increase epileptiform activity but reduce the latter. Various studies have

S61

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 behavioral 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 psychosis 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 cortical inhibition, demonstrated as hypometabolism in PET
studies of psychosis and epilepsy with psychosis.
It is possible to envision a role for secondary epileptogenesis in the development of psychopathology in patients 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 expression may then predominate (40).

NEUROTRANSMITTERS AND
FORCED NORMALIZATION
When one considers various neurobiological substrates that may mediate an antagonistic relationship between seizures and behavior, leading to forced normalization 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 considerations. Although some evidence is available from human studies (for review see ref. 42), most of the evidence
on the CNS changes it produces comes from animal studies using ECS.When the data are collated, however, the
possibility of an antagonistic relationship at the level of
the substrate between seizures and psychopathology becomes 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 epilepsy. Dopamine, glutamate, and GABA are clearly important.
Dopamine is an obvious candidate and has been linked
Epilepsiu, Vol. 40, Suppl. 10, I999

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E. S. KRISHNAMOORTHY AND M. R. TRIMBLE

TABLE 1. Relationship between seizures and psychosis

Neurotransmitter

Seizures

Psychosis

Tentative
relationship

Dopamine
Glutamate
Peptides
Norepinephrine
Serotonin
GABA

Anticonvulsant
Proconvulsant
Unclear
Unclear
?Proconvulsant
Anticonvulsant

Propsychotic
?Antipsychotic
Unclear
Unclear
?Propsychotic
Propsychotic

Antagonism
Antagonism
Unclear
Unclear
Unclear
Antagonism

with the development of psychosis for many years.

Trimble (43) pointed out that antipsychotics are dopamine antagonists but are known to provoke seizures. On
the other hand, dopamine 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 dopamine may have a significant role in mediating forced
normalization. It has been postulated that enhanced glutaminergic excitation is a potential epileptogenic mechanism, particularly with respect to the role of the Nmethyl-D-aspartate glutamate (NMDA) receptor (44).
Both electrical kindling and LTP appear to involve activation of the excitatory amino acid (probably glutaminergic) pathways involving NMDA receptors. In schizophrenia, on the other hand, an endogenous antagonist at
the NMDA receptor, N-acetyl-aspartyl-glutamate, appears 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 schizophrenia. Presynaptic D, receptors on corticostriatal and limbic glutaminergic terminals provide a negative regulation
of glutamate release. Neuroleptic blockade of these presynaptic 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 models of epilepsy, these changes are complex and often subtle (44). Interestingly, AEDs that increase GABA levels are associated with the development
of a psychopathologic state in up to 10% of patients,
characterized by mood changes, agitation, and even psychotic 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
Epilepsia, Vol. 40, Suppl. 10, 1999

responsible. Moreover, it has been proposed that a number of antipsychotics and antidepressants exert their
therapeutic effects by weakening GABergic inhibitory
activity or by potentiation of counterbalancing neurotransmission in the brain, and that a mechanism similar
to kindling, leading to long-lasting reduction of GABergic 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 and functional psychoses. Alterations in the balance of glutaminergic and
GABAergic activity may well cause seizures or psychosis to predominate at different times, and dopamine, with
its complex interactions, may well play an important 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 AED therapy. They
are patients who have regular seizures, usually focal, and
usually limbic-related. This population, with a susceptibility in any case to develop psychopathology, also
seems to possess a susceptibility to the Landolt phenomenon (48). More extensive reviews are available elsewhere but, of the newer agents, psychosis and affective
disorder have been reported with most of them. Included
are felbamate, lamotrigine, tiagabine, topiramate, vigabatrin, and zonisamide (46).
The frequency of the reporting of psychiatric disorder
in these chronic cases varies, perhaps up to 5% for psychosis 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 EEG monitoring. Alternative psychoses, however, are clearly described. In the series described by Thomas et al. (49), of a group of patients who
developed psychosis as a treatment-emergent effect of
vigabatrin, 64% of the population became seizure-free.
Of these, most had total suppression 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.

FORCED NORMALIZ4TION

A further problem to be resolved is the differences

between prescribing these drugs in monotherapy as opposed 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 being diagnosed clinically is the absence of clear, agreedon diagnostic criteria. Therefore, with the exception of
the pioneering studies of Landolt, research into this phenomenon 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 expression of forced normalization, a variant, or is it unrelated? Should this condition be considered only when
there is a clinical presentation with psychotic symptoms,
or is alternative psychoses a ubiquitous term to describe 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, alternative 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 represents 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 alternative expressions of CNS dysfunction, behavioral
disorders becoming paramount. We are beginning to
identify some groups of patients who may be more susceptible to this. These are patients with chronic epilepsy,
probably but certainly not exclusively focal epilepsy at a

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TABLE 2. Proposed criteria for forced normalization

Primary (essential) criteria
1. Established diagnosis of epilepsy based on clinical history,
EEG and imaging
2. Presence of a behavioral disturbance of acutelsubacute onset
characterized by one or more of the following:
Psychosis with thought disorder, delusions, 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
Recent change (within 30 days) of pharmacotherapeutic
regimen
Report of similar episodes of seizure cessation and behavioral
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

To make the diagnosis:

Primary criteria I , 2 and 3A
OR
Primary criteria 1, 2, and 3B and one supportive criterion

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 mechanisms of the development of forced normalization, we
have chosen here to concentrate on the fascinating phenomena 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 antagonistic. We have also attempted to show how key neurotransmitters that are associated not only with epilepsy and
functional psychoses but also with AEDS, such as glutamate, 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 heralded by sleep deprivation and be precipitated by a social
crisis (15,16). This helps to bring together the psychological and the neurologic aspects of the Landolt phenomenon into a psychobiologic unit, as indeed Landolt,
Janz, and Tellenbach first suggested. Landolts careful
observations lead us to review many of our existing cliniEpilepsia, Vol. 40, Suppl. 10, 1999

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 epilepsy.

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