forced normalization - clinical and therapeutic relevance

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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

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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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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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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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forced normalization - clinical and therapeutic relevance

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