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102

Section 3

Organic syndromes of schizophrenia: epilepsy and schizophrenia

of schizophrenia through the looking glass

of forced normalization

Ennapadam S. Krishnamoorthy and Seethalakshmi Ramanathan
Facts box

Meduna’s hypothesis that led to the development of
r

electroconvulsive therapy (ECT). In this chapter, we
Landolt described Forced Normalization
review the phenomenon of FN and its current clini-

(FN) as “the phenomenon characterized by
cal relevance. We explore the modern understanding
the fact that, with the occurrence of
of putative neurobiological mechanisms that may play
psychotic states, the EEG becomes more
a role in the development of FN and the alternative
normal or entirely normal, as compared with
psychosis of epilepsy. Finally, we discuss the lessons
previous and subsequent EEG findings.”

learned and their implications for our understanding
r
The terms “paradoxical normalization” and
of the psychotic process.

“relative normalization” have been suggested
for this phenomenon.

r

Forced normalization in epilepsy –

Although Landolt reported it to be common
in psychosis of epilepsy, subsequent
evolution of a concept

investigators have reported much lower
The biological antagonism between epilepsy and psy-figures.

chopathology has been known since the nineteenth
r
The pathophysiology of FN is incompletely
century. An increased association between epilepsy
understood and various mechanisms
and psychiatric disorders, observed in this time, led
involving kindling, active inhibition,
to the suggestion that an acute onset of a psychi-alternative propagation of epileptic
atric illness could be a form of epilepsy. Terms such
discharge, neurotransmitters (dopamine,
as epileptic equivalents, larval epilepsy, and trans-gamma-aminobutryric acid [GABA],
formed epilepsy appeared in the European litera-glutamate, adenosine, opioids, and so on),
ture referring largely to the acute onset of behav-apoptosis, and vascular dysfunction have
ioral problems resembling paroxysmal episodes of
been suggested.

seizures. In the early part of the twentieth cen-r
FN offers a good model to understand the
tury, however, a conceptual change occurred with
antagonism between epilepsy and psychosis.

authors reporting a decreased incidence of comorbid epilepsy and schizophrenia
[1].
Von Meduna
[2]

suggested that whereas epilepsy was characterized by

hyperfunctioning glial cells, schizophrenia was char-Nearly a century after its conceptualization, the etiol-acterized by hypofunction. Based on the hypothe-ogy of schizophrenia continues to remain elusive. An
sis of biological antagonism between seizures and
important reason for this uncertainty is our inability
schizophrenia, Von Meduna developed convulsive
to predict the potential development of schizophre-therapy. Although it was probably theoretically flawed,
nia in an individual before the clinical onset of the
Von Meduna’s treatment went on to witness consider-illness. Induced psychotic disorders are one way of
able success and continued evolution.

understanding neural mechanisms that play a role in
Nearly half a century later, in 1953, Heinrich Lan-the development of schizophrenia. Of these, the phe-dolt
[3]
observed and described the clinical and elec-nomenon of FN in epilepsy is of particular interest,
trophysiological phenomenon of seizures and psy-in that it indicates a possible antagonism between the
chopathology presenting alternately in certain cases.

103

epileptic and psychotic processes, in line with von
Landolt noted three different types of psychotic
Organic Syndromes of Schizophrenia – Section 3

states associated with epilepsy: a postparoxysmal twi-form to manifest the phenomenon. The severity and
light state of postictal psychosis; the nonconvulsive
intractability of the seizure disorder and laterality of
ictal states; and finally, productive psychotic episodes
seizure focus have also been discussed as being pos-with forced normalization on electroencephalograph
sibly contributory. It has been suggested that follow-

(EEG). Based on the observation of 107 patients with
ing temporal lobectomy, psychosis is more common
epilepsy and psychoses over 10 years, Landolt noted
with left-sided pathology than following right-sided
that 47 (44%) of these patients demonstrated “forced
lobectomy
[9].

normalization” (forcierte Normalisierung)
[4].

As mentioned earlier, in Landolt’s series of FN

Landolt concluded that FN is “the phenomenon
[4],
several of the patients were on a newly intro-characterized by the fact that, with the occurrence of
duced AED, ethosuximide. Since then, FN has been
psychotic states, the EEG becomes more normal or
reported with nearly all AEDs: phenytoin, primi-entirely normal, as compared with previous and subse-done, valproate, carbamazepine, felbamate, vigaba-quent EEG findings.” FN, as described by Landolt
[4],

trin, lamotrigine, tiagabine, topiramate, zonisamide,
was therefore an electrophysiological phenomenon
and levetiracetam. Indeed, it is striking to note that
with the EEG at its helm. Tellenbach’s
[5]
description
FN has, so far, not been reported with those drugs
of “alternative psychosis” or the reciprocal relationship
that do not really have significant antiepileptic effi-between abnormal mental states and seizures differed
cacy. Antiepileptic agents such as gabapentin are a
from Landolt’s in its clinical rather than EEG descrip-case in point. Polytherapy, rapidity of drug introduction. Subsequently, this concept was refined by Wolf
tion, and total dose prescribed appear to play a role,
[6]
, who suggested that the term “paradoxical normal-although the impact of drug type and its mechanism
ization” was more appropriate and closer to what Lan-of action remain unclear. The phenomenon has also
dolt intended, wherein both epileptic processes – sub-been described following temporal lobectomy
[9, 10]

cortical and restricted – and inhibitory processes are
and vagus nerve stimulation
[11].

active at the same time.

One of the largest series of FN has been described
by Wolf
[8]
. He observed that the psychopathology
Forced normalization – clinical

could vary from hallucinations to severe anxiety and in
features and diagnosis

some cases conversion disorder. The psychiatric phenomena of FN generally follow a trait phenomenon
with similar symptoms occurring with every episode
Clinical description

of FN. However, with repeated episodes of FN, the
Landolt reported that 44% of people with psychoses of
clinical presentation can vary. A recent case report
epilepsy manifest FN, suggesting a reasonably frequent
[12]
discusses the longitudinal course of a woman
phenomenon. Other authors
[1]
have reported lower
with complex partial seizures who presented serially
frequencies of FN with no study that has screened for
with psychosis, depression, and later, pseudoseizures
the phenomenon failing to identify cases. FN occurs
all occurring in the context of FN.

following rapid control of seizures often with a novel
Alternative psychosis is characterized by cloud-antiepileptic drug (AED). Indeed, the first series of
ing of consciousness and a pleomorphic presentation
cases described by Landolt became manifest with the
including persecutory, grandiose, referential, somatic,
availability and utilization of ethosuximide, then a
and religious delusions, catatonia, hallucinations, and
novel AED. Even today, drugs that have powerful
affective symptoms, with a rather variable course.

antiepileptic properties and switch off seizures appear
Dramatic presentations of psychopathology, including
to provoke FN with normalization of the EEG, topira-self-mutilation and suicidal behavior, have been wit-mate being a good example
[7].

nessed during the course of this alternative psychosis
The psychiatric symptoms in FN occur in clear
(Michael Trimble; personal communication, 2007).

consciousness generally 2 to 3 days following seizure
Further, it is widely acknowledged that psychoses need
cessation. FN usually manifests after a relatively pro-not be the main manifestation of FN, with the term
longed period of epilepsy and an average duration of
“alternative psychoses” being in itself a misnomer.

15.2 years has been suggested
[8].
It has been observed
Indeed, the senior author has encountered depression,
with both generalized and focal epilepsies – temporal
anxiety, and agitation, episodic dyscontrol, and hyste-

104

lobe epilepsy (TLE) perhaps being the most common
ria as part of the FN syndrome. Subclinical syndromes
Chapter 7 – Understanding the pathophysiology of schizophrenia

of FN are also not uncommon in clinical practice and
In order to make the diagnosis of FN, it is necessary to
often manifest with altered behavior and relative nor-identify primary criteria 1, 2, and 3a, or primary crite-malization of the EEG. Very often, the episodes termi-ria 1, 2, and 3b plus one supportive criterion.

nate with a breakthrough clinical seizure followed by
normal behavior.

Putative neurobiological mechanisms

One of the earliest explanations of FN was put forward
Diagnostic criteria

by Wolf
[6].
He suggested that in FN, epileptic pro-Krishnamoorthy and Trimble
[13]
proposed diag-cesses are still active but subcortical and restricted due
nosed criteria for FN and elaborated on these in a sub-to the influence of active inhibitory processes. These
sequent paper
[14].
The quantification of EEG change
inhibitory processes also lead to insomnia, hypervig-proposed the emergence of the concept of “relative
ilance, and dysphoria. These, along with other risk
normalization” and the integration of the FN and alter-factors such as past psychotic experiences, premor-native psychosis concepts differentiate these writings
bid personality, social competence, and general life sit-from previous attempts. These diagnostic criteria are
uations, lead to the development of psychosis. Thus,
reviewed here.

according to Wolf
[6],
continuing epileptic status in
Primary criteria include:

the limbic system; propagation of epileptiform dis-1. Established diagnosis of epilepsy based on clinical
charges along unusual pathways; a possible role of the
history, EEG, and imaging;

reticular activating system (RAS) and its interactions
2. The presence of behavior disturbance and
with hippocampal structures; a role of AEDs in influ-acute/subacute onset characterized by one or
encing underlying metabolic processes or increasing
more of the following:

activation, leading to sleep withdrawal and psychoses;
reactions of the healthy parts of the brain against the
a. Psychosis with thought disorder, delusions,
epileptic focus of illness and the entire psychosocial
hallucinations, and so on;

consequences of that reaction; and inability of patients
b. Significant mood change – hypomania/mania
with epilepsy to adjust socially to the sudden loss lead
or depression;

to FN. Since then a number of possible explanations
c. Anxiety with depersonalization, derealization,
have been put forward.