epilepsy and anxiety
TRANSCRIPT
Epilepsy&
Epilepsy & Behavior 4 (2003) S20–S25
Behavior
www.elsevier.com/locate/yebeh
Epilepsy and anxiety
Blanca Vazquez* and Orrin Devinsky
School of Medicine, New York University, Comprehensive Epilepsy Center, 403 East 34 Street, Fourth Floor, New York, NY, USA
Received 2 October 2003; accepted 2 October 2003
Abstract
Studies in the general population demonstrate that anxiety disorders are associated with impaired quality of life and function.
Available evidence suggests that comorbid anxiety disorders are frequent among patients with epilepsy but that neither the inter-
relationships between them nor the impact of anxiety disorders on functional outcome is well studied. The study and management of
anxiety disorders are further complicated by the occurrence of seizures, the temporal relationship between seizures and anxiety
symptoms/syndromes, and the influence of antiepileptic drugs. Increased recognition of anxiety disorders among patients with
epilepsy and evaluation of the potential impact of these disorders on functional outcome and the beneficial and detrimental effects of
antiepileptic drugs in clinical practice are needed.
� 2003 Published by Elsevier Inc.
Keywords: Epilepsy; Anxiety; Panic; Obsessive–compulsive disorder; Generalized anxiety disorder; Posttraumatic stress disorder; Pharmacological
treatment; Nonpharmacological treatment
1. Introduction
The relationship between anxiety, fear, and epilepsy
was recognized in antiquity. Hughlings Jackson was oneof the first to recognize that fear is part of a seizure itself
rather than a reaction to what was about to occur [1].
Today it is accepted that anxiety disorders represent a
frequent and clinically important comorbid disorder in
epilepsy patients.
This article reviews the relationship between epilepsy
and anxiety disorders, highlighting the risk factors, ep-
idemiology, typical symptomatology, and temporal as-sociation, as well as the possible influence increased
anxiety may have on seizures and their severity. Char-
acteristics of the most commonly encountered anxiety
disorders in this population, including panic disorder,
obsessive–compulsive disorder, generalized anxiety dis-
order, and posttraumatic stress disorder, are addressed.
Finally, pharmacological and nonpharmacological
treatment options are considered.
* Corresponding author.
E-mail address: [email protected] (B. Vazquez).
1525-5050/$ - see front matter � 2003 Published by Elsevier Inc.
doi:10.1016/j.yebeh.2003.10.005
2. Epidemiology of anxiety disorders in epilepsy
Despite many methodological problems, the available
body of evidence strongly suggests that epilepsy patientshave a higher prevalence of anxiety disorders than
controls, in both hospital and community samples [2].
Community studies of epilepsy patients using well-de-
fined diagnostic criteria have estimated the prevalence of
anxiety disorders to be between 14.8 and 25% [3,4].
Similar data were found in studies specifically address-
ing the prevalence of panic disorder in patients with
epilepsy. A history of panic attacks was reported in 21%of patients in France with epilepsy, compared with 3%
of controls [5]. Hospital-based studies also reveal a high
prevalence of anxiety, ranging between 16% [6] and 25%
[7]. In candidates for epilepsy surgery, prevalence rates
between 10.7 and 31.67% have been reported [2,8].
3. Risk factors mediating development of anxiety dis-orders in epilepsy
Many risk factors predisposing to the development of
anxiety disorders, including neurological, pharmaco-
logical, and psychosocial factors, have been identified.
B. Vazquez, O. Devinsky / Epilepsy & Behavior 4 (2003) S20–S25 S21
3.1. Neurological factors
Among all types of epilepsy, temporal lobe epilepsy
(TLE) is most frequently associated with ictal fear [9].
Seizure severity is a significant predictor of anxiety [10].
Both positron emission tomography (PET) and elec-
trophysiological data support the role of the right tem-
poral structures in the pathogenesis of anxiety in
epilepsy [2]. Surgical treatment for epilepsy can increasethe frequency of anxiety disorders, with some patients
developing new-onset anxiety disorders after surgery. In
one study, patients who experienced <75% reduction in
seizures were more likely to develop anxiety disorders
[11]. However, a recent study examined predisposing
factors and compared preoperative and postoperative
psychiatric morbidity in a consecutive series of 70 epi-
lepsy surgery patients, and obtained somewhat differentresults [12]. The most common nonorganic diagnoses
were anxiety and depressive disorders in 36.2% of pa-
tients. Patients with a preoperative history of anxiety
and depressive (AD) disorders or astheno-emotional
(AE) disorders had a significantly higher risk of
postoperative AD disorders (P < 0:01 and P < 0:001,respectively). Laterality, type of resection, histopatho-
logical diagnosis, and outcome were not significantlyrelated to postoperative psychiatric morbidity.
3.2. Pharmacological factors
Changes in neurotransmitters, including norepi-
nephrine, dopamine, and serotonin, and neuroendocrine
substances such as c-aminobutyric acid (GABA), adre-
nocorticotrophic hormone, and neuropeptide Y aretheorized to play a role in the pathogenesis of anxiety in
epilepsy [13].
3.3. Psychosocial factors
Anxiety may result from or be exacerbated by psy-
chological reactions, including reactions to the unpre-
dictable nature of the epilepsy, restrictions on normalliving and activities and resulting low self-esteem, stig-
matization, and social rejection. Another clinically im-
portant question, whether anxiety can worsen seizure
activity, is still poorly understood, although there are
data suggesting that increased levels of stress and anxi-
ety can indeed increase the frequency of seizures [2,14].
4. Temporal relationship between anxiety and epilepsy
The anxiety disorders can be classified according to
the temporal relationship to the ictal event into preictal,
ictal, postictal, and interictal.
Preictal anxiety refers to symptoms preceding the
onset of a seizure, often by hours or days. When these
premonitory symptoms (e.g., anxiety) are stereotypic,they help predict seizure occurrence [15]. Anxiety can
increase in the days prior to the seizure, as measured by
rating scales, in patients with generalized or partial
seizures [16].
Ictal anxiety, presenting as fear, anguish, or appre-
hension, is a simple partial seizure, most often of tem-
poral lobe origin. Among patients with TLE, fear is an
aura in 10–15% with lateral foci and 15–20% with me-dial foci [17,18]. Hallucinations, d�eej�aa vu, depersonal-
ization, and other psychic, autonomic, and simple
partial seizure symptoms are often present [18,19]. If the
ictus evolves into a complex partial seizure, typical oral
or hand automatisms often occur [2]. Ictal fear can also
develop with seizure foci in anterior cingulate, orbito-
frontal, and other limbic regions of cortex [20]. In an
invasive electrode study, ictal fear evolving into a com-plex partial seizure was associated with a field of seizure
spread involving orbitofrontal, anterior cingulate, and
temporolimbic cortices, regardless of whether the seizure
arose in temporal or frontal regions [21].
Patients with ictal fear are more likely than other
partial seizure patients to undergo psychiatric hospital-
ization, develop interictal anxiety, and score higher on
psychopathology rating scales [22–24]. Amygdala pa-thology—neuronal loss/hypofunction and/or recurrent
hyperexcitability—may contribute to increased psycho-
pathology [20,25].
Interictal anxiety presents as feelings of apprehension
or as a manifest clinical anxiety disorder, such as panic
disorder (PD), generalized anxiety disorder (GAD),
obsessive–compulsive disorder (OCD), or posttraumatic
stress disorder (PTSD) [26–28]. These disorders are mostcommon among patients with limbic epilepsy [6,29,30],
but patients with generalized epilepsy are also at in-
creased risk [31,32]. Rare cases of seizure phobia in
epilepsy patients have been described [33].
Postictal anxiety can last hours anddays after a seizure.
5. Panic disorder and epilepsy
DSM-IV [34] defines PD as recurrent, unexpected
panic attacks, which are discrete periods of intense fear
that develop abruptly and reach a peak within 10 min-
utes. In addition, at least 4 of the following 13 symptoms
must be present: palpitations, sweating, trembling,
shortness of breath, sensation of choking, chest pain,
abdominal discomfort, dizziness, derealization, fear ofloss of control, fear of death, paresthesias, chills. The
patient must also have a persistent worry about having
further attacks or be concerned about the consequences
of an attack for at least 1 month after the initial attack.
TLE seizures commonly include affective symptoms,
fear, and autonomic features, including changes in skin
color, blood pressure, and heart rate [35].
Table 1
Clinical differentiation between panic attacks and complex partial seizures
Panic disorder Partial seizures
Consciousness Usually preserved Impaired with evolution to complex partial
Agoraphobia Common Very rare
Duration of attack >5min <120 s
Family history of panic disorder Common Uncommon
AEDs Occasionally helpful Very often helpful
Antidepressants Helpful Rarely worsen seizures
Abnormal sleep-deprived interictal EEG Usually absent Often present
MRI/abnormal temporal lobe Rare, nonspecific Likely
D�eej�aa vu, olfactory hallucinations Very rare >5%
Anticipatory anxiety Common Uncommon
Automatisms Uncommon Common with evolution to complex partial
Age at onset Most often twenties to thirties Any age
Source. Handal et al. [41].
S22 B. Vazquez, O. Devinsky / Epilepsy & Behavior 4 (2003) S20–S25
PD can be misdiagnosed as epilepsy and vice versa,
and both entities can also coexist [27,36]. Both entities
share a complex relationship as evidenced by overlap-
ping symptoms, comorbidity, and a possible common
neurophysiological substrate [37] or underlying limbic
dysfunction [38–40]. The differential diagnosis between
PD and TLE is complex as 12 of 13 PD symptoms can
be present in partial seizures [41]. Typically in PD, theage of onset is between 20 and 30 years, and con-
sciousness is preserved during the attack, which usually
lasts several minutes to several hours. Anticipatory
anxiety, strong family history, and agoraphobia are also
typical. TLE with ictal fear, by contrast, can occur at
any age, consciousness is impaired when events evolve
into complex partial seizures, the attacks usually tend to
be stereotypic in nature, and they last between 30 sec-onds and 2 minutes and are followed by postepisodic
confusion or amnesia related to the entire event. Witness
accounts of motor automatisms, such as repetitive
swallowing, chewing, or hand movements, support the
diagnosis of TLE [42]. An overview of features typical of
PD and TLE is presented in Table 1.
Routine EEG may not reveal epileptiform abnormal-
ities in all TLE patients, with some requiring either pro-longed EEG or video-EEG to help establish the diagnosis
[18,42,43]. MRI can reveal focal lesions that support but
do not establish the diagnosis of partial epilepsy.
6. Other anxiety disorders in epilepsy
6.1. Obsessive–compulsive disorder
In DSM-IV, OCD is characterized by recurrent
obsessions or compulsions that are excessive or unrea-
sonable [34]. Obsessions present as persistent impulses,
thoughts, or images that are intrusive, inappropriate,
and time consuming. Compulsions are repetitive behav-
iors such as checking, ordering, praying, and counting
that the patient feels driven to perform to reduce thedistress and anxiety caused by the obsessions.
OCD is relatively uncommon in epilepsy although
cases are reported [44,45]. OCD symptoms can occur in
different phases of a seizure. Rarely, auras manifest as
forced thinking [46] and ictal compulsive feelings to
walk in a particular direction [47]. A relationship be-
tween OCD and epilepsy remains uncertain.
6.2. Generalized anxiety disorder
GAD is characterized by excessive anxiety and worry
about a number of issues that occur almost daily for at
least 6 months [34]. The patient is unable to control the
worry and experiences at least one out of the following
six somatic symptoms: restlessness, being easily fa-
tigued, diminished concentration, irritability, muscle
tension, and sleep disturbance. Although patients withepilepsy may experience excessive anxiety and worry, a
neurobiological relationship between GAD and epilepsy
is not established.
6.3. Posttraumatic Stress disorder
PTSD occurs in persons who have experienced a
trauma after they experienced, witnessed, or were con-fronted with an event involving actual or threatened
death, serious physical injury, or threat to one�s physicalintegrity [34]. Examples include combat, physical assault,
rape, and disasters (e.g., home fires). Much earlier, the
disorder was recognized as shell shock or war neurosis, as
it was seen most commonly in wartime situations. The
three major elements of PTSD include: (1) reexperiencing
the trauma through dreams or recurrent and intrusivethoughts; (2) emotional numbing such as feeling detached
from others; and (3) symptoms of autonomic hypera-
rousal such as irritability. Two subtypes are specified:
acute, if duration of symptoms is less than 3 months, and
chronic, if symptoms last 3 months or longer.
Nonepileptic seizures (NES) are associated with an
increased prevalence of psychological trauma and
PTSD. Bowman [48] found that 40% of the NES sample
B. Vazquez, O. Devinsky / Epilepsy & Behavior 4 (2003) S20–S25 S23
(n ¼ 27) qualified for a diagnosis of a lifetime PTSD,while 88% sustained a severe trauma. Other studies
demonstrated higher prevalences of both lifetime and
current PTSD in NES patients compared with epilepsy
patients [49,50]. Psychological trauma and PTSD should
be routinely screened for in NES patients [50].
7. Anxiety disorders in special populations with epilepsy
7.1. Anxiety disorders in children and adolescents with
epilepsy
Anxiety in pediatric patients is more difficult to rec-
ognize than disorders with more overt behavioral
symptoms. Unless a child presents with symptoms of
school refusal, panic attack, or obsessive–compulsivesymptoms, diagnosis is often delayed or missed. There
are very few epidemiological data specifically addressing
the prevalence of anxiety disorders in children with ep-
ilepsy. The available data are based on small clinical
samples. The rate of significant anxiety was 16% in 44
children and adolescents aged 7–18 years [51]. In an-
other study, the State–Trait Anxiety Inventory was ap-
plied to 35 children and adolescents with epilepsy aged 9to 18 years and 35 children who served as a control
group [52]. The mean trait anxiety score was signifi-
cantly higher in children with epilepsy aged 9 to 11
years, and the mean state anxiety score, and trait anxiety
scores were significantly higher in the age group 12 to 18
years compared with healthy controls. In addition, the
anxiety scores were higher in children on AED poly-
therapy compared with those on monotherapy.
7.2. Anxiety in elderly patients with epilepsy
Anxiety disorders are the most common group of
psychiatric disorders in the elderly, and old age is the
most common time to develop seizures [53]. Unfortu-
nately, little is known about anxiety in elderly patients
with epilepsy. Elderly patients frequently do not meet allthe diagnostic criteria for anxiety disorders, but their
symptoms cause substantial impairment [54]. Finally,
many medical conditions are accompanied by somatic
anxiety symptoms. A range of drugs routinely used in
the elderly (steroids, thyroid hormones, anticholinergic
drugs, and some antidepressants) can also produce so-
matic and psychic symptoms of anxiety.
8. AED- and AED withdrawal-related anxiety
All AEDs may be associated with psychiatric side
effects in individual patients [55]. Based on their phar-
macological profiles, they can be broadly classified into
two groups: the first group has ‘‘sedating’’ effects, such
as fatigue, cognitive slowing, and weight gain, as well aspossible anxiolytic and antimanic effects. A predomi-
nance of GABA-inhibitory neurotransmission induced
by drugs such as barbiturates, benzodiazepines, val-
proate, tiagabine, and vigabatrin is thought to be a
major pharmacological basis for sedating effects. The
second group is ‘‘activating’’ drugs that may reduce
glutamate excitatory neurotransmission (e.g., felbamate
and lamotrigine). These agents cause activation, weightloss, and possibly anxiogenic and antidepressant effects.
Agents such a topiramate, zonisamide, and levetirace-
tam have a mixed profile. Consequently, the mode of
action of AEDs could be reflected in the psychiatric
adverse effects [55]. There are reports of benefits from
various AEDs in anxiety disorders [56]. However, the
AEDs can also produce anxiety as an adverse effect. For
example, felbamate has been associated with reports ofanxiety, especially when acute rapid dosing regimens
(attaining 3600mg/day by the third day) were applied
[57,58]. In some patients, topiramate was also associated
with new onset of anxiety [55].
AED withdrawal can also be associated with the
development of anxiety symptoms. In a prospective study
involving 32 patients with epilepsy, all AED therapy was
gradually tapered off (duration range, 5–45 days) [55].Clinically significant anxiety was reported in 69% of
patients. Patients with ictal anxiety were at particular risk
of developing AED withdrawal-emergent anxiety.
9. Treatment considerations
Currently used pharmacological options for treatinganxiety disorders include several drug classes [59]. Several
selective serotonin reuptake inhibitors (SSRIs) are li-
censed in the United States for treating anxiety disorders.
Sertraline is licensed for the treatment of PD, OCD, and
PTSD, while paroxetine is licensed for PD, OCD, GAD,
and social anxiety disorder (SAD), and fluoxetine for
OCD. However, no studies have specifically addressed
pharmacological treatment of DSM-IV anxiety disordersin patients with epilepsy. The evidence in patients without
epilepsy suggests that SSRIs are effective, well-tolerated,
and safe treatment. Nausea and gastrointestinal upset,
insomnia, drowsiness, and sexual dysfunction are the
most commonly reported adverse events. Paradoxically,
increased anxietymay result from SSRI administration in
some patients [20]. Those prescribing SSRIs should con-
sider potential interactions with AEDs, as SSRIs can in-hibit various CYP450 enzymes and can cause significant
pharmacokinetic interactions with some hepatically me-
tabolized AEDs [2]. Other classes of drugs include the
benzodiazepines clonazepam (licensed for PD) and al-
prazolam (licensed for GAD and PD) and the selective
noradrenergic and serotonergic antidepressant venlafax-
ine (licensed for GAD). All benzodiazepines can cause
S24 B. Vazquez, O. Devinsky / Epilepsy & Behavior 4 (2003) S20–S25
sedation, psychomotor slowing, impaired attention andmemory, aswell as tolerance and addiction. Furthermore,
abrupt discontinuation can cause withdrawal symptoms
and seizures. Venlafaxine has been associated with nau-
sea, nervousness, and hypertension.
Nonpharmacological treatment options include psy-
chotherapeutic approaches such as cognitive-behavioral
therapy, psychoeducational programs, and self-help
groups, but likewise the benefits of such interventionshave been poorly studied.
10. Conclusions
Although anxiety symptoms and disorders are fre-
quently seen in patients with epilepsy, their recognition
and treatment remain suboptimal. Increased awarenessof the clinical presentations of anxiety disorders may
help clinicians provide improved, comprehensive treat-
ments to their patients, thus improving overall outcomes
and quality of life in people with epilepsy.
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