- Email: [email protected]
Epilepsy and Anxiety
Epilepsy & Behavior 1, 228 –234 (2000) doi:10.1006/ebeh.2000.0080, available online at http://www.idealibrary.com on
REVIEW Epilepsy and Anxiety Martin Adam Goldstein, M.D.,* ,1 and Cynthia L. Harden, M.D. † *Department of Neurology, New York Hospital–Cornell Medical Center, 525 East 68th Street, New York, New York 10021; and †Department of Neurology and Neuroscience, Weill Medical College, Cornell University, Ithaca, New York Received July 11, 2000; accepted for publication July 12, 2000
There is nothing that man fears more than the touch of the unknown. Elias Canetti There is no terror in a bang, only in the anticipation of it. Alfred Hitchcock
Although the affective and cognitive effects of seizures have long received attention, the anxiety spectrum of psychiatric complications of epilepsy has not been well-studied. Neither purely a mood, thought, or autonomic disorder, anxiety is a unique phenomenon in genesis and expression. Multidisciplinary efforts (neuroanatomy, neurochemistry, neuroendocrine, cognitive neuroscience, functional neuroimaging) are attempting to create a unified neuropsychiatric account of anxiety which, like epilepsy, can be regarded as a model phenomenon in the history of the relationship between neuroscience and mental illness. Comorbid anxiety and epilepsy offers a potentially rich nexus for theoretical and empiric investigation of the neurocircuitry and psychological mechanisms underlying each phenomenon. © 2000 Academic Press Key Words: anxiety; epilepsy; functional neuroanatomy; panic; partial seizure; neuropsychiatry; evolutionary psychology; psychoanalysis.
INTRODUCTION
between epilepsy and anxiety has been less investigated than other psychiatric– epileptic dyads (e.g., affective or cognitive disorders). In this review, anxiety is considered within historical and evolutionary contexts to facilitate conceptual integration of anxiety expression within epilepsy populations.
In the first year after the Decade of the Brain, neurology and psychiatry are accelerating their interdisciplinary rapprochement (1–3). Because of its neurologic basis and psychiatric complications, epilepsy represents a model phenomenon in the history of the relationship between neurology and psychiatry, and interest in the cognitive, affective, and behavioral complications of epilepsy is experiencing a multidisciplinary renewal (4, 5). Anxiety has also been a central focus in both the history of mental illness and current neurobiologic psychiatry (6, 7). Although frequently comorbid, the pathophysiologic relationship
HISTORY OF THE RELATIONSHIP BETWEEN EPILEPSY AND PSYCHIATRY The complicated and enigmatic relationship between epilepsy and psychiatric phenomenology has been observed for thousands of years, starting with Indian Ayurvedic writing (⬎2000 bc) (8). Continuing through ancient Greek and Roman medical literature, Hippocrates made the oft-quoted observation:
1
To whom correspondence should be addressed. E-mail: [email protected].
228
1525-5050/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
229
Epilepsy and Anxiety Melancholics ordinarily become epileptics, and epileptics melancholics: of these two states what determines direction is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy (9).
Although medieval and renaissance improvements in recorded observations of epilepsy included further descriptions of neuropsychiatric complications (8), speculation regarding etiology and treatment devolved into the realm of superstition; for example, in the Malleus Maleficarum, a 15th-century witch-hunter’s handbook, epilepsy was branded a behavioral feature of witches (10). With the advent of “moral treatment” of the mentally ill in the 19th century, larger numbers of patients were available for study, setting the stage for the first actual accounting of the neuropsychiatric aspects of epilepsy by Esquirol and Calmeil in 1824 (11). The beginning of a modern perspective of epilepsy as a condition whose manifestations extend beyond ictal events can be attributed to mid-19th-century French “alienists” whose work focused more on sustained cognitive and behavioral aspects of epilepsy than on solely ictal events (12). In an early collaboration between psychiatry and neurology, their work was expanded by the era’s leading psychiatrists, including Kraepelin and Maudsley. The belief that dementia praecox and epilepsy were commonly associated was supported by Kraepelin, who reported an epilepsy prevalence of 18% in dementia praecox patients (13). However, such collaboration was short-lived, as the upcoming schism between neurology and psychiatry was heralded by the proposal of an epilepsy nosology limited to sensorimotor symptomatology. Prompted by the explanatory power of localizationist theory (as exemplified by Broca’s reports on aphasia), neurologists applied similar principles to the study of seizures (8), culminating in Jackson’s advocacy of a restrictive definition of epilepsy: The word epilepsy should be degraded and be used to imply the condition of nerve tissue in sudden and temporary loss of its function, whether loss of sight, loss of consciousness, or running down of tension in those parts that govern muscles (14).
Although Jackson believed that epilepsy could have behavioral ramifications, he insisted that these be “sudden and temporary” to be considered a component of epilepsy. In 1873, he further distilled his definition: “epilepsy is the name given for occasional, sudden, excessive, rapid and local discharges of gray matter,” (14) a perspective that would not encompass
the views of the alienists, who regarded epilepsy as a “morbius totius substantiae.” Despite the growing division between increasingly biologic neurology and increasingly psychodynamic psychiatry, early 20th-century developments relevant to the neuropsychiatric aspects of epilepsy included Glaus’ 1931 hypothesizing of an antagonism between epilepsy and schizophrenia (15), von Meduna’s initiating the use of convulsive therapy based on the (erroneous) observation that there was a reduced prevalence of schizophrenia in patients with epilepsy (16), the further development of electroconvulsive therapy by Cerletti and Bini in 1938 (17), Landolt’s introduction of the idea of forced normalization (18), and Slater and Beard’s 1963 argument that every symptom described in schizophrenic patients can occur in patients with seizures (19). But, as several recent publications have catalogued, it is the explosion of advancements in the epidemiology, neurochemistry, neuroendocrinology, electrophysiology, and functional neuroimaging of epilepsy populations that has magnified interest in the relationship between epilepsy and psychiatric phenomena. Although affective and thought disorders have received large amounts of attention, anxiety remains a lesser studied psychiatric aspect of epilepsy, despite anxiety’s clinical importance and a corresponding intensification of its study within psychiatry. Why investigate anxiety as an epilepsy-related neuropsychiatric phenomenon?
THE EVOLUTIONARY SIGNIFICANCE OF ANXIETY As epilepsy represents a model phenomenon in the history of the relationship between neurology and psychiatry, anxiety is a model phenomenon in the history of the relationship between mind and brain. Anxiety is the ultimate example of a phenomenon belonging to both psychological and neurophysiologic domains (20). Because of the historical division of study of these domains, there exist artifacts of definitional confusion regarding anxiety resulting from differences between the concepts and methods employed by the psychological and biologic sciences. Common in even current-day neurobiologic and psychiatric theorizing, these artifacts impede synergistic advancement of a unified theory of anxiety. In an effort to counter this, it is worthwhile to consider anxiety within the context of that theoretical glue which Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
230 provides ultimate coherence to all biologic theorizing: evolution. As Hofer observes, of all internal experiences, “anxiety may be the one with the closest parallels in other species and with the most ancient evolutionary heritage” (21). Indeed, anxiety is a predictable product of natural selection, which so depends on danger avoidance capacity that components of the experience we call anxiety have long been integrated into the neurocircuitry of even primitive organisms (21). An evolutionary perspective can facilitate definition of the core meaning of anxiety: a means to detect signals, a way to discriminate those that denote danger, and the capacity to initiate phylogenetically derived and ontogenically learned behavior that results in avoidance of that danger. As evolution progressed, externally directed danger-sensing mechanisms eventually developed the capacity to be directed inward for signaling internal danger as well (20). The competitive survival advantage bestowed by the capacity to anticipate danger, both internal and external, and react on the basis of prior experience nurtured the evolutionary development of relevant cognitive functions (e.g., memory) and their connections via corticolimbic circuits to affective, autonomic, neuroendocrine, and neuroimmune response systems underlying the generation of anxiety (20). The result: anxiety as an emergent neuropsychiatric quality of our evolutionary history. Given anxiety’s evolutionary heritage, it is appropriate that the concept of anxiety as an adaptive reaction to the perception of danger originated with Darwin (Breur and Freud both cite Darwin as the source of their insight that “emotional expression consists of actions which originally had a meaning and served a purpose” (22)). According to Darwin, “If we expect to suffer we are anxious, if we have no hope of relief, we despair” (23). In addition to foreshadowing by a century contemporary interest in a link between anxiety and depressive disorders, this view highlights the relevance of learned helplessness models for interpreting the affective impact of seizure occurrence in an individual patient. Deriving from their evolutionary origins, and their behavioral and experiential qualities, anxiety and fear are closely related concepts, with a history of somewhat arbitrary distinctions. In psychology literature, fear is often defined as a response to a threat that is known, external, definite, or nonconflictual in origin; anxiety is in response to a threat that is unknown, internal, vague, or conflictual in origin. But it is not that clear cut; in fact, the psychodynamic distinction between fear and anxiety arose by accident: Freud’s Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
Goldstein and Harden
early translator mistranslated angst, the German word for “fear,” as “anxiety” (24). Moreover, current interdisciplinary studies investigating the neurobiology of anxiety are based on animal models of the neurocircuitry of fear (25). In sum, the distinction between anxiety and fear remains vague; separation based on the acuteness and definability of the threat continues to operate in the literature.
NOSOLOGY DSM-IV classifies anxiety disorders as a distinct category of axis I disorders (26). Included in this group are generalized anxiety disorder, panic disorder (with and without agoraphobia), posttraumatic stress disorder, and phobias. The class also includes the diagnosis “anxiety disorder due to a medical condition,” applied when anxiety exists as a direct physiologic consequence of another identified pathophysiologic process. Anxiety within epilepsy patients can potentially fall into any of these diagnoses, and varying permutations of anxiety-type combinations can exist within any individual patient.
THEORIES OF PATHOLOGIC ANXIETY Psychodynamic Theory In 1895, Freud theorized in Obsessions and Phobias that the syndrome of “anxiety hysteria” (consisting of conversion symptoms and phobias) had a psychological etiology as a response to the threatened recrudescence of unpleasant emotions linked to unacceptable sexual memories (27). With the publication of Inhibitions, Symptoms, and Anxiety in 1926, Freud formulated a new dual theory of anxiety genesis as secondary to (a) obstruction of libidinal discharge, thereby having a biologic basis, or (b) intrapsychic conflict (e.g., an unacceptable drive or repressed wish pressing for conscious representation and discharge), therefore having a psychological basis (28). As Freud’s “energy”-based theories faded, the fundamental function of anxiety within psychoanalytic theory eventually operationalized as an unconscious warning, known as signal anxiety, which prompts mobilization of ego resources to avert danger. Psychodynamically, anxiety can signify real or imagined threat to personal security, identity, reality-organizing framework, or vital object relations (e.g., crucial relationships) (29). In the post-Freudian pluralistic environment, alternative perspectives em-
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ploy anxiety in different ways to fit each theoretical variation, but all continue to regard anxiety with similar central importance (30).
Learning and Cognitive-behavioral Theory Building on the concepts of Pavlovian conditioning, Watson (considered the father of American behaviorism) believed anxiety was largely explainable as a form of conditioned response (31). By the 1950s, the resemblance between human anxiety and experimentally induced “anxiety” in stressed laboratory animals was recognized, setting the stage for Ellis and Beck’s development of cognitive therapy in the 1960s and 1970s (32, 33). Briefly, the cognitive theory of anxiety posits that faulty, distorted thought patterns contribute to symptom production. Patients with anxiety disorders overestimate the degree of danger and the probability of harm in a given situation while underestimating their abilities to cope with perceived threats (24). Patients with panic disorder can experience thoughts of loss of control and fear of dying that follow physiologic sensations (e.g., palpitations, tachycardia, lightheadedness) (24).
Neurobiologic Theory Multiple neurochemical, neuroanatomic, neuroendocrinologic, and functional neuroimaging efforts are attempting to establish a unified neurobiology of anxiety. These investigations have contributed to the synthesis of anxiety circuitry schematics such as that shown in Fig. 1 (7, 34). As seen in the figure, central to the anxiety model of most theorists is the amygdala, hypothesized to be the key structure integrating interoceptive and exteroceptive stimuli, and distributing processed afferent data to the multiple efferent systems (cortical, limbic, basal ganglia, hypothalamic, brain stem) which produce the autonomic, affective, cognitive, and endocrinologic components of the anxiety response. Seizures, regardless of type and magnitude, represent an acute fundamental disruption to neuropsychiatric homeostasis, thereby necessarily impacting this circuitry. Thus seizures, especially those with limbic involvement, can hijack this system, giving rise to anxiety. Complex mechanisms mediating the connection between seizures and anxiety, including kindling and other neuroplastic processes affecting anxiety/fear circuits, are the targets of intense study.
ANXIETY ASSOCIATED WITH EPILEPSY Like other psychiatric phenomena, anxiety can be related to epilepsy in one or more of the following ways: (a) as an ictal phenomenon (i.e., anxiety as seizure or seizure component): (i) as a simple partial seizure alone, (ii) as an aura component of a complex seizure; (b) as an anticipatory fear associated with an aura heralding a seizure; (c) as an anticipatory fear of having a seizure without premonitory warning; (d) as a secondary neuropsychiatric aftereffect of seizure, i.e., a postictal event; (e) as an interictal manifestation of the same underlying etiologic mechanism as the primary seizure disorder; (f) as an adverse consequence of antiepileptic treatment; (g) as an adverse consequence of intrapsychic maladaption to having epilepsy; (h) as an adverse consequence of social maladaptation to having epilepsy; (i) as an unrelated comorbid primary psychiatric disorder. More broadly categorized, anxiety associated with epilepsy can be divided into ictal and interictal syndromes, with the following characteristics. Ictal Anxiety Seizure activity can produce experiential symptoms and behavioral manifestations that are indistinguishable from a primary anxiety disorder. Fear is a common aura feature, and may at times mimic panic attacks. Among partial seizure patients, fear is reported as an aura in up to 15% of patients (35), and several studies have shown fear to be the most common ictal emotion in patients with epilepsy (36). Young et al. reported five patients with brief simple partial seizures mimicking panic disorder (37). All of these patients had mesial temporal structural lesions associated with intractable epilepsy. Features distinguishing seizures from panic attacks included briefer duration and greater stereotypy (37). Fear and anxiety are common symptoms in electrically induced simple partial seizures (38). Anteromedial temporal seizures and cingulate seizures in particular can cause symptoms varying from mild unease to horror (38). Underscoring the difficulty of distinguishing seiCopyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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FIG. 1.
Functional neuroanatomy of panic/anxiety.
zure-related from non-seizure-related anxiety, Jabourian et al. performed ambulatory EEG monitoring on 150 patients with panic disorder without epilepsy and found Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
that 63.2% demonstrated abnormal EEGs during a 24 hour period. Of these abnormal EEGs, 80% were considered to be epileptiform (39). Important case reports in-
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clude: McNamara and Fogel’s description of five patients with panic disorder refractory to psychotropics who demonstrated temporal lobe EEG abnormalities with good symptom response to anticonvulsant drugs (40), Alemayehu’s report of two cases of panic attacks occurring as ictal manifestations of a parietal lobe focus (41), and Weilberg and co-workers’ description of two patients with focal epileptiform activity on EEG that was temporally related to the development of their panic attacks (42). Toni et al. found a striking overlap in reported psychosensorial symptoms reported by patients with panic disorder–agoraphobia and those with complex partial epilepsy (43). However, as countless other examples in medicine demonstrate, similar phenomenology does not necessarily imply similar pathophysiology: Tokunaga et al. found a very different pattern of benzodiazepine receptor binding potential in anxiety and somatoform disorder subjects compared with epilepsy subjects, suggesting divergent etiologic mechanisms (44). Interictal Anxiety Interictal anxiety is reported in as many as 66% of patients with epilepsy (35). Although most frequently found among patients with partial seizures related to limbic foci, investigators have also observed an increased rate of anxiety symptoms among patients with generalized epilepsy (38). Multiple theories have been proposed to explain interictal anxiety. Two major psychological mechanisms suggested are fear of seizure recurrence (“seizure phobia”) and issues surrounding locus of control, a major concept derived from depression theory. Surprisingly, documented cases of actual seizure phobia are relatively rare (45). In contrast, problems related to a sense of dispersed locus of control can be profound in patients with epilepsy, potentially giving rise to discrete panic attacks or persistent generalized anxiety disorder (46). Connections to learned helplessness models of depression also become relevant. Putative neurobiologic mechanisms underlying a direct connection between seizures and at least some forms of interictal anxiety are multiple and complex, as can easily be appreciated when considering the multiple components of the above neurobiologic pathways that can be impacted by almost any form of epilepsy.
iety. In one study from Brazil in 1993, De Albuquerque and de Campos studied anxiety levels in a population of epilepsy patients versus nonepileptic control subjects using the State–Trait Anxiety Inventory (47, 48). They found higher trait anxiety scores in the epileptic group compared with normal controls. Among epilepsy patients, higher trait anxiety scores were recorded in patients with EEG abnormalities marked by left temporal lobe localization. In addition, the investigators found that briefer duration (less than 2 years) of symptomatic epilepsy was associated with higher anxiety levels (47). Responding to anecdotal case reports and the successful use of electroconvulsive therapy to treat some anxiety disorders (49), Goldstein et al. performed a preliminary study of the relationship between seizure frequency and anxiety. They found the surprisingly counterintuitive result that among adult partial epilepsy patients experiencing persistent breakthrough seizures, relatively high seizure frequency is associated with lower anxiety levels than relatively low seizure frequency (50). A simplified interpretation of these results would return us to Darwin (and Canetti and Hitchcock): Are we seeing that there exists a seizure frequency such that having more seizures actually reduces the anxiety attendant to the anticipation of a seizure? That is, do anxiety-generating neurocircuitry and psychological mechanisms “habituate” to higher seizure frequencies, processing such events as “routine” and thereby making anxiety generation less adaptive? If so, do these mechanisms relate to those underlying learned helplessness?
CONCLUSIONS The neuropsychiatry of epilepsy is an increasingly frequent target for interdisciplinary neuroscientific study. Comorbid anxiety and epilepsy in particular provides a unique window for theoretical and experimental exploration of mechanisms underlying key components of the natural history of each disorder. Finally, epilepsy and anxiety, individually and together, represent model phenomena for the investigation of the interrelationship of mind and brain function.
EMPIRIC EVIDENCE
ACKNOWLEDGMENT
There have been surprisingly few experimental studies of the relationship between seizures and anx-
This work was supported in part by the Ronald F. Coles Fellowship in Neuropsychiatry, Harvard Medical School.
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Glick RA. Freudian and post-Freudian theories of anxiety. In: Roose SP, Glick RA, editors. Anxiety as symptom and signal. London: Analytic Press, 1995: 1–16. Marshall RD, Klein DF. Diagnostic classification of anxiety disorders: historical context and implications for neurobiology. In: Charney DS, Nestler EJ, Bunney BS, editors. Neurobiology of Mental illness. New York: Oxford Univ Press, 1999;437–50. Watson JB. Psychology from the standpoint of a behaviorist. Philadelphia: Lippincott, 1919. Ellis A. Reason and emotion in psychotherapy. Secaucus, NJ: Lyle Stuart, 1962. Beck AT, Emer G, Greenberg RL. Anxiety disorders and phobias: a cognitive perspective. New York: Basic Books, 1985. Davis M. Functional neuroanatomy of anxiety and fear: a focus on the amygdala. In: Charney DS, Nestler EJ, Bunney BS, editors. Neurobiology of mental illness. New York: Oxford Univ Press, 1999: 463–74. Torta R, Keller R. Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications. Epilepsia 1999;40 (Suppl 10):S2–S20. Robertson M, editor. Epilepsy and anxiety. Psychiatric literature, vol 6. New York: Sanofi Winthrop, 1996; 1–15. Young GB, Chandrara PC, Blume WT, McLachlan RS, Munoz, Girvin JP. Mesial temporal lobe seizures presenting as anxiety disorders. J Neuropsychiatry Clin Neurosci 1995;7:352–7. Devinsky O, Vazquez B. Behavioral changes associated with epilepsy. Neurol Clin 1993;11:127– 49. Jabourian AP, Erlich M, Desvignes C, et al. Panic attacks and 24-hour ambulatory EEG monitoring. Ann Med Psychol (Paris) 1992;150:240 – 4. McNamara M, Fogel B. Anticonvulsant responsive panic attacks with temporal lobe EEG abnormalities. J Neuropsychiatry 1990;2:193– 6. Alemayehu S, Bergey G, Barry E, et al. Panic attacks as ictal manifestations of parietal lobe seizures. Epilepsia 1995;36:824 –30. Weilburg J, Schachter S, Sachs G, et al. Focal paroxysmal EEG changes during atypical panic attacks. J Neuropsychiatry 1993; 5:50 –5. Toni C, Casano GB, Peurgi G, et al. Psychosensorial and related phenomena in panic disorder and in temporal lobe epilepsy. Compr Psychiatry 1996;37:125–33. Tokunaga M, Ida I, Higuchi T, Mikuni M. Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-SPECT. Radiat Med 1997;15: 163–9. Newsom DI, Goldstein LH, Fitzpatrick D. Fear of seizures: an investigation and treatment. Seizure 1998;7:101– 6. McConnell HW, Duncan D. Treatment of psychiatric comorbidity in epilepsy. In: McConnell HW, Snyder PJ, editors. Psychiatric comorbidity in epilepsy. Washington, DC: Am Psychiatric Press, 1998: 245–362. De Albuquerque MD, de Campos CJR. Epilepsy and anxiety. Arq Neuropsiquiatr 1993;51:313–18. Spielberger CD. Manual for the state–trait anxiety inventory. Palo Alto: Consultant Psychologist Press, 1983. Schott K, Bartels M, Heimann H, et al. Results of electroconvulsive therapy in restrictive indications. Nervenarzt (Germany) 1992;63(7):422–5. Goldstein MA, Harden CL, Ravdin LD, Nikolov B, Labar D. Does anxiety in epilepsy patients decrease with increasing seizure frequency? Epilepsia 1999;40(Suppl 7):S60 – 61.
REVIEW Epilepsy and Anxiety Martin Adam Goldstein, M.D.,* ,1 and Cynthia L. Harden, M.D. † *Department of Neurology, New York Hospital–Cornell Medical Center, 525 East 68th Street, New York, New York 10021; and †Department of Neurology and Neuroscience, Weill Medical College, Cornell University, Ithaca, New York Received July 11, 2000; accepted for publication July 12, 2000
There is nothing that man fears more than the touch of the unknown. Elias Canetti There is no terror in a bang, only in the anticipation of it. Alfred Hitchcock
Although the affective and cognitive effects of seizures have long received attention, the anxiety spectrum of psychiatric complications of epilepsy has not been well-studied. Neither purely a mood, thought, or autonomic disorder, anxiety is a unique phenomenon in genesis and expression. Multidisciplinary efforts (neuroanatomy, neurochemistry, neuroendocrine, cognitive neuroscience, functional neuroimaging) are attempting to create a unified neuropsychiatric account of anxiety which, like epilepsy, can be regarded as a model phenomenon in the history of the relationship between neuroscience and mental illness. Comorbid anxiety and epilepsy offers a potentially rich nexus for theoretical and empiric investigation of the neurocircuitry and psychological mechanisms underlying each phenomenon. © 2000 Academic Press Key Words: anxiety; epilepsy; functional neuroanatomy; panic; partial seizure; neuropsychiatry; evolutionary psychology; psychoanalysis.
INTRODUCTION
between epilepsy and anxiety has been less investigated than other psychiatric– epileptic dyads (e.g., affective or cognitive disorders). In this review, anxiety is considered within historical and evolutionary contexts to facilitate conceptual integration of anxiety expression within epilepsy populations.
In the first year after the Decade of the Brain, neurology and psychiatry are accelerating their interdisciplinary rapprochement (1–3). Because of its neurologic basis and psychiatric complications, epilepsy represents a model phenomenon in the history of the relationship between neurology and psychiatry, and interest in the cognitive, affective, and behavioral complications of epilepsy is experiencing a multidisciplinary renewal (4, 5). Anxiety has also been a central focus in both the history of mental illness and current neurobiologic psychiatry (6, 7). Although frequently comorbid, the pathophysiologic relationship
HISTORY OF THE RELATIONSHIP BETWEEN EPILEPSY AND PSYCHIATRY The complicated and enigmatic relationship between epilepsy and psychiatric phenomenology has been observed for thousands of years, starting with Indian Ayurvedic writing (⬎2000 bc) (8). Continuing through ancient Greek and Roman medical literature, Hippocrates made the oft-quoted observation:
1
To whom correspondence should be addressed. E-mail: [email protected].
228
1525-5050/00 $35.00 Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
229
Epilepsy and Anxiety Melancholics ordinarily become epileptics, and epileptics melancholics: of these two states what determines direction is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy (9).
Although medieval and renaissance improvements in recorded observations of epilepsy included further descriptions of neuropsychiatric complications (8), speculation regarding etiology and treatment devolved into the realm of superstition; for example, in the Malleus Maleficarum, a 15th-century witch-hunter’s handbook, epilepsy was branded a behavioral feature of witches (10). With the advent of “moral treatment” of the mentally ill in the 19th century, larger numbers of patients were available for study, setting the stage for the first actual accounting of the neuropsychiatric aspects of epilepsy by Esquirol and Calmeil in 1824 (11). The beginning of a modern perspective of epilepsy as a condition whose manifestations extend beyond ictal events can be attributed to mid-19th-century French “alienists” whose work focused more on sustained cognitive and behavioral aspects of epilepsy than on solely ictal events (12). In an early collaboration between psychiatry and neurology, their work was expanded by the era’s leading psychiatrists, including Kraepelin and Maudsley. The belief that dementia praecox and epilepsy were commonly associated was supported by Kraepelin, who reported an epilepsy prevalence of 18% in dementia praecox patients (13). However, such collaboration was short-lived, as the upcoming schism between neurology and psychiatry was heralded by the proposal of an epilepsy nosology limited to sensorimotor symptomatology. Prompted by the explanatory power of localizationist theory (as exemplified by Broca’s reports on aphasia), neurologists applied similar principles to the study of seizures (8), culminating in Jackson’s advocacy of a restrictive definition of epilepsy: The word epilepsy should be degraded and be used to imply the condition of nerve tissue in sudden and temporary loss of its function, whether loss of sight, loss of consciousness, or running down of tension in those parts that govern muscles (14).
Although Jackson believed that epilepsy could have behavioral ramifications, he insisted that these be “sudden and temporary” to be considered a component of epilepsy. In 1873, he further distilled his definition: “epilepsy is the name given for occasional, sudden, excessive, rapid and local discharges of gray matter,” (14) a perspective that would not encompass
the views of the alienists, who regarded epilepsy as a “morbius totius substantiae.” Despite the growing division between increasingly biologic neurology and increasingly psychodynamic psychiatry, early 20th-century developments relevant to the neuropsychiatric aspects of epilepsy included Glaus’ 1931 hypothesizing of an antagonism between epilepsy and schizophrenia (15), von Meduna’s initiating the use of convulsive therapy based on the (erroneous) observation that there was a reduced prevalence of schizophrenia in patients with epilepsy (16), the further development of electroconvulsive therapy by Cerletti and Bini in 1938 (17), Landolt’s introduction of the idea of forced normalization (18), and Slater and Beard’s 1963 argument that every symptom described in schizophrenic patients can occur in patients with seizures (19). But, as several recent publications have catalogued, it is the explosion of advancements in the epidemiology, neurochemistry, neuroendocrinology, electrophysiology, and functional neuroimaging of epilepsy populations that has magnified interest in the relationship between epilepsy and psychiatric phenomena. Although affective and thought disorders have received large amounts of attention, anxiety remains a lesser studied psychiatric aspect of epilepsy, despite anxiety’s clinical importance and a corresponding intensification of its study within psychiatry. Why investigate anxiety as an epilepsy-related neuropsychiatric phenomenon?
THE EVOLUTIONARY SIGNIFICANCE OF ANXIETY As epilepsy represents a model phenomenon in the history of the relationship between neurology and psychiatry, anxiety is a model phenomenon in the history of the relationship between mind and brain. Anxiety is the ultimate example of a phenomenon belonging to both psychological and neurophysiologic domains (20). Because of the historical division of study of these domains, there exist artifacts of definitional confusion regarding anxiety resulting from differences between the concepts and methods employed by the psychological and biologic sciences. Common in even current-day neurobiologic and psychiatric theorizing, these artifacts impede synergistic advancement of a unified theory of anxiety. In an effort to counter this, it is worthwhile to consider anxiety within the context of that theoretical glue which Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
230 provides ultimate coherence to all biologic theorizing: evolution. As Hofer observes, of all internal experiences, “anxiety may be the one with the closest parallels in other species and with the most ancient evolutionary heritage” (21). Indeed, anxiety is a predictable product of natural selection, which so depends on danger avoidance capacity that components of the experience we call anxiety have long been integrated into the neurocircuitry of even primitive organisms (21). An evolutionary perspective can facilitate definition of the core meaning of anxiety: a means to detect signals, a way to discriminate those that denote danger, and the capacity to initiate phylogenetically derived and ontogenically learned behavior that results in avoidance of that danger. As evolution progressed, externally directed danger-sensing mechanisms eventually developed the capacity to be directed inward for signaling internal danger as well (20). The competitive survival advantage bestowed by the capacity to anticipate danger, both internal and external, and react on the basis of prior experience nurtured the evolutionary development of relevant cognitive functions (e.g., memory) and their connections via corticolimbic circuits to affective, autonomic, neuroendocrine, and neuroimmune response systems underlying the generation of anxiety (20). The result: anxiety as an emergent neuropsychiatric quality of our evolutionary history. Given anxiety’s evolutionary heritage, it is appropriate that the concept of anxiety as an adaptive reaction to the perception of danger originated with Darwin (Breur and Freud both cite Darwin as the source of their insight that “emotional expression consists of actions which originally had a meaning and served a purpose” (22)). According to Darwin, “If we expect to suffer we are anxious, if we have no hope of relief, we despair” (23). In addition to foreshadowing by a century contemporary interest in a link between anxiety and depressive disorders, this view highlights the relevance of learned helplessness models for interpreting the affective impact of seizure occurrence in an individual patient. Deriving from their evolutionary origins, and their behavioral and experiential qualities, anxiety and fear are closely related concepts, with a history of somewhat arbitrary distinctions. In psychology literature, fear is often defined as a response to a threat that is known, external, definite, or nonconflictual in origin; anxiety is in response to a threat that is unknown, internal, vague, or conflictual in origin. But it is not that clear cut; in fact, the psychodynamic distinction between fear and anxiety arose by accident: Freud’s Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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early translator mistranslated angst, the German word for “fear,” as “anxiety” (24). Moreover, current interdisciplinary studies investigating the neurobiology of anxiety are based on animal models of the neurocircuitry of fear (25). In sum, the distinction between anxiety and fear remains vague; separation based on the acuteness and definability of the threat continues to operate in the literature.
NOSOLOGY DSM-IV classifies anxiety disorders as a distinct category of axis I disorders (26). Included in this group are generalized anxiety disorder, panic disorder (with and without agoraphobia), posttraumatic stress disorder, and phobias. The class also includes the diagnosis “anxiety disorder due to a medical condition,” applied when anxiety exists as a direct physiologic consequence of another identified pathophysiologic process. Anxiety within epilepsy patients can potentially fall into any of these diagnoses, and varying permutations of anxiety-type combinations can exist within any individual patient.
THEORIES OF PATHOLOGIC ANXIETY Psychodynamic Theory In 1895, Freud theorized in Obsessions and Phobias that the syndrome of “anxiety hysteria” (consisting of conversion symptoms and phobias) had a psychological etiology as a response to the threatened recrudescence of unpleasant emotions linked to unacceptable sexual memories (27). With the publication of Inhibitions, Symptoms, and Anxiety in 1926, Freud formulated a new dual theory of anxiety genesis as secondary to (a) obstruction of libidinal discharge, thereby having a biologic basis, or (b) intrapsychic conflict (e.g., an unacceptable drive or repressed wish pressing for conscious representation and discharge), therefore having a psychological basis (28). As Freud’s “energy”-based theories faded, the fundamental function of anxiety within psychoanalytic theory eventually operationalized as an unconscious warning, known as signal anxiety, which prompts mobilization of ego resources to avert danger. Psychodynamically, anxiety can signify real or imagined threat to personal security, identity, reality-organizing framework, or vital object relations (e.g., crucial relationships) (29). In the post-Freudian pluralistic environment, alternative perspectives em-
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ploy anxiety in different ways to fit each theoretical variation, but all continue to regard anxiety with similar central importance (30).
Learning and Cognitive-behavioral Theory Building on the concepts of Pavlovian conditioning, Watson (considered the father of American behaviorism) believed anxiety was largely explainable as a form of conditioned response (31). By the 1950s, the resemblance between human anxiety and experimentally induced “anxiety” in stressed laboratory animals was recognized, setting the stage for Ellis and Beck’s development of cognitive therapy in the 1960s and 1970s (32, 33). Briefly, the cognitive theory of anxiety posits that faulty, distorted thought patterns contribute to symptom production. Patients with anxiety disorders overestimate the degree of danger and the probability of harm in a given situation while underestimating their abilities to cope with perceived threats (24). Patients with panic disorder can experience thoughts of loss of control and fear of dying that follow physiologic sensations (e.g., palpitations, tachycardia, lightheadedness) (24).
Neurobiologic Theory Multiple neurochemical, neuroanatomic, neuroendocrinologic, and functional neuroimaging efforts are attempting to establish a unified neurobiology of anxiety. These investigations have contributed to the synthesis of anxiety circuitry schematics such as that shown in Fig. 1 (7, 34). As seen in the figure, central to the anxiety model of most theorists is the amygdala, hypothesized to be the key structure integrating interoceptive and exteroceptive stimuli, and distributing processed afferent data to the multiple efferent systems (cortical, limbic, basal ganglia, hypothalamic, brain stem) which produce the autonomic, affective, cognitive, and endocrinologic components of the anxiety response. Seizures, regardless of type and magnitude, represent an acute fundamental disruption to neuropsychiatric homeostasis, thereby necessarily impacting this circuitry. Thus seizures, especially those with limbic involvement, can hijack this system, giving rise to anxiety. Complex mechanisms mediating the connection between seizures and anxiety, including kindling and other neuroplastic processes affecting anxiety/fear circuits, are the targets of intense study.
ANXIETY ASSOCIATED WITH EPILEPSY Like other psychiatric phenomena, anxiety can be related to epilepsy in one or more of the following ways: (a) as an ictal phenomenon (i.e., anxiety as seizure or seizure component): (i) as a simple partial seizure alone, (ii) as an aura component of a complex seizure; (b) as an anticipatory fear associated with an aura heralding a seizure; (c) as an anticipatory fear of having a seizure without premonitory warning; (d) as a secondary neuropsychiatric aftereffect of seizure, i.e., a postictal event; (e) as an interictal manifestation of the same underlying etiologic mechanism as the primary seizure disorder; (f) as an adverse consequence of antiepileptic treatment; (g) as an adverse consequence of intrapsychic maladaption to having epilepsy; (h) as an adverse consequence of social maladaptation to having epilepsy; (i) as an unrelated comorbid primary psychiatric disorder. More broadly categorized, anxiety associated with epilepsy can be divided into ictal and interictal syndromes, with the following characteristics. Ictal Anxiety Seizure activity can produce experiential symptoms and behavioral manifestations that are indistinguishable from a primary anxiety disorder. Fear is a common aura feature, and may at times mimic panic attacks. Among partial seizure patients, fear is reported as an aura in up to 15% of patients (35), and several studies have shown fear to be the most common ictal emotion in patients with epilepsy (36). Young et al. reported five patients with brief simple partial seizures mimicking panic disorder (37). All of these patients had mesial temporal structural lesions associated with intractable epilepsy. Features distinguishing seizures from panic attacks included briefer duration and greater stereotypy (37). Fear and anxiety are common symptoms in electrically induced simple partial seizures (38). Anteromedial temporal seizures and cingulate seizures in particular can cause symptoms varying from mild unease to horror (38). Underscoring the difficulty of distinguishing seiCopyright © 2000 by Academic Press All rights of reproduction in any form reserved.
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FIG. 1.
Functional neuroanatomy of panic/anxiety.
zure-related from non-seizure-related anxiety, Jabourian et al. performed ambulatory EEG monitoring on 150 patients with panic disorder without epilepsy and found Copyright © 2000 by Academic Press All rights of reproduction in any form reserved.
that 63.2% demonstrated abnormal EEGs during a 24 hour period. Of these abnormal EEGs, 80% were considered to be epileptiform (39). Important case reports in-
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clude: McNamara and Fogel’s description of five patients with panic disorder refractory to psychotropics who demonstrated temporal lobe EEG abnormalities with good symptom response to anticonvulsant drugs (40), Alemayehu’s report of two cases of panic attacks occurring as ictal manifestations of a parietal lobe focus (41), and Weilberg and co-workers’ description of two patients with focal epileptiform activity on EEG that was temporally related to the development of their panic attacks (42). Toni et al. found a striking overlap in reported psychosensorial symptoms reported by patients with panic disorder–agoraphobia and those with complex partial epilepsy (43). However, as countless other examples in medicine demonstrate, similar phenomenology does not necessarily imply similar pathophysiology: Tokunaga et al. found a very different pattern of benzodiazepine receptor binding potential in anxiety and somatoform disorder subjects compared with epilepsy subjects, suggesting divergent etiologic mechanisms (44). Interictal Anxiety Interictal anxiety is reported in as many as 66% of patients with epilepsy (35). Although most frequently found among patients with partial seizures related to limbic foci, investigators have also observed an increased rate of anxiety symptoms among patients with generalized epilepsy (38). Multiple theories have been proposed to explain interictal anxiety. Two major psychological mechanisms suggested are fear of seizure recurrence (“seizure phobia”) and issues surrounding locus of control, a major concept derived from depression theory. Surprisingly, documented cases of actual seizure phobia are relatively rare (45). In contrast, problems related to a sense of dispersed locus of control can be profound in patients with epilepsy, potentially giving rise to discrete panic attacks or persistent generalized anxiety disorder (46). Connections to learned helplessness models of depression also become relevant. Putative neurobiologic mechanisms underlying a direct connection between seizures and at least some forms of interictal anxiety are multiple and complex, as can easily be appreciated when considering the multiple components of the above neurobiologic pathways that can be impacted by almost any form of epilepsy.
iety. In one study from Brazil in 1993, De Albuquerque and de Campos studied anxiety levels in a population of epilepsy patients versus nonepileptic control subjects using the State–Trait Anxiety Inventory (47, 48). They found higher trait anxiety scores in the epileptic group compared with normal controls. Among epilepsy patients, higher trait anxiety scores were recorded in patients with EEG abnormalities marked by left temporal lobe localization. In addition, the investigators found that briefer duration (less than 2 years) of symptomatic epilepsy was associated with higher anxiety levels (47). Responding to anecdotal case reports and the successful use of electroconvulsive therapy to treat some anxiety disorders (49), Goldstein et al. performed a preliminary study of the relationship between seizure frequency and anxiety. They found the surprisingly counterintuitive result that among adult partial epilepsy patients experiencing persistent breakthrough seizures, relatively high seizure frequency is associated with lower anxiety levels than relatively low seizure frequency (50). A simplified interpretation of these results would return us to Darwin (and Canetti and Hitchcock): Are we seeing that there exists a seizure frequency such that having more seizures actually reduces the anxiety attendant to the anticipation of a seizure? That is, do anxiety-generating neurocircuitry and psychological mechanisms “habituate” to higher seizure frequencies, processing such events as “routine” and thereby making anxiety generation less adaptive? If so, do these mechanisms relate to those underlying learned helplessness?
CONCLUSIONS The neuropsychiatry of epilepsy is an increasingly frequent target for interdisciplinary neuroscientific study. Comorbid anxiety and epilepsy in particular provides a unique window for theoretical and experimental exploration of mechanisms underlying key components of the natural history of each disorder. Finally, epilepsy and anxiety, individually and together, represent model phenomena for the investigation of the interrelationship of mind and brain function.
EMPIRIC EVIDENCE
ACKNOWLEDGMENT
There have been surprisingly few experimental studies of the relationship between seizures and anx-
This work was supported in part by the Ronald F. Coles Fellowship in Neuropsychiatry, Harvard Medical School.
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