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Keywords:

  • Epilepsy;
  • Depression;
  • Mania;
  • Bipolar disorder;
  • Review

Abstract

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Summary:  Depression has a major impact on quality of life in patients with epilepsy and is also the main risk factor for the increased suicide rate in epilepsy. The frequency of depressive disorders depends on the severity of epilepsy and the localization of the epileptogenic focus, with a prevalence of ≤50% in patients with intractable temporal lobe epilepsy. The diagnosis of depression in epilepsy may be difficult because symptoms of depression may be fluctuating, and some symptoms, such as memory complaints, may be misinterpreted as being a consequence of drug treatment or the epilepsy per se. Affective disorders in epilepsy may differ from those seen in patients without epilepsy. A possibility exists that patients with epilepsy will develop a specific interictal dysphoric syndrome related to limbic system dysfunction. Recent epidemiologic studies suggest a bidirectional relation between depression and epilepsy. Depression does not necessarily occur after the onset of epilepsy; the sequence may as well be the other way round, suggesting a common underlying mechanism for both disorders. Classic bipolar disorder type I is rarely seen in epilepsy, and manic episodes occur almost exclusively in the setting of postictal psychosis or after epilepsy surgery. This article explores the clinical manifestations of depressive and manic disorders in epilepsy and the differences from bipolar disorder.

A consensus of opinion suggests that psychopathology in general occurs more frequently among patients with epilepsy in comparison with the general population; the exact prevalence, however, of specific psychiatric disorders in epilepsy is not well known. This is due to different methods and inhomogeneous patient populations used across studies in the literature. Table 1 summarizes prevalence ranges of some common forms of psychiatric morbidity identified among patients with epilepsy, suggesting an overall five- to 10-fold increased frequency in epilepsy compared with that in the general population (1–5).

Table 1. Prevalence of psychiatric disorders in epilepsy
 Epilepsy (range)General population (range)
  1. aEttinger et al. (1).

  2. bJacoby et al. (35).

  3. cBarraclough (2).

  4. dSchmitz and Wolf (3).

  5. eSigurdardottir et al. (4).

  6. fCostello et al. (5).

Depressiona11–442–4
Anxiety disordersb15–252.5–6.5
Suicidec 5–101–2
Psychosesd2–80.5–0.7
Pseudoseizurese 1–100.1–0.2
ADHDf10–40 2–10

Recent publications raise concerns of underrecognition and undertreatment of psychopathology among patients with epilepsy in general and, in particular, of affective disorders. In patients with complicated epilepsy, depressive syndromes are described in ≤50% of cases; in one study “affective disorders in need of treatment” occurred in 44% of candidates for epilepsy surgery (6).

THE CLINICAL DIMENSION

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Depression in epilepsy is frequent, clinically important, but underrecognized and undertreated

Depression in epilepsy is often regarded by patients and clinicians as an understandable consequence of severe epilepsy and associated psychosocial disadvantages. Many epilepsy patients have a problem accepting a psychiatric diagnosis because of the fear of additional discrimination, and many epileptologists are reluctant to start antidepressive treatments because of a lack of confidence in the efficacy of psychopharmacologic drugs and the fear of side effects and drug interactions. A good example of the neglect of clinicians toward depression in epilepsy is a recent study of 70 patients with temporal lobe epilepsy admitted for evaluation before epilepsy surgery. Although 34% of these patients were diagnosed as having “significant depression,” no patient had received antidepressive treatment (7). In another study on the efficacy of sertraline in epilepsy, 60% of included patients had a history of depression for >1 year, and none of these patients had been treated (8).

The underdiagnosis of affective comorbidity in epilepsy is likely to have many sources. One possible explanation is an insufficient sensitivity among epileptologists toward psychiatric symptoms (epileptologists now receive little or no psychiatric training in most countries). Another reason is the atypical clinical presentation of depressive disorders in patients with epilepsy, which often does not allow a straightforward classification according to standardized psychiatric diagnostic systems such as the ICD10 (9) or the DSM IV (10).

Conversely, mounting evidence suggests that the existence of depression is of paramount importance for the overall outcome in epilepsy. In several recent studies, it could be demonstrated that measurement of depression is a much better predictor for quality of life in patients with chronic epilepsy than is the average seizure frequency (11–13). Furthermore, levels of perceived severity of epilepsy are significantly higher in patients with depression compared with those in patients without depression experiencing similar types of seizures (14). It is possible, although not investigated, that patients with comorbid depression have poorer responses to antiepileptic treatments because of irregular sleep patterns, noncompliance, or drug/alcohol abuse. At the same time, depressed epilepsy patients who do not receive antidepressive treatments have more medical and psychiatric visits than do people who are not treated, suggesting frequent (and costly) health resource use (15).

THE BLUMER SYNDROME

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Is there an epilepsy-specific affective phenomenon?

The clinical diagnosis of depression in epilepsy can be very difficult. First, most patients do not complain about mood problems. Depressive epilepsy patients often describe symptoms that may easily be interpreted as a side effect of antiepileptic drugs (AEDs) or as a consequence of epilepsy per se. Such misleading complaints may relate to sleep problems, changes in appetite, loss of libido, and impairment of cognition. A frequent complaint of depressed epilepsy patients relates to poor memory. An English study demonstrated that patients who complain about memory problems are significantly more depressed and anxious than are “noncomplainers” (16). Elixhauser et al. (17) performed neuropsychological assessments in depressed and nondepressed epilepsy patients who described memory problems. In patients with depression, subjective memory impairment was not related to objective memory performance. These findings highlight the importance of psychiatric assessments to detect depressive syndromes (Table 2).

Table 2. Diagnostic criteria for a depressive syndrome according to ICD-10, DSM-IV
  1. aKnown side effects of anticonvulsants.

Depressed mood
Feelings of worthlessness
Feelings of guilt
Loss of energy and interesta
Insomnia or hypersomniaa
Decrease or increase in appetitea
Loss of libidoa
Psychomotor retardation or agitationa
Diminished ability to think or concentratea
Suicidal ideation

Classic “endogenous”-type depressive symptoms, including feelings of guilt, “Gefühl der Gefühllosigkeit,” and a circadian pattern of symptom severity, are rare in patients with epilepsy. Authors have repeatedly pointed out that the clinical presentation of depression in patients with epilepsy is often atypical [as in 50% of cases in a study by Mendez et al. (18)]. Blumer (20), referring to the classic German psychiatric literature [especially Kraepelin (19)] described a pleomorphic affective disorder in epilepsy, characterized by eight key symptoms. Among these are labile depressive symptoms (depressive mood, anergia, pain, insomnia), labile affective symptoms (fear, anxiety), and supposedly “specific” symptoms (paroxysmal irritability, and euphoric moods). Kanner (8), who highlighted the chronic course of this disorder with symptom-free intervals, preferred the term “dysthymia-like disorder of epilepsy.” He diagnosed this disorder in 70% of his patients with depression who needed treatment. Many clinicians believe in the existence of this dysphoric or dysthymic disorder. Unfortunately, no systematic studies proved that this empirically identified syndrome is specific for epilepsy in general or more specifically for limbic epilepsy.

MANIA IN EPILEPSY

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Why is it so rare?

Mania in epilepsy is rare, with the exception of two specific conditions: postictal psychosis and mania after epilepsy surgery.

Kanemoto (21) studied systematically the differences between 126 patients with interictal and 46 patients with postictal psychoses. With respect to psychopathology (Fig. 1), he identified two distinct patterns. He noticed that mania-related symptoms such as logorrhea and delusions of grandiosity are much more common in postictal psychosis as compared with interictal psychosis, characterized by schizophreniform delusions and hallucinations. He also noted a predominance of patients with temporal lobe epilepsies in both psychosis groups; however, this link was even more striking in patients with postictal psychosis, of whom 87% were diagnosed with temporal lobe epilepsy, 82% had complex partial seizures, and 35% had structural abnormalities of the temporal lobe on magnetic resonance imaging (MRI). The corresponding data for patients with interictal psychosis were 59% for temporal lobe epilepsy, 67% had complex partial seizures, and 20% displayed temporal lobe MRI abnormalities (22).

image

Figure 1. Postictal (PiP) versus interctal psychoses (IiP). Psychopathology. PiP: n = 45; IiP: n = 126.

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The close link between temporal lobe epilepsy, seizure activity, and mania is further stressed by the high incidence of de novo manic episodes after temporal lobectomies in pharmacoresistent patients. After epilepsy surgery, manic episodes occur in ∼10% of patients. These episodes occur within weeks after surgery and take a benign transient course in almost all cases. Postsurgery mania is associated with poor seizure outcome, and patients who undergo right lobectomies carry a higher risk, as do patients with bilateral abnormalities (23,24).

EPILEPSY AND DEPRESSION

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Uni- or bidirectional relation?

Formerly it was believed that depression either is causally related to the epilepsy or occurs secondarily on account of the socially disadvantageous nature of epilepsy. Recent epidemiologic studies suggest, however, a bidirectional relation with a high incidence of secondary epilepsy in primarily depressed patients.

The first study indicating a high frequency of depressive disorders before the onset of epilepsy was published in 1963 (25). In a university hospital–based series with 51 patients with adult-onset epilepsy, 16% had a history of depression before onset of epilepsy. This uncontrolled observation from a selected patient population has been confirmed by a number of better-controlled studies since. In a community-based case–control study from Sweden, it could be shown that patients with new-onset epilepsy were 7 times more likely to have a history of depression preceding epilepsy than were controls. Patients with focal epilepsy were even 17 times more likely to have a history of depression (26).

In a population-based, case–control study from Rochester, patients with a first seizure after age 54 years were investigated. This study controlled for the use of antidepressants and discovered that late-onset epilepsy patients 3.7 times more often had a history of depression than did controls (especially patients with focal seizures). Depressive episodes often occurred relatively close to the onset of epilepsy (27).

In a study using hospital registers in Denmark, looking at a 17-year period and a total of 11,741 patients with depression, the relative risk for secondary epilepsy was 1.32 compared with controls (patients with diabetes and osteoarthritis). The authors stress the role of alcohol abuse as a major etiologic factor, because the relative risk was 9.9 in patients with depression plus alcohol abuse, but only 0.9 in patients with depression without alcohol abuse (28). Whereas alcohol dependency may be relevant in adults, drug abuse is unlikely to explain findings in pediatric populations. Among children in Iceland with new-onset epilepsy, depressive episodes before the first seizure occurred 4 times more often among epilepsy cases than among controls (29). Kanner and Balabanov (8) explained these epidemiologic data by a common underlying pathology involving monoamine systems. They suggested that monoamine deficiency may be responsible for the development of depression and also reduces the seizure threshold.

BIOLOGICAL CORRELATIONS

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Limbic system dysfunction and secondary hypofrontality

Dysphoric or depressive episodes in epilepsy should be classified according to their relation to seizures and treatments (Fig. 2). We distinguish periictal syndromes (preictal, ictal, postictal), alternative syndromes occurring with cessation of seizures and often in the context of forced normalization, and interictal depression, without a simple relation to seizure activity. The pathophysiology of the seizure-related affective disorders is likely to be different from the more sustained interictal manifestations of depression. In the latter, the etiology is likely to be heterogeneous including side effects of AEDs, which are discussed in more detail in the article by Selai et al. (this volume), and psychological factors, which explain depressive reactions, which can be observed not only in patients in whom seizures are difficult to control, but also in patients after successful control of seizures. Psychological concepts that may explain such understandable or superficially paradoxical reactions include the models of “learned helplessness” and the “burden of normality.”

image

Figure 2. Epilepsy and depression: patterns.

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Among potential biologic risk factors for interictal depression, a number of studies have demonstrated a significant correlation with the diagnosis of temporal lobe epilepsy. Quiske et al. (30) showed that patients with mesial temporal lobe epilepsy have significantly higher scores on the Beck depression inventory than do patients with neocortical temporal lobe epilepsies (11 vs. six), suggesting that a focus within the limbic system is relevant for the pathogenesis of depression. Interestingly, depression in patients with temporal lobe epilepsy is associated with frontal lobe dysfunction. This was demonstrated by using different methods of investigation, including functional imaging techniques (31,32) as well as neuropsychological assessments (33). This suggests that depression may be explained as a clinical manifestation of remote dysfunctional effects of the epileptogenic focus within neuronal networks, rather than reflecting a local effect within mesial temporal lobe structures. Interestingly, depression-related hypofrontality is much more common in left-sided epilepsies than in right-sided epilepsies, suggesting a closer functional association between the dominant hemisphere and the frontal lobes bilaterally. This hypothesis is further supported by the observation (Helmstädter, personal communication) of better remissions of depression in successfully operated-on epilepsy patients after left temporal lobectomies compared with those in patients who were either unsuccessfully resected, or to patients who were resected on the right side.

TREATMENT OF DEPRESSION IN EPILEPSY

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Lack of class 1 evidence supporting efficacy of antidepressants in epilepsy

Although a common complication in patients with epilepsy, depression is often not recognized, and therefore many patients are not adequately treated. Unfortunately, no randomized placebo-controlled studies demonstrate the efficacy of antidepressants in patients with epilepsy and comorbid depressive syndromes. The claimed positive psychotropic effects of some AEDs—some of which are licensed for primary psychiatric indications (see Gajwani et al., pp. 38–44)—have not sufficiently been studied in epileptic populations, with the possible exception of lamotrigine (see Selai et al., pp. 50–57).

A survey of 67 neurologists who regularly see epilepsy patients (34) asked the following question: “Do you routinely screen epilepsy patients for depression in your outpatient clinics?” The answer was “no” in 86%. A second question was, “If a randomized controlled trial demonstrated that the treatment of depression improved compliance and health-related quality of life in epilepsy patients, would you systematically screen for depression in your outpatient clinic?” The answer was “yes” in 85%. These data show that an urgent need exists to achieve better evidence for the recommended use of antidepressants in epilepsy (35).

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES

Facts and gaps

Depression has a major impact on quality of life and is also the main risk factor for suicide in epilepsy. Nevertheless, in clinical practice, depression is both underrecognized and undertreated. The etiology of affective disorders in epilepsy is complex, including epileptogenic dysregulation within limbic circuits and psychotropic adverse effects of AEDs. An association is found with secondary “dysfrontality” in patients with temporal lobe epilepsies, underlining the clinical relevance of remote network effects of active epileptogenic foci. Depression is, however, not only a consequence of epilepsy, because a number of epidemiologic studies demonstrated that patients with epilepsy often have a history of depression before their first seizures.

Research is required into the specific clinical manifestations of affective disorders in epilepsy, including the evaluation of Blumer´s hypothesis of an epilepsy-specific dysphoric disorder. It seems that classic bipolar disorder is extremely rare in epilepsy, suggesting an antagonistic relation between the disorders. Other reasons could exist for this clinical impression as well; modulatory effects of AEDs may alter the clinical presentation and course of affective disorders in epilepsy. A psychopathologic overlap is possible between the epilepsy-associated labile affective syndrome of Blumer and atypical or rapid-cycling bipolar disorder in primary psychiatric patients. Remarkably, the latter subgroup of bipolar disorder responds particularly well to treatment with AEDs.

It is unclear whether epilepsy-related depressive disorders respond to psychopharmacologic interventions, and if so, whether antidepressants, or mood-stabilizing agents, including atypical antipsychotics and AEDs, should be preferred.

In conclusion, we established that affective disorders in epilepsy are frequent and clinically relevant. To answer the question whether these problems have anything in common with bipolar disorder, we need detailed psychopathological studies that use sophisticated psychiatric assessments beyond simple mood questionnaires.

REFERENCES

  1. Top of page
  2. Abstract
  3. THE CLINICAL DIMENSION
  4. THE BLUMER SYNDROME
  5. MANIA IN EPILEPSY
  6. EPILEPSY AND DEPRESSION
  7. BIOLOGICAL CORRELATIONS
  8. TREATMENT OF DEPRESSION IN EPILEPSY
  9. CONCLUSIONS
  10. REFERENCES