Therapeutic Uses of Seizures in Neuropsychiatry

Although seizures typically indicate a state of brain dysfunction, there are circumstances in which the biological effects of a seizure may exert therapeutic benefits. The standard technique for inducing controlled therapeutic seizures in humans is electroconvulsive therapy (ECT), a treatment that involves the application of an electrical stimulus to the scalp of a patient under general anesthesia and muscle relaxation. In this review we discuss the contemporary use of ECT for treating certain mental and neurologic disorders, and we preview two experimental forms of seizure therapy that are related to ECT and may hold promise for the future: focal electrically administered seizure therapy (FEAST) and magnetic seizure therapy (MST).

Diagnostic Indications and Efficacy

The primary diagnostic indications for which ECT is safe and effective include each of the major mood episodes (i.e., major depressive, manic, mixed), schizophrenia and schizoaffective disorder, and catatonia (especially malignant variants, such as neuroleptic malignant syndrome). In the United States, ECT is used primarily to treat patients suffering from depression (1). ECT is indicated anytime a patient is gravely ill and in need of a rapid, definitive response (e.g., acutely suicidal, melancholic with severe inanition) and is typically used when other treatments (typically medications) have failed or are poorly tolerated, when the patient has a history of a favorable response to ECT, or when the patient prefers ECT (2).

ECT is the single most effective and most rapidly effective treatment for major depression (3). Randomized, controlled data from the Consortium for Research in ECT indicate that remission occurs in 70% to 90% of patients who receive ECT (4). Remission rates are even higher among patients with psychotic depression and among the elderly (5, 6). This success compares to remission rates of approximately 30% for pharmacotherapy and repetitive transcranial magnetic stimulation in comparably treatment-refractory populations (7, 8). Some patients report immediate improvement after a single ECT treatment, and approximately 60% of patients with major depression achieve full remission after nine treatments (4). ECT’s efficacy does not depend on whether the depression is unipolar or bipolar. However, outcomes may vary with certain technical aspects of the procedure. For example, right unilateral stimulus electrode placement is associated with fewer cognitive side effects, but unless stimulus intensity is optimized, efficacy may be limited. Bitemporal stimulus electrode placement may be more reliably effective but may also be associated with modestly greater cognitive side effects (2). In addition, ECT using right unilateral stimulus electrode placement with ultrabrief pulse width is associated with fewer cognitive side effects but requires more treatment sessions to achieve a response and may be less efficacious than standard brief pulse ECT (9). Therefore, right unilateral ECT may be reserved for situations in which particular importance is placed on minimizing amnestic side effects, whereas bilateral forms of ECT are recommended for situations in which the priority is rapid, definitive treatment response.

Despite its robust efficacy treating acute mood episodes, ECT may not alter the underlying cyclical course of mood disorders. Symptom recurrence occurs in a majority of patients if ECT is discontinued (10). Randomized, controlled data indicate that maintenance therapy with ECT (using the same technique that was effective during the acute course) and pharmacotherapy (lithium plus nortriptyline) are comparable, with both forms of therapy sustaining remission rates for about half of patients after 6 months (11). Randomized, controlled data also indicate that, among elderly persons, the combination of continuing ECT plus venlafaxine is superior to venlafaxine alone at 24 weeks after the completion of an acute course of ECT (12). Many patients with chronically recurring forms of severe depression receive lifelong maintenance ECT.

For patients suffering from mania, ECT remits symptoms approximately 80% of the time (13). The treatment can be life-saving for patients suffering from manic delirium. Remission rates are comparable in schizophrenia, although a higher number of treatments (e.g., 12 to 15) may be required (2). The combination of ECT with clozapine in the treatment of schizophrenia appears to be more effective than ECT alone (14).

Secondary indications for ECT include mood disorders due to general medical or neurologic conditions (e.g., secondary mood disorders) as well as certain neurologic conditions themselves (see Neuropsychiatric Considerations).

Safety and Tolerability

There are no absolute contraindications to ECT. It is safe and effective in children and adolescents, women who are pregnant, and the elderly. In patients with certain general medical conditions, ECT may be safer than pharmacotherapy.

The safety of ECT compares favorably with that of any treatment requiring general anesthesia. ECT mortality in adults is reported as approximately less than 1 death per 10,000 patients (roughly 1 per 80,000 treatments), which is about the same as mortality from general anesthesia for minor surgery (2). Such systemic side effects as headache, nausea, and myalgia are common during and shortly after the post-ECT recovery period. These symptoms are generally mild, transient, and quite responsive to symptomatic treatment (15).

Cognitive side effects are common after ECT and include a brief period of disorientation and, rarely, frank delirium immediately on awakening from anesthesia. ECT is also associated with transient impairments in retrograde and anterograde memory; roughly half of patients will subjectively report some degree of memory trouble (16). Autobiographical memory is less affected (17). The frequency and severity of these amnesic side effects vary with a number of patient factors (e.g., age, preexisting cognitive impairment, general medical health) and ECT technical factors (e.g., stimulus electrode placement, stimulus waveform). In general, the amnesic effects of ECT are short-lived (days to weeks in duration), do not cause major functional impairment, and must be distinguished from the amnesic effects of illness (e.g., depressive pseudodementia) (2, 18). There is no evidence that ECT causes structural brain damage. Misinformation and misunderstanding of these cognitive side effects remain the primary source of stigma and controversy that limit access to ECT (19).

Contemporary ECT Technique

ECT is administered by a specialized team of psychiatrists, anesthesiologists, and nurses. Prior to commencing the course of therapy, this team conducts a thorough general medical and neuropsychiatric examination of the patient in order to confirm the indications for ECT, to optimize the safety of the treatment by identifying and treating any general medical illnesses, to optimize the efficacy of the treatment by reviewing and potentially modifying the patient’s list of medications, and to conduct the informed consent process.

ECT is typically administered in a special treatment suite. The patient should have nothing to eat or drink for at least 6 hours before the procedure. Once baseline vital signs, pulse oximetry, and an ECG have been obtained, the patient is administered a short-acting anesthetic agent (typically methohexital) followed by a short-acting neuromuscular blocking agent (typically succinylcholine). Throughout the procedure, the patient is ventilated with 100% oxygen by mask, and vital signs are continuously monitored. Once the patient is asleep and fully paralyzed, a specially designed bite block is inserted into the patient’s mouth, and a brief electrical stimulus is then delivered across electrodes placed on the patient’s properly prepared scalp. The electrical stimulus dosage and the location of the treating electrodes (right unilateral, bitemporal, bifrontal) are both important to the efficacy and side effects of the procedure. The electrical stimulus elicits a generalized seizure that typically lasts 25 to 90 seconds and is monitored continuously with electroencephalography (EEG). During the initial tonic motor phase of the convulsion, EEG activity is variable, consisting of low-voltage fast activity with polyspike rhythms. EEG activity rapidly evolves into the hypersynchronous polyspikes and waves that characterize the clonic motor phase. These regular patterns begin to slow and eventually disintegrate as the seizure ends, usually terminating abruptly with postictal suppression seen on the EEG. Ventilatory support is maintained until the patient emerges from the anesthesia, and further recovery is provided in an environment with as little stimulation as possible. The entire procedure takes about 20 minutes. Patients are often able to have a snack within an hour of the procedure, after which they are discharged.

When used to treat acute illnesses, ECT is typically administered two to three times per week, on alternating days, until a therapeutic benefit has been maximized (typically six to 12 treatments). Full symptom remission is the goal, and obtaining standardized outcomes is an important step in determining when remission or plateau has been achieved. Response rates range from 65% to 90%, depending on a number of factors (see Diagnostic Indications and Efficacy). If improvement plateaus at a partial response, then the ECT technique may be modified to enhance its effectiveness (e.g., switching from right unilateral to a bilateral form of ECT, continuing the acute course beyond 12 treatments, reviewing the patient’s medications for those that may deliver anticonvulsant effects). After a successful acute course of ECT, it may also be employed as continuation or maintenance therapy to prevent recurrence. During a continuation or maintenance course of therapy, ECT is administered at decreasing frequencies (tapering from weekly to monthly or longer) as tolerated, while monitoring for evidence of relapse. Most patients receive the treatment on an outpatient basis, depending on their clinical status and the availability of appropriate logistical support.

Physiology of ECT

The most clinically important physiologic changes that occur during ECT involve the brain and cardiovascular system. ECT results in a marked activation of the autonomic nervous system, and the relative balance of parasympathetic and sympathetic nervous system activity determines the observed cardiovascular effects. Parasympathetic tone increases during and immediately following the ECT stimulation, whereas sympathetic activation occurs with development of the seizure. Tachycardia and hypertension continue through and shortly after seizure termination, at which point there may be a second brief period of parasympathetic activation. These effects combine to produce a brief increase in cardiac workload and occasional transient arrhythmias, which are well tolerated by most patients. Patients with significant cardiac disease may require modifications in ECT technique to optimize the cardiovascular safety of the procedure.

The ECT seizure is also associated with a variety of transient and benign changes in cerebral physiology, including cerebral blood flow, cerebral blood volume, and cerebral metabolism. The brief increase in intracranial pressure is rarely of clinical consequence, but it is the reason for the well-known proscription against ECT in patients with a space-occupying intracranial mass. Transient disruption of blood-brain barrier permeability likely occurs during the seizure and may account for a transient increase in T1 relaxation times on brain MRI, although the structural integrity of the blood-brain barrier appears to be preserved.

These changes in cerebral and cardiovascular physiology serve as important markers of ECT seizure quality. Indeed, subconvulsive stimulation delivers no antidepressant benefit and brings with it the risks of unopposed vagal stimulation of the cardiovascular system (e.g., bradycardia). Seizure duration, EEG wave amplitude, EEG hemispheric synchronicity, peak ictal heart rate, and postictal suppression all have complex associations with seizure quality (20). Routinely obtaining these measures enables clinicians to modify the ECT technique in cases of inadequate seizures or suboptimal clinical response.

Mechanism of Action

Although we have learned a great deal about the neurobiology of ECT, its precise mechanism of action is unknown. A number of well-documented observations have led to theories behind its powerful clinical effects (3). ECT increases release and enhances transmission of dopamine, serotonin, and norepinephrine (21, 22). It increases GABA transmission (23) and has anticonvulsant properties that are clinically correlated with therapeutic outcome (24). ECT acts on the hypothalamic-pituitary-adrenal axis to normalize levels of hormones (25).

Of particular importance are the recent studies focusing on the ECT-induced increases in brain-derived neurotrophic factor and the induction of neurogenesis (26). Although much of the early study of this neurogenesis and synaptogenesis was derived from rodent models of ECT, the human imaging data are building similar support. A meta-analysis of 32 human neuroimaging studies arrived at three key conclusions. First, ECT consistently increased volumes in bilateral hippocampal regions, which were most often the regions of interest (27). Second, a smaller number of studies found volumetric or cortical thickness increases in regions important for mood regulation, including the anterior cingulate cortex, thalamus, striatum, insula, parahippocampus, and other temporal lobe structures. Finally, nine of 10 studies that applied a whole brain analysis found increases in gray matter volume after an ECT series compared with baseline (28). In their data review, Gbyl and Videbech (28) found no evidence of brain damage after ECT, which remains a myth despite having been scientifically debunked nearly a quarter century ago (29).

Neuropsychiatric Considerations

Mood disorders are common in patients with neurologic illness, and many of those patients will require treatment with ECT. Although there are no controlled data on the efficacy of ECT in these conditions, extensive clinical experience and a primarily retrospective literature support such use. The administration of ECT in such patients may require modifications in the technique of the procedure to optimize safety and efficacy. The neurologist can play an important role in ensuring the appropriate and safe use of ECT in these individuals. ECT should be considered in depressed patients with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, epilepsy, multiple sclerosis, traumatic brain injury, and brain tumor.

In addition, the neurobiological effects of ECT may have beneficial effects on a number of neuropsychiatric disorders, most notably those discussed here.

Neuroleptic Malignant Syndrome (NMS)

ECT has been used to successfully treat severe, refractory cases of NMS (30). NMS is a medication-induced subtype of the malignant form of catatonia and responds to ECT, as do other causes of malignant catatonia. Such patients should be off all dopamine-blocking drugs, however, and a nondepolarizing muscle relaxant (e.g., rocuronium rather than succinylcholine) may be indicated in patients with prolonged immobility due to concern for transient hyperkalemia associated with acetylcholine receptor immaturity (31).

Parkinson’s Disease

ECT may be a useful treatment for the motor disturbances of severe Parkinson’s disease when pharmacotherapy is unsuccessful or not tolerated, regardless of the procedure’s effect on the patient’s mood. These data include a randomized controlled trial with sham ECT of 11 patients with the “on-off” syndrome, an oscillating response to levodopa characterized by an end-of-dose “wearing off” of its beneficial effects on motor function (32). This salutary effect is not surprising, given that ECT has been shown to enhance dopaminergic function (3). The beneficial effects of ECT on motor function may be maintained for months with maintenance ECT treatments.

Intractable Seizures

Animal studies demonstrate that electroconvulsive seizures have anticonvulsant properties in that they block kindling and raise seizure threshold. This anticonvulsant effect, whereby seizure threshold rises and seizure duration shortens during a course of ECT, is also seen in humans (33). There are clinical reports of clinicians who have leveraged this anticonvulsant property of ECT to terminate status epilepticus in some patients or decrease the frequency of seizures in others (34). It has been suggested that a course of ECT might be considered in some patients with intractable epilepsy before undergoing brain surgery.

Delirium

ECT has been administered safely and effectively in patients with delirium associated with a broad range of etiologies (35). ECT may be effective for delirium even when the underlying etiology has not been identified or corrected, and patients with delirium do not appear to be at any greater risk of cognitive side effects from ECT. On the basis of this large clinical experience, ECT is routinely used for the management of delirium in Scandinavia; ECT is probably underused as a treatment for delirium in the United States.

Dementia

Growing evidence suggests that ECT may be helpful for treating symptoms of agitation and aggression in patients with dementia. In such settings, ECT appears to be safe, well tolerated, associated with a reduction in the use of sedating medications (as needed), and, in some cases, rapidly effective (36). ECT does not cause or precipitate dementia (37).

Anti-NMDA Receptor Encephalitis

Accumulating case report data suggest that ECT may be helpful in treating the neuropsychiatric symptoms of anti-NMDA receptor encephalitis, particularly catatonia (38). ECT may have a disease-modifying effect on this form of autoimmune encephalitis.

Novel Forms of Seizure Therapy

The antidepressant effects of ECT may be correlated with functional changes in prefrontal and other mood-modulating brain regions, whereas the amnestic side effects of ECT are associated with changes in the medial temporal lobes. The use of unilateral nondominant stimulus electrode placement (i.e., right unilateral) is one strategy to localize the ECT stimulus. Although it produces less cognitive burden relative to bilateral stimulation, the resultant seizure must still be bilaterally generalized to be effective. A recently developed technique to target even more precisely the spatial location of the ECT stimulus is FEAST. This technique, which is experimental, combines electrode geometry with unidirectional (anode-cathode) stimulation. In nonhuman primates, FEAST has been shown to be a safe and reliable means of inducing both focal and generalized seizures (39). More recent open-label studies have demonstrated the safety and applicability of FEAST in humans (40).

Electrical stimulation, whether focal or not, still poses substantial challenges to eliciting seizures with optimal efficiency. When applied directly to the scalp, electrical energy is impeded and displaced by the physical substance of the scalp and skull, which widens the field of brain stimulation. Magnetic fields, on the other hand, pass through tissue without impedance. The application of magnetic stimulation to induce a therapeutic seizure is known as MST. MST penetrates only 2–4cm beneath the scalp, which offers the theoretical advantage of targeting the seizure to superficial cortical structures that may modulate mood while sparing deeper structures like the hippocampus associated with amnestic side effects (41). Emerging research in nonhuman primates as well as human subjects suggests that MST is feasible and safe and that elicited seizures are more focal and associated with less autonomic, neuroendocrine, and cognitive effects (42).

Conclusions

ECT remains the cornerstone of treatment for severe mood disorders and certain other neuropsychiatric conditions, including those in patients with neurologic disorders. In addition, the neurobiological effects of ECT may have beneficial effects on a number of neurologic disorders, including Parkinson’s disease, epilepsy, and delirium. As with any procedure in medicine, the safety and efficacy of ECT depend critically on appropriate technique and proper patient selection and preparation. Newer forms of seizure therapy, including FEAST and MST, are producing intriguing results, although more research is needed to determine efficacy and to clarify a wide range of technical issues related to their application.