• Adminstration of AEDs
• Clinical effects of AEDs
• Specific AEDs
• Benzodiazepines
• Barbiturates
• Carbamazepine
• Ethosuximide
• Felbamate
• Gabapentin
• Lamotrigine
• Phenytoin
• Tiagabine
• Topiramate
• Valproic acid
• Vigabatrin
• Vagus nerve stimulation
• References

In a review of the use of antiepileptic drugs (AEDs) by epilepsy patients with mental retardation, Coulter3 summarized the typical selection of AEDs on the basis of relative efficacy of the drug against specific seizure type:

• Partial seizures—commonly phenytoin, carbamazepine; also valproic acid, gabapentin, lamotrigine, tiagabine, topiramate
• Absence seizures—ethosuximide; valproic acid and lamotrigine also may be considered
• Generalized myoclonic, tonic, and atonic seizures (all features of the Lennox-Gastaut syndrome common in this population)—valproic acid, lamotrigine, felbamate, topiramate
• Generalized tonic-clonic seizures—phenytoin, carbamazepine, felbamate, lamotrigine, topiramate

In selecting AED therapy, clinicians also must consider drug side effects, including favorable or adverse psychotropic effects. Very few studies have focused on these concerns in developmentally disabled patients, but lessons from our experience with AEDs in other populations can be applied to their management.

Mechanisms of action

The effects of AEDs on behavior may relate to their variable effects on different groups of cortical neurons. AEDs may alter neurotransmitter levels (e.g., norepinephrine and gamma-aminobutyric acid [GABA]) or ion channel function. These in turn may affect both seizures and mood.4 For example, the mood instability of bipolar disorder has been theorized to occur on the basis of decreased GABA-ergic neurotransmission or by altered sodium channel function. Some AEDs may improve mood instability by increasing GABA and modifying sodium channels.

Categories of AEDs

Ketter et al.5 classified AEDs into two categories, "sedating" and "activating," on the basis of their psychotropic properties and mechanisms of action. Animal models and evidence from clinical experience support this classification.

Sedating AEDs are associated with fatigue, cognitive slowing, and possible anxiolytic and antimanic effects. These actions may be related to a predominance of potentiation of GABA-inhibitory neurotransmission. Drugs with these effects include:

• barbiturates
• benzodiazepines
• valproic acid
• gabapentin
• tiagabine
• vigabatrin

Activating AEDs have possible anxiogenic and antidepressant effects. They are associated with attenuation of glutamate excitatory neurotransmission. This group includes:

• felbamate
• lamotrigine

Topiramate possesses both GABA-ergic and antiglutamatergic actions, so it is said to have a mixed profile.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Instruments used to assess drug-induced mood alterations in the general population (e.g., structured interviews, Beck Depression Inventory, Profile of Mood States) are not employed readily in the DD population because of restrictions in patients’ intellectual capacities or their ability to communicate. Some rating scales have been developed,6 but direct observation and quantification of behaviors often are required.7,8 The process may include a thorough analysis of baseline behavior, determination of factors influencing the behavior, and regular monitoring of these features after initiation or discontinuation of a drug.9 Because many patients are supervised closely, caregiver assessments also can be useful measures of drug effects in this population.

Similar issues arise in assessing cognitive effects of AEDs. Although decreases in concentration and memory may be assessed through self-report, this method often is unreliable. Many of the side effects of AEDs are subtle in nature and can be documented only with sensitive neuropsychological measures of attention, motor speed, and memory. Use of these measures in a DD population can be problematic, as their validity and reliability may be affected by general reductions in intellectual functioning. Use of these tests in DD populations also often leads to “floor effects,” whereby test sensitivity and the ability to assess changes in functioning are obscured by reduced variance in the measure. In many cases, caregiver ratings or a systematic analysis of target behaviors is recommended in place of neuropsychological assessment of subtle cognitive deficits.10

The effect of polypharmacy

Clinicians are very likely to encounter DD epilepsy patients who are receiving more than one medication, including AEDs and psychotropic drugs. This confounds the determination of which agent is specifically responsible for positive or negative effects on behavior. The consensus among epileptologists about the value of striving for AED monotherapy in the treatment of the non-DD epilepsy patient should also apply to DD patients. Numerous studies have demonstrated that reduction in AED polypharmacy does not necessarily lead to seizure exacerbation, and patients may enjoy improvements in cognition and behavior when they receive a smaller number of medications.11–13

Other challenges in analyzing psychotropic effects

Another challenge in analyzing the psychotropic effect of AEDs relates to our inability to assess these effects as completely independent variables. Patients who experience a reduction or resolution of seizures as a result of AED therapy may experience associated elevations in mood and improvements in quality of life. Conversely, the stigma of taking AEDs or reactions to the experience of side effects (e.g., cosmetic effects, fatigue, cognitive impairments) may adversely affect mood and behavior.16

Shortcomings of drug literature

Many reports of the psychotropic effects of AEDs are anecdotal, some fail to examine premorbid psychiatric status, and many are based on cases with very high anticonvulsant levels.4 Other methodologic pitfalls in the drug literature include:14

• association of mood changes with the introduction of a new AED, ignoring potential effects of discontinuing the previous agent
• disregard of the positive effects on mood of seizure reduction
• failure to address the complex relationship between drug-induced cognitive impairment and mood
• poor recognition of important inequities in drug trial comparison groups (e.g., groups with noncomparable drug levels)
• limited samples
• selection bias
• failure to apply correction methods in statistical analysis of large numbers of variables
• failure to address the negative effect of polytherapy regardless of the specific agent
• reliance on retrospective data15
• focus on transient acute drug effects15
• inappropriate extrapolation to epilepsy patients of data on drug effects in normal volunteers15

In addition, reported rates of psychotropic effects on mood and behavior may be significantly lower in general drug trial reports than in studies that specifically target these factors.

For most AEDs, conflicting reports abound concerning both positive and negative psychotropic effects, and the reader of the medical literature must remember that mean tendencies may differ from individual patient experience.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Such benzodiazepines as chlorazepate, clobazam, clonazepam, diazepam, lorazepam, and nitrazepam may be used in patients with epilepsy and developmental disabilities (DDs) as antiepileptic, anxiolytic, or sedative hypnotic drugs.17 Benzodiazepines also appear to have limited antidepressant18 and antimanic19 properties. Their tendency to cause sedation, cognitive impairment, tolerance, and addiction limit their utility as chronic antiepileptic therapy.21

Because of their broad-spectrum antiepileptic properties, they have been used to treat Lennox-Gastaut syndrome, an epileptic syndrome characterized by generalized seizures (typically tonic, atonic, myoclonic, and atypical absence), characteristic spike and wave complexes and, usually, cognitive dysfunction.20 When intravenous benzodiazepines are administered to patients with the Lennox-Gastaut syndrome, however, they rarely may induce generalized status epilepticus22 or convert absence status to generalized tonic status epilepticus.23

Adverse psychotropic effects among DD patients include behavioral abnormalities such as:4,17

• hyperactivity
• restlessness
• reduced attention span
• irritability
• disruptiveness
• aggressiveness

Anecdotal experience suggests that clobazam (Frisium) may have fewer adverse effects than does clonazepam (Klonopin), with less impairment of attention, less mood disturbance, and diminished drooling. One study noted no difference in cognitive impairment among patients receiving clobazam and those receiving carbamazepine.24

Special care should be taken in withdrawing benzodiazepines, as delirium, psychosis, and withdrawal seizures have been reported with excessively rapid withdrawal of these drugs.25

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Although many newer AEDs are now available, such barbiturates as phenobarbital and primidone (Mysoline) continue to be prescribed frequently for epilepsy patients with developmental disabilities. This practice may be attributed to physician discomfort with less familiar AEDs rather than superior drug efficacy. This is unfortunate, as the barbiturates may impair cognition significantly.4,26 The risk of withdrawal seizures also may make barbiturates a less-than-optimal AED for use in this population.

Cognitive impairment due to barbiturates may be subtle and may occur in the absence of frank sedation. Anecdotally, it may not be obvious to affected patients until they notice an improvement on withdrawal from the drug.27 Reduction in the use of barbiturates in developmentally disabled patients may be accompanied by significant behavioral improvements.28

Barbiturates have been used in the past to treat anxiety and insomnia.29 Scattered reports have suggested modest efficacy against bipolar disorder.30

Most attention has been placed on their adverse psychotropic profile, however. Barbiturates are associated with a significant risk of depressive symptoms.31 A classic study by Brent et al.32 of patients receiving phenobarbital demonstrated a statistically significant increase in the risk of depression and suicidal ideation when compared to patients taking carbamazepine, particularly among those with a personal or family history of affective disorder. Patients with documented depression should avoid barbiturates.33

In children, adolescents, and patients with mental retardation,27 barbiturates also may cause:

• paradoxical hyperactivity34–36
• conduct problems37
• behavioral agitation
• irritability38,39

Identifying these potential side effects is crucial, as an optimal approach to their treatment would be to remove the responsible agent rather than adding a psychotropic drug to control these behaviors.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Carbamazepine (CBZ), a widely prescribed AED for both partial and generalized tonic-clonic seizures, has structural properties similar to those of the tricyclic antidepressant imipramine. Absence, myoclonic, and atonic seizures, which may occur commonly among patients with developmental disabilities, do not respond to CBZ and actually may worsen in severity.64,65 Other AEDs with similar spectra of action, such as phenytoin and phenobarbital, may have similar effects on these seizure types. Therefore, although CBZ may be useful for patients with developmental disability, epilepsy, and behavioral disturbances, careful consideration should be given to seizure type.

Few reports cite negative behavioral effects associated with CBZ, although one notable retrospective study of patients with mental retardation who were treated with CBZ for mood disorders found adverse behavioral reactions in nearly 10% of cases.61 For the most part, CBZ-related behavioral problems occur in patients with preexisting behavioral difficulties.62 Other studies have shown behavioral improvement in this population when the drug was removed.10

Numerous reports suggest that CBZ may have utility also in treating impulse control disorders, including borderline personality traits with aggression and dyscontrol syndromes.63 Therefore, on the basis of antimanic and mood-stabilizing properties similar to those described with valproic acid, CBZ may be considered also for use in epilepsy patients who demonstrate both behavioral difficulties and seizures.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230. With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Ethosuximide (ESM) is used commonly as a first-line therapy for typical absence seizures occurring in primary generalized epilepsy syndromes. However, atypical absence is more common in the developmentally disabled population. Although ESM may be effective against atypical absence, the common association with other seizures (e.g., atonic, myoclonic, generalized tonic-clonic) that do not respond to ESM renders it a less-than-optimal choice for treating such patients.

Although ESM usually is considered a benign treatment for absence seizures in primary generalized epilepsies, it can cause:

• confusion
• sleep disturbances
• assorted behavioral changes (e.g., aggression, depression, hostility, and even psychosis33)

The controversial entity of “forced normalization”45 has been invoked as a potential explanation for ESM-related behavioral abnormalities, in which ESM-induced “normalization” of the EEG recording results in a paradoxical behavioral abnormality.46

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

When introduced in 1993, felbamate (FBM) was greeted with great enthusiasm. It was particularly welcome for its potential contribution to the treatment of refractory epilepsy syndromes in patients with developmental disabilities, including Lennox-Gastaut syndrome. Subsequent discoveries about its association with fatal hepatitis and aplastic anemia have restricted its use greatly. FBM may re-emerge as an important tool in the treatment of refractory epilepsy syndromes if better methods of predicting which patients are at risk for these complications are discovered.

Anecdotal experience with FBM suggests that it has stimulant-like properties that may be experienced favorably or unfavorably by patients. Some patients have experienced increased alertness, improved attention, and enhanced concentration abilities (in contrast to the commonly encountered sedation associated with other AEDs). Others have reported anorexia, insomnia, and anxiety.111–113 Numerous reports of mania, psychosis, and behavioral disturbances also have been noted.114,115

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

A number of reports from the epilepsy literature suggest that gabapentin (GBP) may promote an improved sense of well-being independent of seizure reduction,66–70 but separating these two effects may be difficult. For example, in a recent open-label study, Harden et al.71 contended that epilepsy patients receiving GBP demonstrated significant reduction in depressive scores on a dysthymia rating scale independent of seizure reduction. Sample size was limited, however, and no significant differences were recorded on other depression or anxiety measures.

GBP has been demonstrated to be effective in treating mood disturbance in patients with partial epilepsy. Some studies showed increases in ratings of quality of life and well-being when patients were switched to this drug.72,73 The results of most studies have demonstrated minimal cognitive side effects associated with GBP.72–74

Open-label and case reports suggest that GBP has efficacy in treating mania75–78 and the depressive phase of bipolar disorder.79,80 Anecdotally, it may reduce agitation and improve sleep patterns in manic patients. It is being evaluated also in behavioral dyscontrol,81 agitation in senile dementia,82 anxiety states,83 social phobia,84 and self-injurious behaviors in neurologic syndromes.85 If further validated with clinical experience and more rigorous studies, these reports may have important relevance for the treatment of developmentally disabled (DD) epilepsy patients with comorbid psychiatric syndromes.

Several reports have cited the development or exacerbation of aggressive and agitated behaviors in children with epilepsy, most of whom had some degree of intellectual impairment.86,87 Clinicians, therefore, should watch carefully for behavioral side effects in treating DD patients with GBP. It may not be the optimal AED for treating some common seizure types encountered in DD epilepsy patients, such as absence and myoclonic and atonic seizures. Further, anecdotal experience in DD adults suggests that some patients may develop agitation.

The absence of protein binding or serious metabolic interactions gives GBP an excellent safety profile when used in combination therapy.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

In a double-blind, placebo-controlled trial of LTG in treating the Lennox-Gastaut syndrome,88 33% of patients receiving LTG experienced a reduction in seizure frequency of at least 50%. This study noted minimal behavioral effects.

Two subsequent series found significant effects, both positive and negative, among DD epilepsy patients treated with LTG:

• Beran and Gibson89 noted the development of aggressive or violent behavior (or both) in 14 of 19 patients who received LTG. One patient demonstrated behavioral improvement.
• Ettinger et al.90 cited 3 of 20 mentally retarded epilepsy patients receiving LTG who developed new or worsened hyperactivity, irritability, and stereotypy. Conversely, another four patients exhibited positive psychotropic effects, including reduction in irritability and hyperactivity, decreased lethargy, diminished perseverative speech, or improvement in cooperation and better social engagement. Although behavioral improvements may have represented a mood-stabilizing effect of LTG in some, with increased alerting leading to irritability in others, the reasons for these disparate effects was unclear. Serum LTG levels did not predict who developed positive versus negative symptoms.

Anecdotal experience in epilepsy patients suggests that LTG may enhance alertness.

LTG now is being used for treatment-resistant bipolar disorder.91–93 Although more published double-blind trials address the use of carbamazepine and valproic acid, LTG (as well as gabapentin) appears to have a more favorable side effect profile, making it a better choice for mood stabilization in bipolar disorder.

A positive psychotropic effect of LTG is supported by the observation that several epilepsy patients who were entered in a randomized double-blind study of LTG and experienced only slight reductions in seizure severity still elected to remain in the drug trial and demonstrated elevated mood on quality-of-life measures.94 Meador and Baker95 also have shown LTG to possess favorable behavioral and cognitive effects.

DD patients receiving LTG should be observed for the development of allergic reactions, including pruritus and rash, which can progress to potentially life-threatening Stevens- Johnson syndrome.96

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Phenytoin (PHT) is used commonly in patients with partial and generalized tonic-clonic seizures but is not effective for absence seizures.40

Dose-related sedation may occur, or a paradoxical excited delirium may be seen with either therapeutic or toxic PHT levels.42

PHT’s mild effects on cognition are well known. Some studies have demonstrated PHT- induced memory impairments, and others have shown impairments in complex reaction time or motor speed.43,44

Variable reports cite a relationship between PHT and depressive symptoms. Some of this relationship may involve reactive symptoms from experiencing the stigma associated with cosmetic side effects of the drug.41

An older literature describes a chronic cumulative encephalopathy that has an impact on both behavior and global cognition4 and an acute reversible encephalopathy (manifested by increased seizures, drowsiness, and cognitive impairment, sometimes with ataxia) accompanying toxic PHT levels.42 These encephalopathic syndromes should be considered in evaluating developmentally disabled patients who have shown declines in cognition or coordination. Switching of AEDs should be considered if this potentially reversible syndrome is suspected.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Tiagabine (TGB), approved as adjunctive therapy for partial seizures, is a generally well-tolerated AED. Its central nervous system side effects resemble those of most other AEDs, including dizziness, headache, ataxia, and nervousness.97

One study of its use in treating patients with intractable epilepsy demonstrated mood improvements among patients converted to TGB monotherapy. Mood elevation was not correlated with seizure reduction, suggesting that positive psychotropic benefits may be independent of antiepileptic effects.98 Other series have noted TGB-related emotional lability and depression.100

Limited case series also note potential benefits against bipolar disorder.99

A rare cause of personality changes and behavioral abnormalities in patients receiving TGB for partial seizures is TGB-induced absence status epilepticus.101

The literature regarding the use of TGB in people with developmental disabilities (DD) is sparse, perhaps because of its limited utility in generalized seizure disorders. Some have suggested that significant numbers of patients left TGB drug trials as a result of developing depressive symptoms.102 However, Dodrill et al.103 demonstrated improved mood and psychosocial adjustment when patients were switched from other AEDs to TGB monotherapy.98 Studies of TGB in DD populations have shown no obvious deleterious cognitive side effects.103,104

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Attentional disturbances and psychomotor slowing have been reported commonly.116 In double-blind, placebo-controlled, and open label trials of TPM for partial seizures, the most common adverse effects observed in more than 10% of subjects included:

• somnolence
• psychomotor slowing
• difficulty with memory
• difficulty with concentration or attention
• speech or language problems (Dr. Natalie Addi, Ortho-McNeil Pharmaceuticals, personal communication, November 1999)117

Slow escalation of TPM dose and reduction of polypharmacy may improve tolerance of the drug.118,119

Among healthy young adults randomly assigned in blinded fashion to receive TPM, gabapentin, or lamotrigine,74 only the TPM group demonstrated statistically significant declines in measures of attention and word fluency at acute doses and persisting at 2- and 4-week intervals. Although TPM acute dosing was higher and chronic administration was escalated more rapidly than in current clinical practice, this study supports previous experience with TPM. Self-reported ratings on the anger-hostility subscales of the Profile of Mood States inventory also were elevated in the TPM group.

A recent, double-blind, randomized trial of TPM in treating Lennox-Gastaut syndrome found that 33% of patients had at least a 50% reduction in seizures.120 In this study, adverse effects included

• somnolence (42%)
• anorexia (40%)
• nervousness (21%)
• behavioral problems (21%)

Although no patients discontinued therapy because of an adverse event, one wonders whether this population may have been too cognitively impaired to communicate about the severity of their distress from side effects. It remains unclear whether TPM's compromising effects on cognitive function in patients with developmental disability are mild or severe, and how much impact these effects have on the drug’s risk-benefit ratio.

Anecdotal experience and several reports also suggest that TPM may cause symptoms of depression,121–124 although this may be partially a reaction to the cognitive side effects. Anxiety, irritability, behavioral problems, and even symptoms of psychosis also have been noted in patients treated with TPM.5,125 Acute psychotic symptoms have been shown to be associated with initiation of TPM.

In contrast, a few recent reports indicate that TPM may be useful in treating both the manic and depressive phases of bipolar disorder.126–128 Unlike other medications used to treat bipolar disorder, which tend to cause significant weight gain, TPM promotes weight loss.129

Patients using TPM should be advised to drink plenty of fluids, as TPM may be associated with a twofold to fourfold increased risk for nephrolithiasis.121,130

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Valproic acid (VPA) has broad-spectrum anticonvulsant properties and is effective against many seizure types (e.g., atonic, myoclonic, atypical absence, and generalized tonic-clonic seizures) common to the population with developmental disability (DD).47 In one recent series, VPA was the AED prescribed most commonly in a population-based cohort of adults with a learning disability and epilepsy.48

Like carbamazepine, VPA is used commonly to treat bipolar affective disorder, particularly in patients who do not respond adequately to lithium, so it is speculated to have mood-stabilizing properties in epilepsy patients as well.49,50

VPA also may be useful in the treatment of panic and, possibly, of obsessive-compulsive disorder.51 Agitation and mood problems in association with central nervous system abnormalities, such as head trauma or seizures, may be particularly responsive to VPA therapy.52

VPA may lessen irritability and aggressive or self-injurious behavior among nonepileptic DD patients, including patients with dementia.53,54

Although, for most patients, VPA has minimal cognitive side effects,56,57 it may cause somnolence and rare acute toxic encephalopathies.58,59 In children with learning disabilities and complex partial seizures, VPA has been reported to induce or exacerbate hyperactivity and aggressive behavior.60 Similar kinds of reports have been noted with other AEDs, such as gabapentin, however.

Notable adverse effects of VPA include:55

• weight gain
• gastrointestinal upset
• hyperandrogenism
• polycystic ovary syndrome (PCOS)
• neural tube defects in the offspring of pregnant patients

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Vigabatrin (VGB), which has been prescribed extensively outside the United States, appears to have a significant risk of inducing adverse psychiatric events, particularly psychosis.105 Patients at risk for such outcomes may include those with:

• severe epileptic disorders
• sudden reduction in seizure frequency
• history of psychosis

In children with static encephalopathies or hyperactive behavior, VGB (especially in high doses) may exacerbate hyperkinesia.106,107 Caution is advised, therefore, in using VGB in patients with established psychopathology or static encephalopathies. Doses should be advanced slowly, and acute withdrawal of the drug should be avoided.108

Some reports of favorable psychotropic effects, such as its utility in treating posttraumatic stress disorder, also have been published.109 Concerns about VGB- associated restriction of visual field may limit its widespread use in epilepsy patients.110 http://www.epilepsy.com/medications/i_sabril_visual_effects.html

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

Vagus nerve stimulation (VNS)—a novel therapy for partial and generalized epilepsy—involves the repetitive stimulation of the left vagus nerve via connections from a programmable neurocybernetic prosthesis implanted in the left upper chest region.131 Intermittent stimulation of the vagus nerve may be supplemented by additional activation of the device at the onset of a seizure by holding a magnet over the left chest wall region.

VNS is a generally well-tolerated treatment. Adverse events include hoarseness, tingling sensations in the neck, or intermittent voice alterations, all of which usually abate significantly over time.

Although VNS therapy is more invasive than the administration of antiepileptic drugs (AEDs), it has a number of advantages over typical AED treatment, especially an absence of central nervous system side effects such as sedation and impairment of cognition.

Although VNS has been studied more extensively in the epilepsy patients with partial seizures and no developmental disabilities (DD), it is a welcome addition to the therapeutic armamentarium against refractory generalized epilepsy syndromes common to the DD population, such as Lennox-Gastaut syndrome.133 Preliminary reports of VNS experience in this population have been impressive, reporting reductions in seizures and increased attention and alertness.134 In one report of 15 children with the Lennox-Gastaut syndrome or myoclonic epilepsies of infancy,135 more than 25% of patients had seizure reduction greater than 50%. The methods for supporting the claim that behavioral improvements occurred independent of seizure reduction were not clarified.

Many clinicians may be concerned about implanting devices in DD patients, fearing that patients will pull at the operative site in the chest wall. Recent experience with VNS has defied these concerns, with good tolerance of the implant. Nevertheless, such patients should be watched carefully in the immediate postoperative period (Paul Devereaux, Cyberonics Corporation, personal communication, November 1999).

Animal models and recent human studies suggest that VNS may enhance memory. Electrical stimulation of the vagus nerve delivered after an aversive learning experience has been shown to improve later retention performance in rats.136 In non-DD epilepsy patients, a protocol administering electrical stimulation of the vagus nerve versus sham stimulation demonstrated statistically significant higher recognition memory resulting from the former protocol.137 These studies offer hope for patients with the cognitive impairments so common among epilepsy patients.

Preliminary evidence from two studies suggests that VNS may reduce symptoms of depression in adult epilepsy patients.138,139 One study found a trend toward statistically significant reduction of dysthymic symptoms on the Cornell Dysthymia Rating Scale as compared to symptoms in control patients, although notably no significant differences were noted on other mood inventories. No correlation was seen between seizure reduction and mood improvements, but specifics of this analysis must be clarified further. Studies also are under way examining the potential role of VNS in treating primary depression in nonepilepsy patients.

Little information is available about the psychotropic effects of VNS in DD epilepsy patients. However, the aforementioned studies in nonepilepsy patients and the potential to reduce the dosage or number of AEDs given to such patients offer optimism for improving mood and cognition in this population.

Adapted from: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised June 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

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4. Rivinus TM. Psychiatric effects of the anticonvulsant regimens. J Clin Psychopharmacol 1982;2:165–192.

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From: Ettinger AB, Barr WB, and Solomon SP. Psychotropic properties of antiepileptic drugs in patients with developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;219–230.
With permission from Elsevier (www.elsevier.com).

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