Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial.

OBJECTIVE: To assess progesterone treatment of intractable seizures in women with partial epilepsy. METHODS: This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles. RESULTS: There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3. CONCLUSION: There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.

Evidence-based guideline update: intraoperative spinal monitoring with somatosensory and transcranial electrical motor evoked potentials: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Clinical Neurophysiology Society.

OBJECTIVE: To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predicts adverse surgical outcomes. METHODS: A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified according to the evidence-based methodology of the American Academy of Neurology. Objective outcomes of postoperative onset of paraparesis, paraplegia, and quadriplegia were used because no randomized or masked studies were available. RESULTS AND RECOMMENDATIONS: Four Class I and 8 Class II studies met inclusion criteria for analysis. The 4 Class I studies and 7 of the 8 Class II studies reached significance in showing that paraparesis, paraplegia, and quadriplegia occurred in the IOM patients with EP changes compared with the IOM group without EP changes. All studies were consistent in showing all occurrences of paraparesis, paraplegia, and quadriplegia in the IOM patients with EP changes, with no occurrences of paraparesis, paraplegia, and quadriplegia in patients without EP changes. In the Class I studies, 16%-40% of the IOM patients with EP changes developed postoperative-onset paraparesis, paraplegia, or quadriplegia. IOM is established as effective to predict an increased risk of the adverse outcomes of paraparesis, paraplegia, and quadriplegia in spinal surgery (4 Class I and 7 Class II studies). Surgeons and other members of the operating team should be alerted to the increased risk of severe adverse neurologic outcomes in patients with important IOM changes (Level A).

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): vitamin K, folic acid, blood levels, and breastfeeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. METHODS: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. RESULTS: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. RECOMMENDATIONS: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. METHODS: A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008. RESULTS: For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%-92%) of remaining seizure-free during pregnancy. RECOMMENDATIONS: Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%-92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).

Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society.

OBJECTIVE: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. METHODS: Systematic review of relevant articles published between January 1985 and June 2007. RESULTS: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. RECOMMENDATIONS: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).

Pregnancy registries in epilepsy: a consensus statement on health outcomes.

Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

Reassessment: neuroimaging in the emergency patient presenting with seizure (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To reassess the value of neuroimaging of the emergency patient presenting with seizure as a screening procedure for providing information that will change acute management, and to reassess clinical and historical features associated with an abnormal neuroimaging study in these patients. METHODS: A broad-based panel with topic expertise evaluated the available evidence based on a structured literature review using a Medline search from 1966 until November 2004. RESULTS: The 15 articles meeting criteria were Class II or III evidence since interpretation was not masked to the patient's clinical presentation; most were series including 22 to 875 patients. There is evidence that for adults with first seizure, cranial CT will change acute management in 9 to 17% of patients. CT in the emergency department for children presenting with first seizure will change acute management in approximately 3 to 8%. There is no clear difference between rates of abnormal emergent CT for patients with chronic seizures vs first. Children <6 months presenting with seizures have clinically relevant abnormalities on CT scans 50% of the time. Persons with AIDS and first seizure have high rates of abnormalities, and CNS toxoplasmosis is frequently found. Abnormal neurologic examination, predisposing history, or focal seizure onset are probably predictive of an abnormal CT study in this context. CONCLUSIONS: Immediate noncontrast CT is possibly useful for emergency patients presenting with seizure to guide appropriate acute management especially where there is an abnormal neurologic examination, predisposing history, or focal seizure onset.

An analysis of lifetime fractures in women with epilepsy.

OBJECTIVE: To clarify the relationship between fractures and antiepileptic drug (AED) use. METHODS: Menopausal women with epilepsy were interviewed at two clinics regarding site, year and circumstances of any fracture, duration of AED use and menopause. Fracture sites were analyzed according to AED use. RESULTS: Twenty-nine fractures occurred in 20 of the 50 interviewed subjects (mean age 54). Nine occurred prior to AEDs; seven attributed to accident and two to clumsiness. Twenty occurred on AEDs; 10 attributed to clumsiness (most in the leg and foot), eight to seizure (most in the arm or hand) and two to accident. Duration of AED exposure was similar in both groups and in osteoporotic vs non-osteoporotic sites. CONCLUSIONS: Epilepsy therapy may contribute more to the lifetime occurrence of fracture than seizures themselves. More screening for osteoporosis is required. While adjusting doses to prevent seizures, ongoing screening for neurotoxicity must be maintained in order to avoid fractures.

Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Seizure frequency is associated with age at menopause in women with epilepsy.

OBJECTIVE: To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. METHODS: Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. RESULTS: Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. CONCLUSIONS: Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.

Topiramate titration and tolerability.

OBJECTIVE: To evaluate the tolerability and efficacy of two titration rates for topiramate initiated as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization, in a multicenter, double-blindtrial. METHODS: After a two-week baseline phase, 188 patients were randomized to either a 50/50 titration schedule (initial dosage 50 mg/d increased in 50-mg/d increments at weekly intervals; n = 95) or to a 100/200 titration schedule (initial dosage 100 mg/d increased by 100-200 mg/d at weekly intervals; n = 93). The maximum dosage of 400 mg/d was therefore achieved in eight weeks or three weeks, respectively. RESULTS: Compared with the 100/200 titration rate, the 50/50 titration rate significantly reduced the cumulative incidence of treatment-emergent adverse events (TEAEs) leading to changes in topiramate therapy (ie., dosage reductions, interruptions or discontinuations of therapy) (p = 0.048) and significantly reduced treatment interruptions or withdrawals due to TEAEs (p = 0.040). Mild or moderate effects involving the central nervous system were the most frequent adverse events. At the final visit, therapeutic responses were comparable in the 50/50 and 100/200 titration groups: median percent seizure reduction was 42% vs. 33%, proportion of patients with 250% seizure reduction was 42% vs. 38%, and proportion of patients with no seizures during double-blind treatment was 14% vs. 10%, respectively. Seizure frequency was substantially reduced from baseline during topiramate titration. At day 22, with the 50/50 titration group receiving 150 mg/d and the 100/200 titration group receiving 400 mg/d, the mean percent seizure reduction was 51% and 54%, respectively. CONCLUSIONS: Gradual initiation of topiramate therapy can significantly enhance patient tolerability without delaying therapeutic response.

Therapeutic safety monitoring: what to look for and when to look for it.

This review focuses on the safety problems associated with antiepileptic drugs (AEDs) as revealed by laboratory testing and clinical examination. There are two classes of side effects: (a) common and mild and (b) rare and severe. Allergic reactions to AEDs are common and usually mild. However, on rare occasions, they can progress to more severe cutaneous disorders, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Severe allergic reactions to AEDs range from immune responses with fever to multiorgan dysfunction. Allergic rashes may be genetically or immunologically determined. Laboratory abnormalities produced by AEDs are common and mild, and include hepatic enzyme elevation associated with phenytoin and mild elevation in ammonia associated with valproate. Serious, although rare, idiosyncratic side effects, such as aplastic anemia, hepatotoxicity, and thrombocytopenia, have also occurred with AEDs. These reactions are largely confined to the "classic" AEDs. With the exception of felbamate, AEDs approved in the past decade have not been plagued by severe idiosyncratic reactions. Subtle endocrine abnormalities, including variations in thyroid function tests and bone metabolism, and the often subclinical effects on peripheral nerve conduction produced by phenytoin and carbamazepine, are also examined.

The effect of menopause and perimenopause on the course of epilepsy.

PURPOSE: The purpose of this study was to obtain preliminary information about the effect of menopause and perimenopause on the course of epilepsy, and to determine whether seizure type, use of hormone-replacement therapy (HRT), or a history of catamenial seizure pattern would influence this course. METHODS: We performed a questionnaire study of women with epilepsy currently in menopause and perimenopause, requesting information regarding the course of their epilepsy and treatment. Statistical analysis was performed by using Pearson chi2 with 95% confidence limits. RESULTS: Forty-two menopausal women (ages 41-86 years) responded. Twelve subjects reported no change in seizures at menopause, 17 reported a decrease in seizure frequency, and 13 reported an increase. Sixteen (38%) took synthetic HRT. Sixteen (38%) additional subjects (having some overlap with the HRT group) reported having a catamenial seizure pattern before menopause. HRT was significantly associated with an increase in seizures during perimenopause (p = 0.001). A history of catamenial seizure pattern was significantly associated with a decrease in seizures at menopause (p = 0.013). Thirty-nine perimenopausal women (ages 38-55 years) responded. Nine subjects reported no change in seizures at perimenopause, five reported a decrease in seizure frequency, and 25 reported an increase. Eight (15%) subjects took synthetic HRT, and 28 (72%) reported having a catamenial seizure pattern before menopause. HRT had no significant effect on seizures; however, a history of catamenial seizure pattern was significantly associated with an increase in seizures at perimenopause (p = 0.02). CONCLUSIONS: These pilot data suggest that synthetic HRT may be associated with an increase in seizure frequency in menopausal women with epilepsy. A catamenial seizure pattern may be associated with seizure decrease during menopause but with an increase during perimenopause.

A beneficial effect on mood in partial epilepsy patients treated with gabapentin.

PURPOSE: Antiepileptic drugs (AEDs) are frequently used for their beneficial psychoactive effects on affective disorders. We sought to demonstrate a psychoactive effect of gabapentin (GBP) when used as add-on AED therapy. METHODS: Forty adult patients with partial epilepsy were studied in a prospective, non-randomized fashion with interviewer-rated and self-rated scales of mood and anxiety: the Cornell Dysthymia Rating Scale (CDRS), Beck Depression Inventory (BDI), and Hamilton Depression (Ham-D) and Anxiety (Ham-A) Scales. After completion of baseline mood and anxiety scales (time 1), 20 of the 40 patients were prescribed add-on GBP (treated group). The remaining 20 patients served as a control group. Both groups were similar in age and sex distribution. Follow-up mood and anxiety scales were performed in all patients approximately 3 months later (time 2). The average GBP dose at time 2 was 1,615 mg/day. All patients were taking stable doses of one to four AEDs at baseline and throughout the study. Seizure frequency was monitored throughout. Statistical significance was assessed by analysis of variance (ANOVA) by using a two-factor repeated-measures model. RESULTS: The GBP-treated group had a significant decrease in CDRS score over time compared with the control group (p = 0.04). No significant differences between the control and the treated groups were found for any of the remaining mood scales (BDI, p = 0.58; Ham-D, p = 0.59; Ham-A, p = 0.93). There was no significant difference or change in seizure frequency between groups. CONCLUSIONS: GBP treatment is associated with mood improvement as measured by the CDRS. This improvement was not accounted for by seizure improvement.

Pseudoseizures and dissociative disorders: a common mechanism involving traumatic experiences.

Patients with psychogenic non-epileptic seizures (pseudoseizures) have been diagnosed as having conversion disorder or dissociative disorder. Pseudoseizure patients frequently report a history of physical and sexual abuse, and traumatic experience is considered part of the mechanism for producing dissociation. Pseudoseizures may be a manifestation of dissociative disorder, especially when a history of sexual or physical abuse is documented. A common mechanism involving traumatic experience may be present in both pseudoseizures and dissociative disorders. A complete neurodiagnostic evaluation along with an awareness of this relationship is needed to provide appropriate care for this patient population.

Felbamate levels in patients with epilepsy.

The usefulness of felbamate (FBM) levels in managing epilepsy patients has not been determined. The purpose of the present study was to determine if FBM levels obtained at routine office visits correlated with side effects reported by patients. We determined FBM levels by high-pressure liquid chromatography (HPLC) of 46 epilepsy patient plasma specimens (41 patients) and assessed medication toxicity and seizure frequency by a questionnaire. Thirty-six patients were treated with other antiepileptic drugs (AEDs); concomitant AED levels not in ranges believed to cause toxicity. FBM levels ranged from 9 to 134 microgram/ml, and were divided into three groups for analysis, resulting in low-range (9-36 microgram/ml), midrange (37-54 microgram/ml), and high-level (44-134 microgram/ml) groups. Anorexia and complaints of severe side effects were reported significantly more often in the high-level group as compared with the low- and midrange groups. Significantly more patients in the high-level group (10/13) reported decreased seizure frequency, as compared with 12 of 30 patients in the low- and midrange groups combined. FBM levels correlated linearly with doses overall, but most closely in FBM monotherapy patients.