What constitutes high quality of care for adults with epilepsy?

BACKGROUND: Providers are increasingly being held accountable for the quality of care provided. While quality indicators have been used to benchmark the quality of care for a number of other disease states, no such measures are available for evaluating the quality of care provided to adults with epilepsy. In order to assess and improve quality of care, it is critical to develop valid quality indicators. Our objective is to describe the development of quality indicators for evaluating care of adults with epilepsy. As most care is provided in primary and general neurology care, we focused our assessment of quality on care within primary care and general neurology clinics. METHODS: We reviewed existing national clinical guidelines and systematic reviews of the literature to develop an initial list of quality indicators; supplemented the list with indicators derived from patient focus groups; and convened a 10-member expert panel to rate the appropriateness, reliability, and necessity of each quality indicator. RESULTS: From the original 37 evidence-based and 10 patient-based quality indicators, the panel identified 24 evidence-based and 5 patient-based indicators as appropriate indicators of quality. Of these, the panel identified 9 that were not necessary for high quality care. CONCLUSION: There is, at best, a poor understanding of the quality of care provided for adults with epilepsy. These indicators, developed based on published evidence, expert opinion, and patient perceptions, provide a basis to assess and improve the quality of care for this population.

Long-term seizure outcome in patients initially seizure-free after resective epilepsy surgery.

OBJECTIVE: To evaluate the likelihood of and risk factors for seizure recurrence in patients initially seizure-free after resective surgery for intractable epilepsy. METHODS: One hundred seventy-five patients who underwent lobectomy between 1972 and 1992 and were seizure-free during the first postoperative year were retrospectively studied. Outcome was measured by relapse risk, presence of auras in otherwise seizure-free patients, and seizure frequency among relapsers. Factors significant in bivariate or Kaplan-Meier analysis or considered potentially predictive a priori were included in multivariate models. RESULTS: Of the 175 patients (mean follow-up 8.4 years), 63% never relapsed. The likelihood of being seizure-free was 83 +/- 6% 3 years after surgery, 72 +/- 7% after 5 years, and 56 +/- 9% after 10 years. After adjusting for age at surgery, duration of preoperative epilepsy, and resection site, normal pathology was associated with increased risk of relapse compared to mesial temporal sclerosis or other pathology (p = 0.036; hazard ratio [HR] 2.38; 95% CI 1.06 to 5.34). Among patients otherwise seizure-free, preoperative illness of > or =20 years was associated with increased risk of postoperative auras (p = 0.040; HR 3.55; 95% CI 1.06 to 11.90). Among relapsers, 51% experienced one or fewer seizures per year. Normal pathology and earlier relapse were associated with higher postoperative seizure frequency. CONCLUSIONS: In patients seizure-free during the first year after resective epilepsy surgery, the likelihood of remaining seizure-free declined to 56% over 10 years, but half of patients who relapsed had at most one seizure per year. Longer preoperative illness and normal pathology predicted poorer outcome.

Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.

OBJECTIVES: To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized. RESULTS: No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events. CONCLUSION: In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.

GABA and the ornithine delta-aminotransferase gene in vigabatrin-associated visual field defects.

Vigabatrin use in some epilepsy patients has been associated with persistent visual field constriction and retinal dysfunction. The mechanism is unknown, but could be related to vigabatrin, chronic epilepsy, GABA toxicity, or the effect of a metabolite in combination with a predisposing genotype. The aim of this study was to investigate the latter two hypotheses. Levels of brain gamma-aminobutyric acid (GABA) measured by nuclear magnetic resonance spectroscopy were similar in subjects taking vigabatrin who developed visual field constriction and those who did not. We tested whether allelic heterogeneity of the ornithine aminotransferase gene occurs in the affected patients. No clinically significant mutation was detected, although a common intronic polymorphism was identified.

Monotherapy trials: endpoints.

Monotherapy antiepileptic drug (AED) trials can optimally provide information concerning efficacy and tolerability of one drug compared with placebo, as well as to different doses or rates of administration. Commonly, a drug is compared with one or more other drugs. The outcome measures will be dictated by the questions being asked. In most comparative studies, the single overall result that best defines success or failure is time of continuation on drug as expressed in a life table. Discontinuation before planned completion of the study implies insufficient efficacy or unacceptable adverse effects. A statistically significant difference between treatments provides important support for recommending the drug or dose with the best outcome. The criteria for continuation/discontinuation are defined in the design based on the expected outcome. The outcome of primary importance is efficacy in prevention of seizures or a decrease in severity. Complete control for the duration of the study is the ultimate goal but in some populations may not be possible. The number of subjects entering remission gives further information about long term outcome. Time to first (nth) seizure provides similar evidence of efficacy. Seizure rates allow comparisons of subjects retained for different lengths of time in the trial. Differences in seizure severity may be of clinical importance and multiple efforts have been made to develop instruments to accurately measure this outcome. Adverse effects of the drugs are the second major outcome. These can be expressed as incidence and/or prevalence. The presence and frequency of side effects will depend on how the study is designed and whether these effects are specifically sought by the investigators. Serious systemic safety outcomes are monitored, but the relative infrequency of occurrence and number of subjects in the trials usually do not provide enough power to detect statistically significant differences except for rash. Tolerability is more easily documented but is difficult to access accurately in the absence of placebo controls. Frequency, severity and persistence are measurable. Specific unwanted types of drug effects can be specifically studied using detailed neuropsychological test batteries. Some information concerning pharmacokinetic properties may be obtained but are better assessed in other types of trials. A final important outcome is the effect of drug therapy on quality of life. Although a favorable finding in this outcome is most desirable, the measures used are much less precise than those for efficacy and adverse effects.

Topiramate rapidly raises brain GABA in epilepsy patients.

PURPOSE: The short- and long-term pharmacodynamic effects of topiramate (TPM) on brain gammay-aminobutyric acid (GABA) metabolism were studied in patients with complex partial seizures. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Fifteen patients (four men) were studied serially after the first, oral dose (100 mg) of TPM. RESULTS: The first dose of TPM increased brain GABA within 1 h. Within 4 h, GABA was increased by 0.9 mM (95% CI, 0.7-1.1). Brain GABA remained elevated for > or =24 h. Pyrrolidinone and homocarnosine increased slowly during the first day. Daily TPM therapy (median, 300 mg; range, 200-500) increased GABA (0.3 mM; 95% CI, 0.1-0.5), homocarnosine (0.4 mM; 95% CI, 0.3-0.5), and pyrrolidinone (0.15 mM; 95% CI, 0.10-0.19), compared with levels before TPM. There was no dose response evident with daily TPM doses of 200-500 mg. CONCLUSIONS: TPM promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the effects of increased homocarnosine and pyrrolidinone within 24 h.

Human GABA(B) receptor 1 gene: eight novel sequence variants.

GABA (gamma-aminobutyric acid) is the principal inhibitory neurotransmitter in the brain. The human GABA(B) receptor (GABBR1) maps to the human leukocyte antigen (HLA) region of chromosome 6. Its function and location in a susceptibility region for schizophrenia, epilepsy, and dyslexia make GABBR1 a candidate gene for neurobehavioral disorders. We report the characterization of GABBR1 gene mutations in 100 chromosomes from a mixed American population. Eleven distinct mutations were found, including two previously reported missense mutations (A20V and G489S) and a previously reported silent 1977 T>C transition. Here, we report four novel silent substitutions (39C>T, 1473T>C, 1476T>C, 1545T>C) and four novel intron variants. These DNA variants may be useful in association and linkage studies of neurobehavioral disorders, and in pharmacogenetic studies of drugs targeting GABBR1.

Homocarnosine and seizure control in juvenile myoclonic epilepsy and complex partial seizures.

OBJECTIVE: To assess the relationship between seizure control and gamma-aminobutyric acid (GABA), homocarnosine, and pyrrolidinone levels in the visual cortex of patients with epilepsy taking valproate or lamotrigine. Previous studies suggested that poor seizure control was associated with low GABA and homocarnosine levels. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made in a 14-cm(3) volume of the occipital cortex using (1)H spectroscopy with a 2.1-Tesla MR spectrometer and an 8-cm surface coil. Twenty-six adults (eight men) taking valproate or lamotrigine were recruited; 12 had complex partial seizures (CPS) and 14 had juvenile myoclonic epilepsy (JME). RESULTS: Median homocarnosine levels were normal for patients with JME and below normal for patients with CPS. Better seizure control was associated with higher homocarnosine levels for both groups. Median GABA was below normal for patients with JME, lower than for patients with CPS. Brain GABA was lowest in patients with JME even when seizure control was excellent. Pyrrolidinone levels were above normal in almost all patients with JME. CONCLUSIONS: Low GABA levels are associated with poor seizure control in patients with CPS, but not in JME. Higher homocarnosine levels are associated with better seizure control in both types of epilepsy.

A comparison of four new antiepileptic medications.

In order to select a new medication for a patient with epilepsy, it would be helpful to have an idea of which drug might have the greatest overall chance for success. Since epilepsy is a chronic disorder, the long-term effectiveness and tolerability of the medications are very important. Here, we compared gabapentin, lamotrigine, topiramate and vigabatrin using Kaplan-Meier survival analysis to see how long patients chose to stay on each drug and if they stopped, why they stopped. The results seem to suggest the type of responses to be expected in a hospital seizure clinic.

Effects of gabapentin on brain GABA, homocarnosine, and pyrrolidinone in epilepsy patients.

PURPOSE: Gabapentin (GBP) was introduced as an antiepileptic drug (AED) and has been used in the management of neuropathic pain. We reported that daily dosing increased brain gamma-aminobutyric acid (GABA) in patients with epilepsy. This study was designed to determine how rapidly brain GABA and the GABA metabolites, homocarnosine and pyrrolidinone, increase in response to the first dose of GBP. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cc volume in the occipital cortex by using a 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (four women) were studied serially after the first oral dose (1,200 mg) of GBP. Five patients (three women) taking a standard daily dose (range, 1,200-2,000 mg) of GBP were rechallenged with a single high dose (2,400 mg). RESULTS: The first dose of GBP increased median brain GABA by 1.3 mM (range, 0.4-1.8 mM) within 1 h. Homocarnosine and pyrrolidinone did not change significantly by 5 h. Daily GBP therapy increased GABA (0.5 mM; 95% CI, 0.2-0.9), homocarnosine (0.3 mM; 95% CI, 0.2-0.4), and pyrrolidinone (0.10 mM; 95% CI, 0.06-0.14). Rechallenging patients taking GBP daily increased median brain GABA by 0.4 mM (range, 0.3-0.5) within 1 h. CONCLUSIONS: GBP promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Patients may expect to experience the anticonvulsant effects of increased homocarnosine and pyrrolidinone with daily therapy.

Effects of vigabatrin on the GABAergic system as determined by [123I]iomazenil SPECT and GABA MRS.

PURPOSE: To evaluate effects of vigabatrin (VGB) by using [123I]iomazenil single-photon emission computed tomography (SPECT) to estimate central gamma-aminobutyric acid (GABA(A))/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels. METHODS: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g p.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T1-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [123I]iomazenil concentration to estimate BZR distribution volume (V(T)-p and V'(T), respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V(T)-p or V'(T). SPM96 (either no global normalization or proportional scaling) was used to compare BZR V(T)-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls. RESULTS: Occipital GABA levels were increased threefold (without VGB, 1.1+/-0.1 micromol/g; with VGB, 2.9+/-0.5 micromol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V(T)-p (without VGB, 6.00+/-0.91 ml/g; with VGB, 5.86+/-0.44 ml/g; p = 0.92) or V(T) (without VGB, 41.1+/-11.2 ml/g; with VGB, 41.2+/-9.9 ml/g; p = 0.75). No significant changes were detected by SPM96. CONCLUSIONS: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation.

Acute effects of vigabatrin on brain GABA and homocarnosine in patients with complex partial seizures.

PURPOSE: The acute, subacute, and chronic effects of vigabatrin (VGB) were studied in patients with refractory complex partial seizures. VGB increases human brain gamma-aminobutyric acid (GABA) and the related metabolites, homocarnosine and 2-pyrrolidinone. METHODS: In vivo measurements of GABA and homocarnosine were made of a 14-cc volume in the occipital cortex by using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Six patients (three women) were studied serially during the initiation and maintenance of VGB as adjunct therapy. RESULTS: The first, 3 g dose of VGB increased brain GABA by 2.0 micromol/g within 81 min of oral administration. After 2 h, median edited GABA remained essentially the same for 2 days. The response to the second, 3-g dose of VGB given at 48 h was considerably less than that to the first dose, with a median increase of 0.5 micromol/g within 72 min. After 2-3 months, rechallenging patients taking 1.5-g VGB twice daily with 6 g increased GABA by 0.4 micromol/g within 87 min. Homocarnosine increased more gradually than GABA to above-normal levels after a week of VGB therapy. CONCLUSIONS: VGB promptly elevates brain GABA and presumably offers partial protection against further seizures within hours of the first oral dose. Once-a-day dosing is sufficient to increase GABA. Patients may be expected to experience the effects of increased homocarnosine within 1 week.

New antiepileptic drugs: comparison of key clinical trials.

PURPOSE: Data accrued from clinical trials of five new antiepileptic drugs (AEDs) are compared for efficacy in reducing seizures and self-reported adverse events as a basis of selection among new AEDs. Drawbacks to use of these data also are demonstrated. METHODS: A review of double-blind, placebo-controlled clinical trials of a new AED or placebo added to a standard AED provided data on reduction of complex partial seizures (CPSs). Success is > or =50% fewer CPSs with a new AED or placebo; Overall Improvement is the success rate with drug minus the success rate with placebo. Adverse events were tabulated from product-labeling lists of COSTART items (incidence, > or =5%). The Summary Complaint score is the total number of reports of individual events for each AED. RESULTS: Efficacy data demonstrate differences in Overall Improvement rates among five new AEDs and placebos (p = 0.001). However, rates of response to placebo also differed significantly among trials (p = 0.01). Adverse events predominantly affect central nervous system, psychiatric, and general body systems. However, patients in the placebo control groups did not consistently report adverse effects. Summary Complaint scores differ among the five new AEDs, but variability in use of COSTART terms nullifies comparisons. CONCLUSIONS: Comparisons of data for five new AEDs provide information for selection among treatments when a second drug is needed to improve control of CPSs. However, significant differences among the control groups and other problems make comparisons between trials problematic. The final choice should be based on the need of the individual patient for superior seizure control versus minimal adverse effects.

Effects of valproate and other antiepileptic drugs on brain glutamate, glutamine, and GABA in patients with refractory complex partial seizures.

Preclinical studies suggested valproate increased brain gamma-aminobutyric acid (GABA) with no major effects on brain glutamate or glutamine. Valproate increased human cerebrospinal fluid GABA and glutamine in some studies; others reported no effect. In vivo measurements of glutamate, glutamine, and GABA were made of a 14 cm3volume in the occipital cortex using a1H spectroscopy with a 2.1 Tesla magnetic resonance spectrometer and an 8 cm surface coil. Ten control subjects and 14 patients with refractory complex partial seizures were examined. Brain glutamine concentrations were above normal in three of five patients taking valproate and two of nine taking carbamazepine or phenytoin. Mean glutamine levels of patients taking valproate were higher than control subjects and patients taking carbamazepine or phenytoin. Brain glutamate concentrations were above normal in four of nine patients taking phenytoin or carbamazepine and two of five taking valproate. Brain GABA levels were below normal in four of nine patients taking carbamazepine or phenytoin and one of five taking valproate. Above normal glutamate or below normal GABA was present in nine of 14 patients and may contribute to their refractory epilepsy. Increased brain glutamine associated with valproate therapy may reflect mild hyperammonemia.

Localized 1H NMR measurements of 2-pyrrolidinone in human brain in vivo.

Localized 1H NMR homonuclear J editing spectroscopy was used to measure the concentration of 2-pyrrolidinone (PRDN) in the human occipital lobe of five normal and six epileptic subjects taking vigabatrin. PRDN is a lactam cyclization product of gamma-aminobutyric acid (GABA). From a localized volume of 13.5 cm3 in the occipital cortex, the concentration of PRDN ranged from 0.2 to 0.3 micromol/g in normal subjects, whereas in epileptic subjects on vigabatrin PRDN was elevated to 0.6 +/- 0.1 micromol/g. The elevated PRDN in patients on vigabatrin was in accord with raised GABA levels compared with normals. 1H NMR measurements of PRDN will be important in assessment of the role of this metabolite for improved seizure control.

Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy.

OBJECTIVE: To measure the effects of topiramate on brain gamma-aminobutyric acid (GABA) in patients with epilepsy. BACKGROUND: Topiramate is a new antiepileptic medication with multiple putative mechanisms of action. In a recent meta-analysis of the newer antiepileptic drugs, topiramate was the most potent. Homocarnosine and pyrrolidinone are important metabolites of GABA with antiepileptic actions. METHODS: In vivo measurements of GABA, homocarnosine, and pyrrolidinone were made of a 14-cm3 volume in the occipital cortex using 1H spectroscopy with a 2.1-Tesla magnetic resonance spectrometer and an 8-cm surface coil. Twelve patients (eight women) with refractory complex partial seizures were studied while using topiramate. Nine epilepsy-free, drug-free volunteers served as control subjects. RESULTS: Topiramate increased mean brain GABA, homocarnosine, and pyrrolidinone concentrations in all patients. In paired measurements, brain GABA increased by 0.7 micromol/g (SD 0.3, n 7, 95% CI 0.4 to 1.0, p < 0.01). Homocarnosine increased by 0.5 micromol/g (SD 0.2, n 7, 95% CI 0.3 to 0.7, p < 0.001). Pyrrolidinone increased by 0.21 micromol/g (SD 0.06, n 7, 95% CI 0.16 to 0.27, p < 0.01). In two additional patients, GABA, homocarnosine, and pyrrolidinone increased after they were switched from vigabatrin to topiramate. CONCLUSIONS: Topiramate increased brain GABA, homocarnosine, and pyrrolidinone to levels that could contribute to its potent antiepileptic action in patients with complex partial seizures.

Vigabatrin increases human brain homocarnosine and improves seizure control.

Homocarnosine, a dipeptide of gamma-aminobutyric acid (GABA) and histidine, is thought to be an inhibitory neuromodulator synthesized in subclasses of GABAergic neurons. Homocarnosine is present in human brain in greater amounts (0.4-1.0 micromol/g) than in other animals. The antiepileptic drug vigabatrin increases human cerebrospinal fluid homocarnosine linearly with daily dose. By using 1H nuclear magnetic resonance spectroscopy, serial occipital lobe GABA and homocarnosine concentrations were measured in 11 patients started on vigabatrin. Daily low-dose (2 g) vigabatrin increased both homocarnosine and GABA. Larger doses of vigabatrin (4 g) further increased homocarnosine but changed GABA levels minimally. Seizure control improved with increasing homocarnosine and GABA concentrations. Patients whose seizure control improved with the addition of vigabatrin had higher mean homocarnosine, but the same mean GABA concentrations, than those whose seizure control did not improve. Increased homocarnosine may contribute to improved seizure control.

Medial temporal lobe epilepsy: videotape analysis of objective clinical seizure characteristics.

PURPOSE: The syndrome of temporal lobe epilepsy has been described in great detail. Here we focus specifically on the clinical manifestations of seizures originating in the hippocampus and surrounding mesial temporal structures. METHODS: Seizure origin was confirmed in 67 cases by depth EEG recording and surgical cure after mesial temporal resection. RESULTS: Among nonlateralized manifestations, we commonly found oral automatisms, pupillary dilatation, impaired consciousness, and generalized rigidity. Appendicular automatisms were often ipsilateral to the seizure focus, whereas dystonia and postictal hemiparesis were usually contralateral. Head deviation, when it occurred early in the seizure, was an ipsilateral finding, but was contralateral to the seizure focus when it occurred late. Clear ictal speech and quick recovery were found when seizures originated in the non-language-dominant hemisphere, but postictal aphasia and prolonged recovery time were characteristic of seizure origin in the language-dominant hemisphere. CONCLUSIONS: These signs help to define the mesial temporal lobe epilepsy (MTLE) syndrome and often provide information as to the side of seizure origin.

Medical management of epilepsy in adults.

Optimal treatment of epilepsy in adults requires a tailored approach that weighs the efficacy of individual drugs in the specific diagnosis against the patient's risks for adverse events. Partial seizures, which are the most common seizure type in adults, can be effectively controlled by virtually all the standard and newer antiepileptic drugs (AEDs). For the generalized epilepsies, valproate remains the drug of choice. Data continue to accumulate regarding use of the newer agents. Overall, many of the newer AEDs may offer a better tolerability than the standard agents because of more favorable pharmacokinetic characteristics and lack of interactions with drugs other than AEDs. Serious adverse events have been associated with felbamate and lamotrigine, however, and more experience is needed with many of the other newer AEDs to better define their safety profiles. Monotherapy should be the goal when AED treatment is instituted for the adult with epilepsy. Dosage modification on the basis of seizure control and toxicity should be implemented, as well as single-drug trials with alternative AEDs, before resorting to polytherapy. With the introduction of several promising newer AEDs, safe and effective seizure control may become a reality for an increasing number of adults with epilepsy.