Interictal Cardiovascular Autonomic Responses in Patients with Epilepsy

Summary: Purpose: To evaluate the interictal autonomic nervous system function in 84 patients with epilepsy: 37 with newly diagnosed, previously untreated epilepsy, and 47 patients receiving long-term carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA) monotherapy, or CBZ plus PHT, or CBZ plus VPA for their seizure disorder. Methods: We assessed autonomic control of the cardiovascular regulatory system, by standardized cardiovascular reflex tests measuring changes in heart rate (HR) and blood pressure (BP) at rest and after certain stimuli. Results: The HR and BP responses were similar to those of control subjects in patients with newly diagnosed epilepsy. However, HR variation during normal breathing and maximum systolic BP increase in isometric work were diminished in patients, who had been treated with antiepileptic drugs (AEDs) for epilepsy for a long time. Diminished HR responses to the Valsalva maneuver were noted in patients receiving CBZ as monotherapy and during deep breathing in patients receiving CBZ combined with PHT or VPA. Furthermore, patients receiving CBZ had diminished BP responses in isometric work. When analyzed in relation to epilepsy type, suppressed HR responses in normal breathing were associated with primary generalized epilepsy (PGE), whereas diminished BP responses in isometric work were associated with partial epilepsy. Two patients with recently diagnosed partial epilepsy and 1 patient receiving long-term CBZ monotherapy for partial epilepsy had two abnormal cardiovascular response test results. Conclusions: Our results show that cardiovascular responses mediated by both the parasympathetic and sympathetic nervous system are diminished in patients with epilepsy. However, the changes appear to be clinically significant in only a few of them and appear to be associated with CBZ medication. Further studies are needed to detect the underlying complex interactions and clinical significance of autonomic nervous system dysfunction in patients with epilepsy.     

Adverse effects of carbamazepine,phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients

Objective

Antiepileptic drugs (AEDs) have been widely used in patients with epilepsy but the adverse effects in adult Chinese patients have not been investigated. This study evaluated the adverse effects of four commonly prescribed AED monotherapies with carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), and lamotrigine (LTG) in adult Chinese patients with epilepsy.

Methods

The prospective open-label clinical trial was conducted at the Chongqing Epilepsy Center. The study enrolled 505 adults with newly diagnosed epilepsy, including generalized tonic–clonic (n = 110), partial and partial secondarily generalized (n = 395) seizures. Patients were evaluated by two clinicians at the Center and were prescribed one type of AED monotherapy with CBZ, PHT, VPA or LTG for a 24-month period. An adverse effect profile, as well as efficacy of monotherapy, was obtained through a face-to-face interview with the patient at each visit. A physical examination and routine laboratory tests were performed during a clinical screening.

Results

A total of 62.6% (316/505) patients successfully completed the AED monotherapy study: 64.3% of those receiving CBZ, 55.9%—PHT, 61.5%—VPA, and 66.2%—LTG. However, 34.7% of the patients discontinued the AED monotherapy because of unsatisfactory seizure control. Overall, 18% of patients experienced adverse effects: for CBZ (25/168; 14.9%), PHT (18/59; 30.5%), VPA (32/192; 16.7%) and LTG (16/86; 18.6%). The most common drug-related adverse events included gastrointestinal disturbances, loss of appetite and nausea, weight gain and fatigue/tiredness. Tremor and nystagmus occurred in some patients receiving PHT and VPA. Two CBZ, one PHT and four LTG patients (n = 7) discontinued the study due to rash.

Conclusion

Adult Chinese patients with epilepsy accepted and tolerated monotherapy with CBZ, PHT, VPA, and LTG. No fatal adverse events occurred. Unsatisfactory seizure control was a primary reason for withdrawal from the AED monotherapy study.     

Efficacy and Adverse Effects of Established and New Antiepileptic Drugs*

Summary: Antiepileptic drug (AED) selection is based primarily on efficacy for specific seizure types and epileptic syndromes. However, efficacy is often similar for the different AEDs, and other properties such as adverse effects, pharmacokinetic properties, and cost may also be of importance. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the AED of choice is valproate (VPA). Secondarily generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single AED or combination of AEds. The AEDs of choice for absence seizures are ethosuximide (ESM) and VPA. For control of primary generalized tonic-clonic seizures, any of the other major AEDs can be effective. If VPA cannot be prescribed, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), or primidone (PRM) may be effective, but ESM or a benzodiazepine (BZD) must be added to control associated absence or myoclonic seizures. The AEDs of first choice for partial epilepsies with partial and secondarily generalized tonic-clonic seizures are CBZ and PHT. Increasing evidence suggests that VPA is a good alternative when CBZ and PHT fail. PB and PRM are second-choice selections because of adverse effects. A combination of two of the five standard AEDs may be necessary to treat intractable seizures, but no studies have been done to indicate an optimal combination. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, alcoholic epilepsy, and status epilepticus require specific AED treatment. Ultimately, AED selection must be individualized. No “drug of choice” can be named for all patients. The expected efficacy for the seizure type, the importance of the expected adverse effects, the pharmacokinetics, and the cost of the AEDs all must be weighed and discussed with the patient before a choice is made. A number of new AEDs with unique mechanisms of action, pharmacokinetic properties, and fewer adverse effects hold important promise of improved epilepsy treatment.     

Infant Monkey Hyperexcitability After Prenatal Exposure to Antiepileptic Compounds

Summary: Purpose : A monkey (Macaca fascicularis) model was previously used to assess infant hyperexcitability after prenatal exposure to phenytoin (PHT), stir-ipentol (STP) or PHT + STP. To explore this issue further, we studied additional monkey infants in those groups, as well as groups prenatally exposed to carba-mazepine (CBZ) in monotherapy (n = 5) or CBZ + STP poly therapy (n = 10).
Methods : The drug-exposed groups were compared with a group of control infants (n = 10) for whom procedures were matched except that there was no prenatal drug exposure. All adult female monkeys were equipped with tether systems and stomach catheters so that drug administration (or water for controls) could be initiated before they were mated and continued throughout pregnancy. During pregnancy, PHT, STP, and CBZ plasma levels were maintained between 4–12, 4–10, and 1–6 μg/ml, respectively (for both monotherapy and polytherapy). At birth, infants were separated from mothers and transferred to the University of Washington's (Seattle, WA, U.S.A.) Infant Primate Research Laboratory (IPRL) for postnatal care and follow-up testing. During tests of recognition memory administered between 2 weeks and 3 months of age, infants were rated on a hyperexcitability scale.
Results : Previously reported data indicated that infants prenatally exposed to PHT, in monotherapy or polytherapy with STP, were at increased risk for hyperexcitability (screeching, refusing to attend to stimuli, lack of visual orientation). This was not the case for infants prenatally exposed to STP monotherapy.
Conclusions : Our results confirm previous findings and also demonstrate that infants prenatally exposed to CBZ or CBZ + STP, like controls, are not hyperexcitable during testing.     

Clobazam in the Treatment of Epilepsy: A Review of the Literature

Summary: The literature was reviewed to define the role of clobazam (CLB) in the treatment of epilepsy. CLB is an effective antiepileptic drug (AED) in most varieties of seizures and epilepsies for both short-term and long-term treatment. Tolerability of CLB is satisfactory, better than for conventional benzodiazepines. CLB has no significant interaction with other drugs. Tolerance may develop, but this aspect may have been overemphasized: a long-term benefit figure of 28% can be expected without tolerance. When CLB maintains efficacy, patients continue to benefit for years without drug dependence or unwanted side effects. CLB appears to be a useful treatment for epilepsy as intermittent or short-term add-on therapy; but it should also be tried as long-term therapy in some situations, especially as add-on therapy for patients with refractory epilepsy, as add-on or monotherapy for patients with anxiety, or in some women in association with oral contraceptives.     

Growth and lipid metabolism in girls and young women with epilepsy during pubertal maturation

Summary:  Purpose: To assess growth and the serum lipid profile in girls with epilepsy receiving monotherapy at a mean age of 12.6 years and approximately 6 years later.
Methods: A population-based cohort of 77 girls with epilepsy and 49 healthy controls participated in this follow-up study including two cross-sectional evaluations (age range, 8–18.5 years on the first evaluation, and 12.5–25.8 years on the second evaluation). Forty of the patients were initially taking valproate (VPA), 19, carbamazepine (CBZ), and 18, oxcarbazepine (OXC). Growth data were compiled, body mass index (BMI) was calculated, and serum total (TC), and high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol and triglyceride concentrations were analyzed.
Results: Linear growth and final height did not differ between the patients and the controls. At follow-up, the mean BMI of the patients who were off medication (61%) was similar to that of the controls, whereas the patients initially treated with VPA who were still taking any medication had a higher BMI. On the first evaluation, the patients taking VPA had low serum HDL-C, and those taking CBZ or OXC had high serum TC and LDL-C concentrations. At follow-up, serum lipid levels were similar in the patients off medication and the controls.
Conclusions: Neither epilepsy nor antiepileptic therapy affects linear growth or final height, but they may have unfavorable effects on body weight and serum lipid concentrations. Lipid-profile impairment seems to be transient if the medication is discontinued. Overweight is common in patients treated with VPA during puberty if epilepsy and medication continue into adulthood.     

Systematic Testing of Medical Intractability for Carbamazepine, Phenytoin, and Phenobarbital or Primidone in Monotherapy for Patients Considered for Epilepsy Surgery

Summary: Purpose: To assess medical intractability in patients considered for restrictive epilepsy surgery.
Methods: Seventy-four patients received single drug treatment with carbamazepine (CBZ), phenytoin (PHT), and either phenobarbital (PB) or primidone (PRM). Medical intractability was established if seizure control was not obtained despite maximum tolerable doses of the drug. In all, 120 single drug treatments were administered with the drugs that has not been administered at maximal doses in monotherapy before the study.
Results: Complete seizure control was not achieved in any patient. However, 7 patients (9.5%) had significant seizure reduction of at least 80%. In 4 patients, only the third antiepileptic drug (AED) proved effective.
Conclusion: The poor result of AED monotherapy in our patients may be attributed to the patients'long-standing chronic epilepsies and high seizure frequencies. Our findings suggest that despite the failure of one or two major AEDs in controlling seizures completely, further single drug treatment may still improve the quality of life in some patients who are candidates for epilepsy surgery.     

Seizure freedom with different therapeutic regimens in intellectually disabled epileptic patients.

BACKGROUND: Epilepsy is a frequent condition in persons with intellectual disability and is more often difficult to treat than in the average population. Seizure freedom is the primary therapeutic goal which has important implications for the patient's quality of life. The aim of this study was to find out which antiepileptic therapy regimens (monotherapy or combination therapy) are effective in achieving this goal in intellectually disabled epilepsy patients. We were especially interested in the impact of the new antiepileptic drugs (AEDs) which were introduced during the past decade. METHOD: We investigated retrospectively the antiepileptic regimens on which the resident patients of a large epilepsy centre (as a rule with additional intellectual disabilities of different degrees) were seizure free in 2002. Information on antiepileptic medication and seizure frequency was taken out of the individual case documentation. It was also determined whether seizure free patients had already been seizure free in 1992. RESULTS: Two hundred and forty out of 675 patients (35,6%) with epilepsy were seizure free. The proportion of seizure freedom was 43,7% in patients with borderline intelligence, 39,2% in mild, 33,2% in moderate, 31,9% in severe, and 21,9% in profound intellectual disability. One hundred and twenty-two (50,8%) seizure free patients were on monotherapy; 53 of them were on CBZ (PB: 34, VPA: 25, PHT: 7, LTG: 3). Ninety-three patients (38,7%) were on duotherapies, CBZ/PB (27 patients), PB/PHT (17), and LTG/VPA (14) being the commonest. Of 18 (7,5%) triple therapies, LTG/PB/VPA (4 patients) was the commonest. Taken together, the five most frequent therapeutic regimens were CBZ monotherapy, PB monotherapy, CBZ/PB, VPA monotherapy and PB/PHT (a clear preponderance of classic AEDs). A distinction was made between "old seizure free" (seizure free already in 1992) and "new seizure free" (in 1992 still seizures) patients. In the 132 old seizure free patients the classic AEDs prevailed again, monotherapies with CBZ, PB and VPA being the most frequent regimens. In comparison, in the 78 new seizure free patients the novel combination LTG/VPA was the third most frequent, after the classic regimens CBZ/PB and CBZ; PB monotherapies were rare. CONCLUSION:In a majority of intellectually disabled patients with epilepsy (including those who became seizure free since 1992), complete seizure control has been achieved by monotherapy or duotherapy with classic AEDs. Of the new AEDs LTG in combination with VPA appears to be an important innovation.     

Positive and Negative Psychotropic Effects of Lamotrigine in Patients with Epilepsy and Mental Retardation

Summary: Purpose: To describe significant positive or negative psychotropic effects of lamotrigine (LTG) observed in epilepsy patients with mental retardation (MR).
Methods: Seven mentally retarded epilepsy patients, [5 with Lennox-Gastaut syndrome (LGS)] who experienced significant behavioral improvements or worsening after addition of LTG to their medication regimen were studied.
Results: LTG produced behavioral improvements in 4 patients. Patient 1, a 14-year-old girl, had LTG added to valproate (VPA) and thioridazine, resulting in diminished lethargy, less hyperactivity, and more appropriate speech. In a 17-year-old boy (patient 2) LTG added to VPA, phenytoin (PHT), and gabapentin (GBP) lessened irritability and hyperactivity. In patient 3, a 41-year-old woman, LTG added to PHT, VPA, and carbamazepine (CBZ) diminished lethargy and enhanced her social interactions. In patient 4, a 27-year-old man, LTG monotherapy diminished irritability and hyperactivity. Adverse behavioral effects were noted in 3 patients. In patient 5, a 43- year-old man, LTG added to PHT, phenobarbital (PB), lorazepam, sertraline, and thioridazine produced irritability, hyperactivity, and poor cooperation. In patient 6, a 29-year-old woman, LTG added to VPA produced frequent screaming, temper tantrums, increased rocking movements, and hyperactivity. In patient 7, a 29-year-old man, LTG added to VPA and PHT resulted in severe exacerbation of baseline behaviors, including self-injurious activity, temper tantrums, and failure to obey simple instructions.
Conclusions: In some patients with epilepsy and MR, LTG has significant positive or negative effects on behavior.     

Clinical Side Effects of Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate During Monotherapy in Children

The rate of onset of side effects was examined in 392 pediatric outpatients who received long-term monotherapy with phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), or valproate (VPA) for epilepsy or febrile convulsions. The severity of side effects (based on need to alter treatment), the nature of each drug's most common side effects, and the doses and plasma levels of occurrence were recorded. Our results show that usually accepted therapeutic ranges are well tolerated. Indeed, although some form of side effect occurred in 50% of patients, treatment had to be changed in only 18% and the drug had to be stopped in only 7%. In decreasing order, the rates for side effects were PHT (71%) greater than PB (64%) greater than CBZ (43%) greater than VPA (43%) greater than PRM (29%). Serious side effects requiring withdrawal of treatment occurred at the following rates: PHT (10%) greater than VPA (8%) greater than PRM (8%) greater than PB (4%) greater than CBZ (3%). Among our patients, the best tolerated antiepileptic drug (AED) was CBZ, and the least tolerated was PHT. Behavioral disorders were most common with PB, neurologic disorders with PHT, digestive tract disorders with VPA, and gingival hyperplasia and hirsutism with PHT. Behavioral disorders involving excitement seen with PB and PRM occurred most commonly at low plasma levels. Behavioral disorders involving depression seen with PB and VPA, those involving excitement seen with PHT and VPA, and digestive disorders seen with VPA occurred particularly when plasma levels were high.     

Long-Term Follow-Up of Childhood Epilepsy Associated with Tuberous Sclerosis

Summary: Purpose: To study the clinical and electroencephalographic (EEG) characteristics of patients whose epilepsy is associated with tuberous sclerosis, with special reference to their clinical course.
Methods: We investigated the electroclinical and radiologic features of 38 patients with epilepsy associated with tuberous sclerosis.
Results: Eleven patients showed only generalized epilepsy, and 10 showed only localization-related epilepsy throughout their clinical course. Among the other 17 cases, the nature of the epilepsy changed between generalized and localization-related epilepsies during the clinical course. A shift from generalized to localization-related epilepsies was more common than the reverse. Seventeen had West syndrome (WS), three had Lennox-Gastaut syndrome (LGS), and eight had epilepsies that evolved from WS to LGS. Tonic spasms, mostly in series, were seen in all 28 patients with generalized epilepsy. Eleven of the 28 patients had partial seizures and tonic spasms in the same period. Six of them showed "simultaneous seizures," consisting of tonic spasms in series and a partial seizure. Partial seizures were the main seizure type in 27 patients with localization-related epilepsy, but three of them also showed tonic spasms that included "simultaneous seizures." Ictal EEGs revealed multiple active foci in the same period that could shift during the clinical course. Neither the location nor number of tubers was related to the clinical course. As for seizure outcome, 12 (32%) of 38 patients were free from seizures at follow-up.
Conclusions: In epilepsies associated with tuberous sclerosis, there may be an interrelation between generalized and localization-related epilepsies, as well as one between generalized and partial seizures.     

Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy

PURPOSE: Pregabalin (PGB) is an alpha2-delta ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures. METHODS: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multiple-dose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ). RESULTS: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.     

An Economic Appraisal of Carbamazepine, Lamotrigine, Phenytoin and Valproate as Initial Treatment in Adults with Newly Diagnosed Epilepsy

Summary: We undertook an economic appraisal of four drugs used in monotherapy during the first 2 years of treatment for newly diagnosed patients with epilepsy: carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), and valproate (VPA). We adopted the cost-minimization model because, although no single trial compares all four drugs directly, the clinical trials comparing two or more of these drugs in newly diagnosed cases show no significant difference in efficacy between the drugs in terms of seizure frequency: Considered in the cost analyses were frequency of side effects, retention rates, medical consultations, inpatient and accident and emergency costs, laboratory investigations, and drug changes. A Delphi panel provided the treatment pathways, including frequency of clinical consultations, second-line monotherapy, and side-effects management. A sensitivity analysis was performed, varying the assumptions on which the calculations were based. Analysis was completed for a prospective, intention-to-treat perspective and also for those patients continuing the initial drug. The direct medical costs of 2-years therapy (intention-to-treat analysis) calculated for each trial were £795–829 for CBZ, £1,525-2,076 for LTG, £736–768 for PHT, and £868–884 for VPA. A sensitivity analysis provided similar relative estimates. We found that LTG for newly diagnosed patients is significantly more expensive in direct health service costs incurred. This analysis incorporated seizure control, side effects, and tolerability. We recommend that a similar type of analysis be considered as part of all clinical trials of antiepileptic drugs in which efficacy of outcome is similar as a guide to assess optimal cost effectiveness.     

Outpatient sleep recording during antiepileptic drug monotherapy

The effects of sleep and sleep deprivation on epilepsy are well known, but the effects of seizures and antiepileptic drugs (AEDs) on sleep have been less well studied. We recorded nocturnal sleep in 17 patients receiving antiepileptic monotherapy with ambulatory cassette EEG devices. Twelve patients had complex partial seizures and five had tonic-clonic convulsions. Two patients' seizures were largely nocturnal, and no seizures occurred during sleep recording. Five patients each were taking phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA), and two were taking clonazepam (CZP), all with therapeutic serum levels and no toxic symptoms. Total sleep time was reduced, wakefulness increased, and sleep latency prolonged in partial seizures as compared with generalized epilepsy. REM sleep was reduced and its latency decreased in partial seizure patients. Both groups had decreased slow wave sleep; that of partial seizure patients was decreased more markedly. PHT increased sleep latency and decreased sleep time, and CBZ increased awakening and diminished slow wave and REM sleep. Patients taking VPA had slight reduction in slow wave sleep; those taking CPZ had decreased sleep and REM latencies. Epilepsy may affect nocturnal sleep, and the effects of partial and generalized seizure disorders may be different. AEDs may also have differential effects on nighttime sleep. These may prove important in the long-term management of epileptic patients.     

Lamotrigine Monotherapy in Newly Diagnosed Untreated Epilepsy: A Double-Blind Comparison with Phenytoin

PURPOSE: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. METHODS: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for < or =48 weeks. RESULTS: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. CONCLUSIONS: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.     

Treatment guidelines for adult epilepsy]

We reviewed the treatment strategies and choices of drugs for adult patients with epilepsy. As evidence from controlled studies for the older drugs is scarcely available from the literature, we added a clinical study performed in our hospital and an expert consensus study. Published randomized clinical studies revealed carbamazepine (CBZ) to be the treatment of choice, but provided little evidence for the differences in efficacy between phenytoin (PHT), valproate (VPA), phenobarbital (PB) and zonisamide (ZNS). The clinical study in our patients with intractable localization-related epilepsy indicated the superior efficacy of CBZ and PHT over VPA or ZNS. Sixty-nine experts converged on the opinion that monotherapy should be started with VPA for seizures of both idiopathic and symptomatic generalized epilepsy, and with CBZ for seizures of localization-related epilepsy. When the trials with 2-3 monotherapy failed, surgery should be considered for localization-related epilepsy. We proposed practical guidelines for treatment of patients with adult epilepsy, including rehabilitation and care for improvement of quality of life.     

Mono- or Polytherapy and the Severity of Epilepsies

Abstract: 1. Out of 295 outpatients who were followed up by our staff for longer than 4 years, a total of 196 patients was subjected to this retrospective study. The inclusion criterion was that they had inevitably been placed on polytherapy of two or more anti-epileptic drugs (AEDs). In other words, they had failed to reach monotherapy for some reasons.
2. One of the determinant factors for the success or failure of monotherapy was the type of epilepsies. Namely, primary generalized epilepsy (PGE) was relatively easy to attain by monotherapy regardless of the seizure type, whereas secondary generalized epilepsy (SGE) with combined seizures and secondary partial epilepsy (SPE) with mixed seizures were not infrequently difficult to be placed on a monotherapy regimen. In the latter case, however, an abrupt withdrawal of AEDs was apt to cause an exacerbation of seizures.
3. There were some patients who could reach a complete freedom from seizures as a result of bi- or polytherapy and became socially adaptable and acceptable. They themselves are, if not all, afraid of a possible relapse of seizures produced by a reduc tion in the number of AEDs hitherto prescribed. In some cases, a family member may refuse monotherapy, or even physicians are reluctant to switch to monotherapy because the patients have experienced status epilepticus in the past.
In other words, there are two reasons why polytherapy should not, by all means, be avoided; one is the type or severity of epilepsies from which a given patient has been suffering, and the other is the patient's social factor or "quality of life" in which he or she hesitates to accept a monotherapy regimen. In conclusion, monotherapy WBS not necessarily regarded as the only rational way of having antiepileptic drug (AED) treat ment.     

One-Year Mortality in Bordeaux Cohort: The Value of Syndrome Classification

Summary:  Purpose: To evaluate the usefulness of the International Classification of Epilepsy Syndromes for 1-year mortality in a prospective incidence study of first epileptic seizures.
Methods: Date and cause of death from the treating physician in an incidence study of first afebrile seizures collected 15 years ago in Southwest France. Cases were classified by epilepsy syndrome. A total of 804 patients were included: acute symptomatic (n = 277), unprovoked (n = 439), or unclassifiable (n = 88).
Results: One hundred and fifty-one patients died within the first year: none with idiopathic partial or generalized epilepsy, 16/104 with symptomatic (standardized mortality ratio (SMR) 6.4, 95% CI 3.6–10.3), 1/59 with cryptogenic (SMR 1.7, 95% CI 0.1–9.7 CI) partial epilepsy, 1/14 (SMR 28.1, 95% CI 0.4–156.6) with symptomatic/cryptogenic generalized epilepsy, 2/23 with undetermined epilepsy, 1/135 with isolated seizure (SMR 0.6, 95% CI 0.1–3.1), and 90/277 (SMR 10.3, 95% CI 8.3–12.7) with acute symptomatic seizures. Unclassifiable seizures could not be classified as acute symptomatic or unprovoked: associated with alcohol abuse (death: 3/32, SMR 7.7, 95% CI 1.6–22.6), brain tumors (death: 31/39, SMR 41.5, 95% CI 28.2–58.9), and dementia (death: 6/17, SMR 5.4, 95% CI 2.0–11.7). Most deaths were due to progression of underlying disease, only 5.9% were seizure-related.
Conclusions: Although a syndromic diagnosis is important for treatment decisions and some prognostic aspects of seizure disorders, its value in mortality studies is limited. Mortality can be calculated only at the first (partial, generalized, and undetermined epilepsies, and special syndromes) and the second (idiopathic vs. symptomatic or cryptogenic) levels of the International Classification of Epilepsies.     

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis

Purpose: Long‐term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long‐term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Methods: One hundred sixty adult patients who were receiving AED monotherapy, including two enzyme‐inducers (carbamazepine, CBZ; and phenytoin, PHT), an enzyme‐inhibitor (valproic acid, VPA), and a noninducer (lamotrigine, LTG) for more than 2 years, and 60 controls were enrolled in this study. All study participants received measurement of common carotid artery (CCA) intima media thickness (IMT) by B‐mode ultrasonography to assess the extent of atherosclerosis. Other measurements included body mass index, and serum lipid profile or levels of total homocysteine (tHcy), folate, uric acid, fasting blood sugar, high sensitivity C‐reactive protein (hs‐CRP), or thiobarbituric acid reactive substances (TBARS). Key Findings: Long‐term monotherapy with older‐generation AEDs, including CBZ, PHT, and VPA, caused significantly increased CCA IMT in patients with epilepsy. After adjustment for the confounding effects of age and gender, the CCA IMT was found to be positively correlated with the duration of AED therapy. Patients with epilepsy who were taking enzyme‐inducing AED monotherapy (CBZ, PHT) manifested disturbances of cholesterol, tHcy or folate metabolism, and elevation of the inflammation marker, hs‐CRP. On the other hand, patients on enzyme‐inhibiting AED monotherapy (VPA) exhibited an increase in the levels of uric acid and tHcy, and elevation of the oxidative marker, TBARS. However, no significant alterations in the markers of vascular risk or CCA IMT were observed in patients who received long‐term LTG monotherapy. Significance: Patients with epilepsy who were receiving long‐term monotherapy with CBZ, PHT, or VPA exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. This information offers a guide for the choice of drug in patients with epilepsy who require long‐term AED therapy, particularly in aged and high‐risk individuals.