Differential effects of antiepileptic drugs on neonatal outcomes

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.     

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.     

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.     

Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy

Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17 years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.     

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.     

Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) 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. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.     

Comparison of antiepileptic drug levels in sudden unexpected deaths in epilepsy with deaths from other causes

PURPOSE: (a) To compare postmortem antiepileptic drug (AED) levels in patients with sudden unexpected death in epilepsy (SUDEP) with those in a control group of subjects with epilepsy. If SUDEP patients more frequently had undetectable or subtherapeutic AED levels, this would suggest that compliance with AED treatment is poorer in this group and that poor compliance is a risk factor for SUDEP. (b) To determine whether a particular AED was detected more commonly in the SUDEP group, suggesting that this AED is associated with a higher risk of SUDEP. METHODS: A retrospective study of coronial cases was performed. Postmortem AED levels in 44 SUDEP cases and 44 control cases were compared. The control group consisted of epileptics who died of causes other than epilepsy, including natural disease (e.g., ischemic heart disease, accidents, and suicide). The AEDs measured included carbamazepine (CBZ), phenytoin, (PHT), valproate (VPA), phenobarbitone (PB), lamotrigine (LTG), clonazepam (CZP), and clobazam (CLB). The number of SUDEP and control cases in which CBZ only was detected were compared, as were the number in which PHT only was detected. RESULTS: Compared with the controls, the SUDEP group showed no difference in the number with no detectable AEDs (13 vs. 11), the number with subtherapeutic AEDs (10 vs. 13), and the number with therapeutic levels (21 in both groups). CBZ only was detected in 11 SUDEPs and 11 controls, and PHT only in five SUDEPs and 10 controls. CONCLUSIONS: Our study suggests the SUDEP group were no less compliant with AED treatment than the control group. This study does not support the hypothesis that poor compliance with AED treatment is a risk factor for SUDEP. There was no evidence that PHT or CBZ is associated with a higher risk of SUDEP.     

The importance of drug interactions in epilepsy therapy

Long-term antiepileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to control seizures effectively, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. The fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients also must be considered. Therefore the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and on drug discontinuation. Although pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine (LTG) and valproic acid (VPA); these drugs exhibit synergistic efficacy when coadministered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions, and enzyme-inducing drugs such as phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) will readily enhance the metabolism of other AEDs [e.g., LTG, topiramate (TPM), and tiagabine (TGB)]. The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g., oral contraceptives, antidepressants, and warfarin) so that therapeutic efficacy of coadministered drugs is lost unless the dosage is increased. VPA inhibits the metabolism of PB and LTG, resulting in an elevation in the plasma concentrations of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of CBZ by VPA results in an elevation of the metabolite CBZ-epoxide, which also increases the risk of toxicity. Other examples include the inhibition of PHT and CBZ metabolism by cimetidine and CBZ metabolism by erythromycin. In recent years, a more rational approach has been taken with regard to metabolic drug interactions because of our enhanced understanding of the cytochrome P450 system that is responsible for the metabolism of many drugs, including AEDs. The review briefly discusses the mechanisms of drug interactions and then proceeds to highlight some of the more clinically relevant drug interactions between AEDs and between AEDs and non-AEDs. Understanding the fundamental principles that contribute to a drug interaction may help the physician to better anticipate a drug interaction and allow a graded and planned therapeutic response and, therefore, help to enhance the management of patients with epilepsy who may require treatment with polytherapy regimens.     

Pharmacological outcomes in newly diagnosed epilepsy

The response to antiepileptic drugs (AEDs) has been examined in 780 adult and adolescent patients with newly diagnosed epilepsy presenting with a range of seizure types and epilepsy syndromes over a 20-year period. Carbamazepine (CBZ, n=312), sodium valproate (VPA, n=315), and lamotrigine (LTG, n=249) were the most common AEDs prescribed as monotherapy. More patients with localization-related epilepsies became seizure free with LTG (63%) than with CBZ (45%, P=0.006) or VPA (42%, P=0.006). For idiopathic generalized epilepsies a greater proportion of patients achieved control with VPA (68%) than with CBZ (31%) or LTG (45%). In particular, more patients with juvenile myoclonic epilepsy responded to VPA (75%) compared with LTG (39%, P=0.014). Seizure freedom was achieved with modest or moderate daily doses (median CBZ 400mg, VPA 1000 mg, (LTG) 150 mg) of all three AEDs in the majority of patients achieving remission. Time to first seizure did not differ among these three drugs when given as first treatment. Adverse effects leading to withdrawal were more frequent with CBZ (16%) than with VPA (7%, P=0.03) or LTG (7%, P=0.018). In patients failing initial monotherapy, response to a combination of two AEDs (27%) was not different from that with alternative monotherapy (32%). The majority of patients with newly diagnosed epilepsy responding to treatment did so rapidly and completely with moderate doses of AEDs, with no differences in time to first seizure.     

Drug Interaction Profile of Topiramate

Summary: In separate studies, potential pharmacokinetic interactions of topiramate (TPM) with phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) were evaluated. TPM was added to the baseline antiepileptic drug (AED) at a dosage of up to 800 mg/day, after which the baseline drug was discontinued, when possible. Addition of TPM produced no change in plasma levels of CBZ or CBZ epoxide (CBZ-E). Modest increases in PHT plasma levels in six of 12 patients treated with PHT and TPM, and a small mean decrease in VPA levels noted in patients receiving VPA with TPM, were considered unlikely to require adjustments in the dosage of the concomitant AED when TPM is added or discontinued. When patients were changed from concomitant therapy with PHT or CBZ to TPM monotherapy, TPM clearance was reduced by approximately 50%, suggesting that an adjustment in TPM dose may be required when PHT or CBZ is discontinued from TPM-treated patients. A slight increase in plasma TPM levels during monotherapy compared to concomitant therapy with VPA was considered clinically insignificant and not likely to require TPM dosage adjustment. In another study, oral clearance of digoxin was slightly increased when TPM was added, resulting in a small decrease in peak plasma levels of digoxin. In vitro studies conducted to date on a number of specific cy-tochrome P450 isoforms show an effect of TPM only on the CYP2C_meph isoform. The risk for clinically meaningful changes in plasma levels of traditional AEDs when TPM is added to or discontinued from concomitant regimens appears to be minimal. However, adjustments in TPM dosages are likely to be needed when potent enzyme inducers, such as PHT or CBZ, are added or discontinued. TPM has a relatively low propensity for clinically significant drug interactions, and its pharmacokinetic and drug interaction profiles represent a clear advance over those of the traditional AEDs.     

Metabolic and hormonal disturbances in women with epilepsy on antiepileptic drug monotherapy

PURPOSE: Women with epilepsy (WWE) tend to have hormonal and metabolic abnormalities, raising concerns about an increased risk of cardiovascular disorders. This study was performed to determine whether epilepsy itself and/or antiepileptic drug (AED) medication cause metabolic abnormalities. METHODS: WWE in premenopausal state aged 18 to 45 years old, currently on AED monotherapy for more than six months, were recruited for this study. The subjects checked their oral temperature each morning, and tested serum levels for lipid profiles, insulin, glucose, and leptin. A HOMA-index was used as a marker for insulin resistance. RESULTS: Of the 54 total patients, 18 women were diagnosed with primary generalized epilepsy (PGE) and the other 36 were diagnosed with localization-related epilepsy (LRE). Among the subjects, 19 women were on carbamazepine (CBZ), 12 on valproate (VPA), 12 on lamotrigine (LTG), and 11 on topiramate (TPM). Body mass index increased and HDL-cholesterol decreased in patients on VPA monotherapy compared with CBZ, LTG, or TPM (p=0.046 and 0.002). Metabolic syndrome was more frequently associated with VPA-treated patients (41.7%) than CBZ (5.3%), LTG (0%), or TPM group (0%) (p=0.005). There were no differences in hormonal and metabolic indices between PGE and LRE groups. CONCLUSIONS: WWE on VPA monotherapy are more obese and more frequently suffer from metabolic syndrome. LTG or TPM may be safer when prescribed to the patients with high risk of cardiovascular disease.     

Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

PURPOSE: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. METHOD: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). RESULTS: sixty-two patients (33.6+/-11.3 years, 47+/-9.9 kg) receiving LTG monotherapy (n=19) or polytherapy with VPA (n=15), inducer(s) (n=32) or both (n=5) were evaluated. LTG dose of 369+/-236 mg per day (8.1+/-5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8+/-3.3 microg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/F) were 0. 69+/-0.2, 1.60+/-0.65 and 0.2+/-0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/F. CONCLUSION: LTG Cl/F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.     

Self-reported symptoms in patients on antiepileptic drugs in monotherapy

Wieshmann UC, Tan GM, Baker G. Self‐reported symptoms in patients on antiepileptic drugs in monotherapy.
Acta Neurol Scand: 2011: 124: 355–358.
© 2011 John Wiley & Sons A/S. Objective – To ascertain the frequency of self‐reported symptoms in patients taking antiepileptic drugs (AED). Methods – We included patients on carbamazepine (CBZ) n = 36, valproate (VPA) n = 21, levetiracetam (LEV) n = 12, phenytoin (PHT) n = 11, lamotrigine (LTG) n = 20, patients not taking anticonvulsive drugs n = 19, and healthy control subjects (CTRL) n = 41 to complete the Liverpool Adverse Event Profile (LAEP). Results – The mean LAEP scores were CBZ/PHT/LEV/VPA/LTG/noAED/CTRL = 44.97/42.00/41.00/40.33/32.42/42.00/30.80. LEV scored overall in the same range as the older AED but had a different adverse effect profile with self‐reported anger (33%) and shaky hands (42%) particularly frequent. Patients with depression or uncontrolled epilepsy had significantly higher LAEP scores than patients without depression or uncontrolled epilepsy. Conclusion – Our unblinded observational study of self‐reported symptoms suggested LTG was overall the drug with the least self‐reported symptoms. Larger studies are needed to determine whether this was a truly significant difference. LEV had a different side effect profile to older AED. Confounding factors were depression and uncontrolled epilepsy. This observation should be further tested with randomized studies.     

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.     

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.     

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.     

Is lamotrigine a significant human teratogen? Observations from the Australian Pregnancy Register

Lamotrigine (LTG) is increasingly being prescribed in pregnancy for women with epilepsy in place of valproate (VPA), because of the teratogenic risks associated with the latter. It is therefore important to know the teratogenic hazard associated with LTG, relative to VPA and to other commonly used antiepileptic drugs (AEDs). Data from the Australian Register of Antiepileptic Drugs in Pregnancy was examined to determine the incidence of teratogenicity determined 1 year from completion of pregnancy in women who took AEDs in monotherapy during pregnancy. Compared with a 3.4% malformation incidence in women who took no AEDs (N = 118), the incidences for LTG (N = 243), carbamazepine (CBZ) (N = 302) and VPA (N = 224) were, respectively, 4.9%, 5.3% and 15.2%, the latter statistically significantly greater than the risk for no AED therapy in pregnant women with epilepsy. Logistic regression analysis showed no tendency for foetal hazard to increase with increasing LTG dose in pregnancy, unlike the situation for VPA. However, seizure control in pregnancy tended to be not as good in the women taking LTG compared with those taking VPA, though the data examined were not adequate to permit definite conclusions regarding this matter. We conclude that LTG monotherapy in pregnancy is safer than valproate monotherapy from the point of view of foetal malformations, and no more hazardous in this regard than therapy with other commonly used AEDs.     

Cross-reactivity pattern of rash from current aromatic antiepileptic drugs

We have investigated cross-reactivity of rash among the current aromatic antiepileptic drugs, particularly between the new and the traditional compounds. A retrospective survey of medical records concerning all aromatic antiepileptic drug (AED) treatment in consecutive adult patients with epilepsy was performed. Altogether 663 patients were included comprising 2567 exposures to AEDs. Skin reactions occurred in 93 patients and sequential rashes related to aromatic drugs in 17. Phenytoin (PHT), carbamazepine (CBZ) and oxcarbazepine (OXC) caused rashes in the range of 27-35% in patients with a history of another AED-related rash, whereas lamotrigine (LTG) caused another rash in 17%. A history of an AED-related rash was significantly associated with reactions to PHT, CBZ, and OXC (p<0.001). The association was only borderline significant for LTG (p=0.05). Nevertheless, the occurrence was consistently increased in all subgroups with reactions to other AEDs. A CBZ rash was not significantly associated with an LTG reaction, and vice versa, but the number of patients was limited. Less than one third of patients with a CBZ rash also reacted to OXC. No evidence for increased severity of sequential rashes was found. Clinicians should be aware of the cross-reactivity of the aromatic AEDs regarding cutaneous adverse events, as well as their differences in this respect. LTG appears to be involved in cross-reactions less often than CBZ, OXC and PHT.