Deterioration Of Seizure Control Research Articles

Prescription trends of antiseizure medications before and during the COVID-19 pandemic.

Given the lack of evidence on how the COVID-19 pandemic impacted antiseizure medication (ASM) use, we examined the trends of ASMs before and during COVID-19. We conducted a population-based study using provincial-level health databases from Manitoba, Canada, between 1 June 2016 and 1 March 2021. We used interrupted time series autoregressive models to examine changes in the prevalence and incidence of ASM prescription rates associated with COVID-19 public health restrictions. Among prevalent users, the COVID-19 pandemic led to a significant increase in new-generation ASMs with a percentage change of 0.09% (p = 0.03) and a significant decrease in incidence use of all ASMs with a percentage change of -4.35% (p = 0.04). Significant trend changes were observed in the prevalent use of new-generation ASMs (p = 0.04) and incidence use of all (p = 0.04) and new-generation ASMs (p = 0.02). Gabapentin and clonazepam prescriptions contributed 37% of prevalent and 54% of incident use. With the introduction of public health measures during COVID-19, small but significant changes in the incident and prevalent use of ASM prescriptions were observed. Further studies are needed to examine whether barriers to medication access were associated with potential deterioration in seizure control among patients. The results from this study have been presented as an oral presentation at the 38th ICPE, International Society of Pharmacoepidemiology (ISPE) annual conference in Copenhagen.

Analyzing excipient-related adverse events in antiseizure drug formulations

There have been several reports that switching formulations of antiseizure medications (ASMs) has been associated with a deterioration of seizure control, seizure relapse or increased adverse effects. Considering recent findings that excipients, namely purported inactive ingredients, may nevertheless exert biological effects, it is possible that the variation in adverse event profile of antiseizure drugs may be related to differences in excipients. To test our hypothesis, we constructed a new research tool to connect FDA-compiled adverse event reports to the excipient in the medicine. Analysis of adverse events to formulations of five different second-generation antiseizure drugs – gabapentin, lamotrigine, levetiracetam, oxcarbazepine, and topiramate – showed several significant associations between specific excipient in the formulations and an adverse event when compared to the same medicine formulated with other excipients. Epilepsy and seizure adverse events were associated with multiple excipients across gabapentin, lamotrigine, and levetiracetam formulations. A different group of excipients were associated with reports of hypersensitivity reactions including urticaria, rash, erythema, and Stevens-Johnson syndrome. Our study provides a novel approach to analyzing post-market surveillance reports by including excipients. It may be useful to clinicians when evaluating select patient groups that may be refractory to pharmacological treatment or experience worsening adverse events when switching formulations of the same antiseizure medicine.

Physicians' attitudes toward generic substitutions of antiseizure drugs in epilepsy.

The safety of generic substitution of antiseizure drugs (ASDs) has been questioned for many years. This study aimed to identify physicians' attitudes to the generic substitution of ASDs in epilepsy and which factors were of significance when deciding on compound substitutions. A cross-sectional web-based survey was sent to neurologists and neurology residents in public health care and at private practices in two Swedish regions between February and March 2020. The 30-item survey covered drug- and patient-related factors, as well as considerations relating to practical, cost-related, and pharmacokinetic issues. The total response rate was 55.8%. Respondents were generally positive to cutting costs through generic ASD utilization (74%) and prescribing generic compounds when starting a new ASD treatment (84.9%). The most substantial concern was a deterioration in seizure control (17.1%). Physicians refrained from switching if the patient wished to remain on the original compound (76.1%), had a cognitive impairment (52.5%), was on a drug with a narrow therapeutic index (47%), or had shown prior susceptibility to adverse effects (45.6%). Opinions on substitution decisions differed significantly between the Stockholm and Skåne regions. Less than one-third of the respondents were aware of supporting guidelines. Neurologists generally accept the use of generic antiseizure compounds. Patient preference to remain on brand-name drug treatment was the most important factor that led to avoiding a switch. Our results may constitute material for consensus discussions to decide on quality indicators of interest for future research on substitution outcomes.

Practical management of epilepsy and pregnancy

The goal of the management of epilepsy during pregnancy is to maintain control of in particular major convulsive seizures with minimal exposure the fetus to potentially teratogenic drugs. We have learned that antiepileptic drugs (AEDs) differ in their teratogenic potential. In particular, valproate has been associated with greater risks for major congenital malformations and adverse effects on the child’s cognitive and behavioral development. Valproate should therefore, whenever possible, be avoided in pregnancy, and regulatory bodies, such as EMA, have issued restrictions on its use in women of childbearing age. Topiramate has been associated with impaired intrauterine growth, and there are signals of increased risk for malformations with this drug. In general, teratogenic risks appear to be dose-dependent and the aim should be to established the lowest effective dose before pregnancy, regardless of which AED that is used. Many AEDs undergo pronounced changes in their pharmacokinetics during pregnancy, resulting in significant decline in the serum concentration with associated risk of deterioration in seizure control. This is particularly pronounced for lamotrigine, but seen also with oxcarbazepine and levetiracetam. Drug level monitoring is therefore often recommended during pregnancy. The value of this is increased if the optimal serum concentration has been documented before pregnancy to serve as an individual reference and target concentration. Whether a decline in serum concentrations as such during pregnancy should prompt a dose increase, or if this should be considered only in case of loss in seizure control, is still debated.

Status epilepticus in pregnant women with epilepsy after valproate adjustment: A case series

PurposeValproate is an effective wide-spectrum anti-epileptic drug that is also known to be teratogenic. Its administration in epileptic women remains controversial. This report aims to draw more attention to valproate adjustment before and during pregnancy. MethodsWe collected medical records of pregnant women with epilepsy at West China Hospital in Chengdu, China who developed status epilepticus during pregnancy after valproate withdrawal or reduction in dose from January 2013 to July 2015. ResultsA total of 281 pregnancies in patients with epilepsy were examined; 6 episodes of status epilepticus occurred during these pregnancies. Four patients with status epilepticus took long-term valproate before pregnancy. Among them, 2 patients stopped taking valproate 3 months prior to pregnancy, and 2 patients discontinued valproate or reduced their valproate dose when pregnancy was confirmed. All 4 suffered from a convulsive status epilepticus; 3 experienced an increased frequency of seizures. One child was diagnosed with neonatal asphyxia, hypoxic-ischemic encephalopathy, and neonatal pneumonia. ConclusionValproate adjustment prior to or during pregnancy may result in deterioration of seizure control, which may include resultant status epilepticus. Valproate during pregnancy increases the risk of major congenital malformations, but the significance of maintaining seizure control in pregnant women should be also taken into consideration. Open and careful discussion with every pregnant woman with epilepsy should discuss the risk-benefit ratio of epilepsy medications.

Seizure control and treatment changes in pregnancy: Observations from the EURAP epilepsy pregnancy registry

To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate. Seizure control and AED treatment were recorded prospectively in 3,806 pregnancies of 3,451 women with epilepsy taking part in European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), an international AED and pregnancy registry. Of all cases, 66.6% remained seizure-free throughout pregnancy. Generalized tonic-clonic seizures (GTCS) occurred in 15.2% of the pregnancies. Women with idiopathic generalized epilepsies were more likely to remain seizure-free (73.6%) than women with localization-related epilepsy (59.5%; p < 0.0001). Worsening in seizure control from the first to second or third trimesters occurred in 15.8% of pregnancies. The AED dose was increased during pregnancy in 26.0% and a second AED added to the initial monotherapy in 2.6% of all pregnancies. Seizures were more likely to occur in the first trimester in pregnancies with an increased drug load (35%; increased dose and/or addition of another AED) than in pregnancies without an increased drug load (15.3%) (p < 0.0001). Compared with other monotherapies, pregnancies exposed to lamotrigine were less likely to be seizure-free, 58.2% (p < 0.0001); had more GTCS, 21.1% (p < 0.0001); had a greater likelihood of deterioration in seizure control from first to second or third trimesters, 19.9% (p < 0.01), and were more likely to require an increase in drug load, 47.7% (p < 0.0001). The mean dose increases from the first to third trimesters were 26% for lamotrigine, 5% for carbamazepine, 11% for phenobarbital, and 6% for valproate. There were 21 cases of status epilepticus (10 convulsive): none with maternal mortality and only one with a subsequent stillbirth. Although the majority of women remain seizure-free throughout pregnancy, our data suggest that a more proactive approach to adjusting the dose of all AEDs in pregnancy should be considered, in particular for those pregnancies with seizures occurring in the first trimester and those exposed to lamotrigine, to reduce the risk of deterioration in seizure control.

Add‐on treatment with verapamil in pharmacoresistant canine epilepsy

Verapamil add-on treatment has been suggested as a novel therapeutic concept for overcoming transporter-mediated pharmacoresistance. Efficacy data have been limited so far to case reports in individual epileptic patients. Therefore, we aimed to thoroughly evaluate the efficacy and tolerability of verapamil add-on treatment. In a prestudy in healthy Beagle dogs the tolerability of verapamil add-on treatment was investigated. The efficacy of verapamil was then evaluated in 11 dogs with phenobarbital-resistant epilepsy. Verapamil add-on treatment (6.2-7.3 mg/kg) did not affect phenobarbital concentrations in plasma or cerebrospinal fluid. Side effects observed in healthy as well as in epileptic dogs comprised bradycardia and a decrease in blood pressure. Therefore, we had to limit the dosage to 1-1.5 mg/kg in the main study. In phenobarbital nonresponders, verapamil failed to improve seizure control. Verapamil treatment was discontinued prematurely in five animals due to worsening of seizure control or lack of an effect. In the remaining animals, seizure frequency tended to increase during the verapamil add-on phase, reaching a mean of two seizures per month compared to the pre-verapamil phase with phenobarbital monotherapy (mean of 1.4 seizures per month). In view of the detrimental effects in the majority of the dogs, the study had to be discontinued and no further animals were enrolled. The failure of the maximum tolerated dosage to improve seizure control in dogs with phenobarbital-resistant epilepsy argues against the suitability of verapamil add-on treatment to overcome pharmacoresistance. Deterioration of seizure control in some individual animals suggests that verapamil might also exert unfavorable effects on seizure thresholds or its spread.

Continuous spikes and waves during slow sleep in an adult

Continuous spikes and waves during slow wave sleep (CSWS) is rare and is considered to be an age-related epileptic syndrome occurring only in children. We report the case of a 21-year-old patient diagnosed with this syndrome. The patient had a history of seizures since the age of 3 and was admitted for continuous video/EEG monitoring to evaluate seizure exacerbation and unprovoked outbursts of anger. During 3 days of monitoring, awake EEG recordings showed focal slow wave activity in the right temporal region. CSWS were observed. After a change in his antiepileptic drug regimen, subsequent EEG recordings showed resolution of CSWS. As shown in our patient, CSWS can be observed in adults. In addition, continuous video/EEG monitoring including sleep is important in the evaluation of patients with sudden deterioration of seizure control accompanied by behavioral changes.

Overtreatment in Epilepsy

In pharmacotherapy, overtreatment may be defined as an excessive drug load (that is, excessive drug dosages or unnecessary polypharmacy) leading to a suboptimal risk-to-benefit ratio. The risk of overtreatment in the pharmacological management of epilepsy is substantial and may have serious consequences in terms of a greater incidence and severity of adverse effects. These effects can range from subtle CNS impairment to overt toxic effects, including teratogenicity. Overtreatment also causes increased treatment costs and may even lead to a paradoxical deterioration in seizure control. The prevention and correction of overtreatment requires a thorough understanding of the situations and mechanisms that lead to inappropriate prescribing of antiepileptic drugs. These include initiating treatment in conditions where it is not indicated (for example, long-term prophylaxis after head trauma or supratentorial surgery in seizure-free patients), use of excessively fast titration rates, prescription of excessively high initial target dosages, failure to consider conditions associated with reduced dosage requirements (for example, old age or comorbidities associated with impaired drug clearance), and failure to consider the dose-response characteristics of the selected drug. Many patients whose seizures do not respond to the initially prescribed medication can be optimally managed by switching to monotherapy with an alternative agent; premature use of combination therapy represents another common form of overtreatment. Overtreatment may also result from a failure to adjust the dosage to prevent or compensate for adverse pharmacokinetic or pharmacodynamic drug interactions, and from a failure to reduce drug load in patients who have not benefited from high dosages or polypharmacy. While the measurement of drug concentrations can aid in minimising adverse effects, there is also a danger of overtreatment resulting from inappropriate interpretation of drug concentration data. Continuation of drug therapy in seizure-free patients in whom the risk-benefit ratio is in favour of gradual withdrawal may also be regarded as overtreatment. Tailoring therapy to the needs of the individual patient is the key to the successful management of epilepsy. Even though the importance of complete seizure control cannot be overemphasised, no patient should be made to suffer more from the adverse effects of treatment than from the manifestations of the seizure disorder.

Methsuximide lowers lamotrigine blood levels: A pharmacokinetic antiepileptic drug interaction.

To determine whether methsuximide (MSM) affects lamotrigine (LTG) blood levels and whether any change is of clinical significance. LTG serum levels in 16 patients taking MSM were compared with those before starting or after stopping the MSM. The 16 patients, (11 boys, five girls) were young people (mean age, 15.5 years; range, 9-19 years) with a variety of seizure types and syndromes. In six cases, LTG levels were available both before MSM was started and after it was stopped. The mean LTG serum concentration before starting or after stopping MSM was 13.4 mg/L, and the mean level while taking MSM was 6.3 mg/L. This difference was highly significant (p < 0.0005, paired t test). MSM lowered the LTG serum concentration in every case, with a mean decrease of 53% (range, 36-72%). In some patients this led to a deterioration in seizure control when MSM was added or an improvement in seizure control after MSM was stopped. Although MSM is a valuable add-on, broad-spectrum drug when used in combination with LTG, adjustment of the LTG dose may be necessary when MSM is started or stopped, to allow for the fact that MSM lowers LTG blood levels.

Adverse reactions to new anticonvulsant drugs.

A lack of systematic pharmacoepidemiological studies investigating adverse drug reactions (ADRs) to anticonvulsants makes it difficult to assess accurately the incidence of anticonvulsant-related ADRs. Most of the available information in this regard stems from clinical trial experience, case reports and postmarketing surveillance, sources that are not, by any means, structured to provide precise data on adverse event epidemiology. For various ethical, statistical and logistical reasons, the organisation of structured clinical trials that are likely to provide substantial data on ADRs is extremely difficult. This review concentrates on current literature concerning serious and life-threatening ADRs. As with the older anticonvulsants, the majority of ADRs to newer anticonvulsants are CNS-related, although there are several that are apparently unique to some of these new drugs. Gabapentin has been reported to cause aggravation of seizures, movement disorders and psychiatric disturbances. Felbamate should only be prescribed under close medical supervision because of aplastic anaemia and hepatotoxicity. Lamotrigine causes hypersensitivity reactions that range from simple morbilliform rashes to multi-organ failure. Psychiatric ADRs and deterioration of seizure control have also been reported with lamotrigine treatment. Oxcarbazepine has a safety profile similar to that of carbamazepine. Hyponatraemia associated with oxcarbazepine is also a problem; however, it is less likely to cause rash than carbamazepine. Nonconvulsive status epilepticus has been reported frequently with tiagabine, although there are insufficient data at present to identify risk factors for this ADR. Topiramate frequently causes cognitive ADRs and, in addition, also appears to cause word-finding difficulties, renal calculi and bodyweight loss. Vigabatrin has been reported to cause seizure aggravation, especially in myoclonic seizures. There have been rare reports of other neurological ADRs to vigabatrin, such as encephalopathy, aphasia and motor disturbances. Vigabatrin-induced visual field constriction is the latest and most worrying ADR. Many questions regarding the nature of this potentially serious ADR remain unanswered, as no prospective controlled study examining the phenomenon has been published. Rare cases of behavioural ADRs and IgA and IgG2 deficiency associated with the use of zonisamide have been reported. However, relatively few patients so far have been exposed to this drug, and therefore more postmarketing information is required. The relatively late establishment of aplastic anaemia and hepatic failure as potentially fatal ADRs of felbamate, and of visual field constriction with vigabatrin, should serve as ample reminders that ADRs can appear at any time.

Topiramate in intractable childhood onset epilepsy--a cautionary note.

To study the effectiveness and safety of topiramate in clinical practice, for a group of patients with childhood onset epilepsy. All patients treated with topiramate at the three study centers between November 1995 and December 31, 1997 were analyzed retrospectively, using a standardized study protocol. Data were gathered on demographic features, seizures response and medication related adverse events. Eighty-seven patients were treated with topiramate. Over 90% seizure reduction was achieved in 8 (9%) patients, 50%-90% in 21 (24%), < 50% in 54 (62%) patients. Four patients (5%) had a deterioration in seizure control. Adverse events required topiramate discontinuation in 36 (41%). Of these 27 (31%) complained of unacceptable cognitive dulling. The rate of dose escalation and final dose in mg/kg were similar in those who remained on topiramate and those who were intolerant because of cognitive side effects. Although topiramate resulted in > 50% seizure reduction in 29 (33%) of this group of patients with difficult epilepsy, its usefulness was limited by a high incidence of adverse effects. Adverse events prevented ongoing therapy for 36 (41%) and cognitive dulling resulted in topiramate discontinuation by 27 (31%) of the group.

A follow-up study of adults with learning disabilities and epilepsy

A programme to review the drug treatment of 215 adults with epilepsy and learning disabilities occurred in Leicestershire between 1982 and 1985. In 1997, a Leicestershire-wide study of epilepsy suffered by adults with learning disabilities was undertaken. The study sought information about many aspects of the epilepsy including the prescribing of medicines. One hundred and thirty-eight adults were common to both studies. A greater proportion was suffering active epilepsy in 1997 than in 1985. The deterioration in seizure control occurred despite an increase in polypharmacy, the introduction of new antiepileptic drugs and in some cases increases in dosage.

The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy

We report the effects of the addition of lamotrigine, a novel antiepileptic drug, to the therapy of 125 patients with severe refractory epilepsy. Forty-five patients (36%) reported adverse experiences and in 19 (15%), the drug was withdrawn. The commonest adverse experiences were diplopia, headache, ataxia, drowsiness, skin rash and deterioration in seizure control. Two patients were withdrawn for other reasons. The remaining 104 patients were followed for a mean of 11 months (range 3–27): 26 (25%) of these showed a marked improvement in seizure frequency (a 50% or more reduction when compared with the pre-trial period), but no patient was rendered seizure-free. Tolerance to the effects of the drug was not seen.

Nifedipine as an add-on drug in the management of refractory epilepsy

We report the effects of the addition of nifedipine, a calcium channel antagonist, to the antiepileptic therapy of 20 patients with severe medically refractory epilepsy. Six patients developed side effects and in two the drug had to be discontinued because of these. The commonest side effects were headaches, dizziness and lethargy. Two patients experienced deterioration in seizure control and only 2 patients showed improved seizure control. One of these patients subsequently developed tolerance at 5 months. In 16 patients there was no change.

Withdrawal of sedative anticonvulsant drugs from mentally retarded persons: Development of guidelines

Forty-four institutionalized mentally retarded persons with epilepsy had a sedative anticonvulsant drug withdrawn because of lack of effectiveness, toxicity, or suspected lack of need for anticonvulsant therapy. The records were reviewed retrospectively to determine which factors were associated with subsequent deterioration of seizure control. Seizure control was better or unchanged in 35 subjects and worse in 9. Deterioration was significantly related to prior seizure frequency and to absence of co-medication (nonsedating anticonvulsant drugs) but not to degree of mental retardation or type of seizure. Behavior improved in 15 subjects and deteriorated in none. These results suggest that sedative anticonvulsant drugs are often unnecessary and may be safely withdrawn from most mentally retarded persons with epilepsy. Suggested guidelines are provided for avoiding sedative anticonvulsant drugs and for identifying patients from whom they can be safely withdrawn.