Epilepsy and the outcomes of pregnancy

This review article discusses some issues regarding problems facing women with epilepsy who are contemplating pregnancy. Risks to the offspring from seizures and antiepileptic medication are considered, and it is concluded that seizures pose a greater overall risk than do medications used properly. The risk for congenital malformations is greater as more medications are used, and the highest rate of malformation occurs when three or more drugs are used. Although some studies have reported higher rates of mental retardation in infants born to mothers with epilepsy, these conclusions are not supported by well-controlled studies. In general, women with epilepsy have a relative risk ratio for poor outcome of pregnancy of only 1.25 as compared to the general population.     

Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study

OBJECTIVE: To determine incidence of and risk factors for sudden unexpected death in epilepsy (SUDEP). METHODS: Three epilepsy centers enrolled 4,578 patients and prospectively followed these patients for 16,463 patient-years. The cohort was screened for death annually. Deaths were investigated to determine whether SUDEP occurred. Potential risk factors were compared in SUDEP cases and in controls enrolled contemporaneously at the same center. RESULTS: Incidence of SUDEP was 1.21/1,000 patient-years and was higher among women (1.45/1,000) than men (0.98/1,000). SUDEP accounted for 18% of all deaths. Occurrence of tonic-clonic seizures, treatment with more than two anticonvulsant medications, and full-scale IQ less than 70 were independent risk factors for SUDEP. The number of tonic-clonic seizures was a risk factor only in women. The presence of cerebral structural lesions and use of psychotropic drugs at the last visit were not risk factors for SUDEP in this cohort. Subtherapeutic anticonvulsant levels at the last visit were equally common in the two groups. No particular anticonvulsant appeared to be associated with SUDEP. CONCLUSIONS: These results support the idea that tonic-clonic seizures are an important proximate cause of SUDEP. This information creates a risk profile for SUDEP that may help direct preventative efforts.     

Febrile seizures. From molecular biology to clinical practice

Febrile seizures occur between the age of 3 months and 5 years with a temperature of 38 degrees C or higher, and are either simple or complex. Eight gene loci have been identified to be associated with certain cases of autosomal dominant familial febrile seizures, and 12 genes have been associated with some of the familial epilepsy syndromes that can start with febrile seizures. The mutations and the protein products are known for only some of these 20 genes. The risk of recurrence of convulsions in a further febrile illness is on average 30%, and of developing epilepsy is on average 6%, but both vary depending on the presence and number of risk factors in any given patient. The immediate treatment of a febrile convulsion is intravenous or rectal diazepam, but febrile status epilepticus requires intravenous Phenobarbital and possibly other medications. Long-term antiepileptic drugs are not recommended in most patients with febrile seizures. However, exceptions should be considered on an individual basis in patients with complex febrile seizures with multiple risk factors for development of later epilepsy.     

Initiation and discontinuation of antiepileptic drugs

The issues of when to initiate and discontinue antiepileptic drugs (AEDs) are reviewed using an approach that emphasizes weighing the relative risks and benefits of the therapeutic decisions. The majority of children and adults who present with a first unprovoked seizure will not experience further seizures. Treatment reduces recurrence risk but does not alter long-term prognosis. Treatment should be deferred until a second seizure has occurred. The majority of children and adults who are seizure free for two or more years on medications will remain so when medications are withdrawn. The risk of reoccurrence is somewhat higher in adults. The consequences of recurrence are much more significant in adults. Most children who are seizure free on medications should have at least one attempt at medication withdrawal. In adults, the decisions need to be individualized based on a variety of factors including age, sex, occupation, and the presence or absence of risk factors for reoccurrence.     

Chronic management of seizures in the syndromes of idiopathic generalized epilepsy

As a group, idiopathic generalized epilepsies (IGEs) have the highest rates of complete seizure control with medication. However, there are little evidence-based data to guide drug choice for treatment. Examples of IGE include absence epilepsy, generalized tonic-clonic epilepsy, and juvenile myoclonic epilepsy. Generalized epilepsies seem to be particularly vulnerable to seizure aggravation, and medications that are primarily effective against partial seizures are more commonly involved in seizure aggravation than other medications. A review of current research has shown that only a few medications can control IGE without potentially causing seizure aggravation. Broad-spectrum antiepileptic drugs such as valproate (VPA), lamotrigine, and topiramate are extremely effective at controlling a variety of seizures without causing excessive seizure aggravation. Among these drugs, VPA has the longest clinical experience history and the largest body of published data.     

Problems and Management of the Pregnant Woman with Epilepsy

Summary: Pregnancies occurring in women who are epileptic are considered to be high risk. These women are at increased risk of seizures during pregnancy, labor, and delivery and of pregnancy complications and adverse pregnancy outcomes. Pregnancy alters the pharmacokinetics of anticonvulsant drugs, the levels of which decline as pregnancy advances. Not all drugs are altered in a similar manner, however. The rate of congenital malformations in infants of epileptic mothers is 2.4 times higher than in the general population. Malformations occur with all of the commonly used anticonvulsant drugs. The possible mechanisms of teratogenicity include folic acid antagonism, fetal tissue binding, and toxic effects of metabolic intermediates. Therapy with more than one drug increases the risk of congenital malformations. A unique hemorrhagic phenomenon in the infants of epileptic mothers has been reported and appears to be the result of a deficiency of vitamin K-dependent clotting factors. When taken by a pregnant woman, all antiepileptic drugs except valproic acid manifest themselves in breast milk, but only if the infant exhibits evidence of sedation should breastfeeding be discontinued. The dilemma for the physician treating the pregnant epileptic woman is to protect the mother from seizures and the fetus from unnecessary exposure to anticonvulsant medications.     

Practical Management Issues for Idiopathic Generalized Epilepsies

Summary:  The idiopathic generalized epilepsies (IGE) are a group of epilepsies that are genetically determined, have no structural or anatomic cause, and usually begin early in life. Neurologic examination, intelligence, and imaging studies are normal, and EEG shows only epileptiform abnormalities (i.e., no abnormal slow activity or evidence for diffuse encephalopathy). In some IGE, the genetic substrate has been identified, whereas in most, it remains unknown. Depending on the age at onset and predominant seizure type, individual subtypes of IGE (syndromes) are defined. However, overall, there are more similarities than there are differences among the various subtypes, and the IGE are best viewed as a spectrum or continuum of conditions. In general, IGE respond to treatment, with 80–90% becoming fully controlled. However, not all antiepileptic drugs (AED) are equally effective in IGE. Some AED are ill advised because they either do not work or exacerbate seizure types other than generalized tonic–clonic (GTC) seizures, that is, absence and myoclonic seizures. These include carbamazepine, oxcarbazepine, phenytoin, gabapentin, and tiagabine. Their use is the main cause of "pseudo-intractability," and at least in the United States where PHT and CBZ are the most commonly used AEDs, patients with IGE are often on inadequate medications. For patients with clear IGE, the drug of choice is generally valproic acid because it effectively controls absence myoclonic seizures and GTC seizures. Second-line drugs (when first-line drugs fail or are not tolerated) may include benzodiazepines, but the use of second-line drugs is evolving rapidly. Some of the newer AEDs are considered broad spectrum, meaning that they work in IGE and focal epilepsies, although the evidence is largely preliminary at this point. These newer AEDs include lamotrigine, topiramate, levetiracetam, and zonisamide.     

Focal status epilepticus as atypical presentation of pyridoxine-dependent epilepsy

Pyridoxine-dependent epilepsy usually presents in the neonatal period or even in utero, is refractory to antiepileptic medications, and is treatable with lifelong administration of pyridoxine. The seizures are typically generalized tonic-clonic, although myoclonic seizures or infantile spasms have been described. We report an infant who presented at 5 months of age with a right-sided clonic seizure with fever. Subsequently, she had recurrent right focal or generalized seizures despite sequential treatment with various antiepileptic medications. At 7 months, she was hospitalized with status epilepticus, which was finally controlled with pyridoxine. After she became seizure free, she continued to have a strong left arm preference with mild weakness of the right arm and delayed language skill. Eventually, she outgrew these symptoms. This case illustrates that pyridoxine-dependent epilepsy, although rare, must be included in the differential diagnosis of focal seizures, especially when the seizures are refractory to traditional antiepileptic drugs.     

Discontinuing antiepileptic drugs in children with epilepsy: A prospective study

In a prospective study, antiepileptic drugs were discontinued in 264 children with epilepsy after a mean seizure-free interval of 2.9 years. They were then followed for a mean of 58 months to ascertain whether seizures recurred. Seizures recurred in 95 (36%) of the children. Etiology was a significant predictor of outcome (relative risk [RR] = 1.81). On multivariable analysis, significant factors in the idiopathic group included age at onset above 12 years (RR = 5.4), a family history of seizures (RR = 3.1), the presence of slowing on the electroencephalogram prior to medication withdrawal (RR = 2.4), and a history of atypical febrile seizures (RR = 2.8). Specific epileptic syndromes such as juvenile myoclonic epilepsy and benign rolandic epilepsy were also significant predictors of outcome. In the remote symptomatic group, significant predictors of outcome included age at onset older than 12 years (RR = 3.6), moderate to severe mental retardation (IQ < 50) (RR = 2.8), a history of atypical febrile seizures (RR = 2.0), and a history of absence seizures (RR = 0.4). The majority of children with epilepsy in remission while on antiepileptic drug therapy will remain seizure free when medications are withdrawn. A few readily available parameters distinguish those with a good prognosis from those in whom seizures are likely to recur. These data provide the framework for the clinical decision making for withdrawal of medications in these children.     

Basic Science

Ying Wang-Tilz , Christian Tilz , Bing Wang , Gernot P. Tilz , and Hermann Stefan
Some individuals with epilepsy appear resistant to most or all antiepileptic medications. One possible explanation for this resistance is the presence of a gene called MDR1 that causes production in the brain of a substance called p-glycoprotein (P-gp). We studied a model of epilepsy in rats produced by repeated injections of Coriaria lactone, an epileptogenic plant toxin. The clinical antiepileptic drugs, topiramate and lamotrigine, significantly reduced seizures. With these two drugs, P-gp was not increased in brain. In contrast, carbamazepine and valproate did increase brain P-gp, and these drugs were less beneficial against the seizures. These results suggest that attention could usefully be paid to whether medications activate multiple drug-resistance genes in brain, because such an effect could counteract the effectiveness of a medication.     

Predictors and characteristics of seizures in survivors of progressive multifocal leukoencephalopathy

This study aims to determine the risk factors for epileptogenesis and characteristics of seizures in patients with progressive multifocal leukoencephalopathy (PML) who survive more than 1 year from onset of neurological symptoms (PML survivors). We reviewed clinical data including seizure history and MR imaging studies from PML survivors evaluated at our institution between 1997 and 2014. PML progressors who passed away within 1 year and patients with a history of seizures prior to PML diagnosis were excluded from the analysis. Of 64 PML survivors, 28 (44 %) developed seizures. The median time from the onset of PML symptoms to the first seizure was 5.4 months (range 0–159) and 64 % of patients with seizures had them within the first year. The presence of juxtacortical PML lesions was associated with a relative risk of seizures of 3.5 (p?<?0.02; 95 % confidence interval (CI) 1.3–9.4) in multivariate analyses. Of all seizure types, 86 % were focal and 60 % most likely originated from the frontal lobes. Among seizure patients, 89 % required treatment, including one (54 %), two (25 %), or three (10.5 %) antiepileptic drugs. Seizures are a frequent complication in PML and can develop throughout the entire course of the disease. However, late onset seizures did not signify PML relapse. Seizures may require treatment with multiple antiepileptic medications and are a significant co-morbidity in PML.     

Effects of In Utero Antiepileptic Drug Exposure

Recent studies demonstrate an increased teratogenic risk for valproate and a probable increased risk for phenobarbital. Carbamazepine and lamotrigine appear relatively safe; however, results are inconclusive concerning a specific risk for cleft lip/palate for both drugs as well as a dose-dependent effect for malformations associated with lamotrigine. Data regarding teratogenic risks for other antiepileptic drugs are inadequate. Additional studies are needed to delineate further the risks for all antiepileptic drugs and determine the underlying mechanisms.Although the majority of children born to women with epilepsy are normal, they are at increased risk for malformations as well as for poor neuropsychological outcomes (1,2). Antiepileptic drugs (AEDs) have the potential to affect fetal development throughout pregnancy. In the United States alone, at least 45,000 children are exposed to AEDs during pregnancies of mothers with epilepsy (2). Given that less than half of AEDs are prescribed for epilepsy and that the majority are prescribed for psychiatric and pain indications, the total number of children exposed to this category of drugs is substantially higher. The risk of in utero exposure has to be measured against the risk of the underlying disease. For most women with epilepsy, the risks imposed by seizures affecting both the mother and child usually outweigh the risks of drug exposure. Women should not discontinue AEDs without discussion with their physicians, as trauma is the leading cause of nonobstetrical death in pregnant women with epilepsy (3). In a UK survey, the death rate during pregnancy for women with epilepsy was increased tenfold compared to the general population, primarily as a result of seizures (4). Thus, understanding the magnitude and differential effects of AEDs on teratogenesis is important.     

Neuropsychological aspects of epilepsy.

Brain dysfunction between seizures is common in epilepsy and a systematic assessment of it assists in planning directed programs of remediation. A battery of well-validated neuropsychological tests formulated with the needs of persons with epilepsy in mind can be of particular help in this regard. Increasing impairment in brain functions is shown to be associated with increasing emotional problems. Medical variables pertaining to seizure history include seizure type, cause, age at onset of seizures, duration of disorder, and seizure frequency. An exploration of relationships between these variables and measures of abilities and adjustment reveals a number of findings, some of which are complex. A review of the cognitive effects of antiepileptic drugs shows that the barbiturates have at least slightly greater adverse cognitive and behavioral effects than other drugs including carbamazepine, phenytoin, and sodium valproate. Whether cognitive differences exist among these latter medications is currently in question. Carbamazepine has the best-established favorable psychiatric effect.     

Treatment of Refractory and Super-refractory Status Epilepticus

Refractory and super-refractory status epilepticus (SE) are serious illnesses with a high risk of morbidity and even fatality. In the setting of refractory generalized convulsive SE (GCSE), there is ample justification to use continuous infusions of highly sedating medications—usually midazolam, pentobarbital, or propofol. Each of these medications has advantages and disadvantages, and the particulars of their use remain controversial. Continuous EEG monitoring is crucial in guiding the management of these critically ill patients: in diagnosis, in detecting relapse, and in adjusting medications. Forms of SE other than GCSE (and its continuation in a “subtle” or nonconvulsive form) should usually be treated far less aggressively, often with nonsedating anti-seizure drugs (ASDs). Management of “non-classic” NCSE in ICUs is very complicated and controversial, and some cases may require aggressive treatment. One of the largest problems in refractory SE (RSE) treatment is withdrawing coma-inducing drugs, as the prolonged ICU courses they prompt often lead to additional complications. In drug withdrawal after control of convulsive SE, nonsedating ASDs can assist; medical management is crucial; and some brief seizures may have to be tolerated. For the most refractory of cases, immunotherapy, ketamine, ketogenic diet, and focal surgery are among several newer or less standard treatments that can be considered. The morbidity and mortality of RSE is substantial, but many patients survive and even return to normal function, so RSE should be treated promptly and as aggressively as the individual patient and type of SE indicate.     

Seizures in Alzheimer Disease: Clinical and Epidemiological Data

Alzheimer disease (AD) and epilepsy are disorders commonly seen in the elderly. Many studies have shown that patients with AD are at increased risk for developing seizures and epilepsy. Whereas, patients with specific types of epilepsy, such as temporal lobe epilepsy (TLE), experience some degree of cognitive dysfunction, questions have been raised as to whether these disorders share some underlying pathophysiologic mechanisms or whether one is an epiphenomenon of the other. In this report, we review some of the available clinical and epidemiologic literature on various aspects of the topic of seizures in AD, including seizure rates and types, risk factors for seizures, electroencephalographic findings, treatment options, limitations, and methodological issues. Overall, multiple aspects of the literature on seizures and epilepsy in AD, including diagnosis, risk factors, the role of EEG in diagnosis, and the response to treatment are not clear and suffer from many methodological limitations and gaps.Epilepsy and AD are common neurologic disorders for which increasing age is a common and well-established risk factor (1, 2). The potential relation between these two disorders has been supported by experimental and clinical data. From a clinical aspect, patients with AD have an increased risk of developing seizures and epilepsy; thus AD may be an important cause of epilepsy in the elderly. AD and other neurode-generative conditions represent the presumed etiology for 10% of new onset epilepsy in patients older than 65 (3).The diagnosis of seizures in patients with AD is not always easy because the manifestation of partial seizures might be hard to recognize and distinguish from other behaviors common in these patients. This may lead to underestimation of the real frequency of seizures in AD. At the same time, the possibility that “funny” or “unusual” behaviors of demented patients are considered seizures, particularly by nonepileptologists, may lead to overestimation of seizure rates.We briefly review and comment on studies reporting on the risk of seizures in AD, the possible factors modifying this risk, the role of EEG in the diagnosis of epilepsy and its limitations, the efficacy of antiepileptic drugs and the relationship between seizures and interictal epileptiform activity and AD course.     

Childhood epilepsy: Management in resource-limited setting

Objective:

To optimize the use of phenobarbital and/or phenytoin as frontline drugs for treatment of childhood epilepsy.

Design:

Before-and -after study.

Setting:

Epilepsy clinic at paediatric OPD, Sassoon General Hospital, Pune.

Materials and Methods:

Epilepsy is a condition in which seizures are triggered recurrently from within the brain. For epidemiological classification purpose epilepsy is considered to be present when two or more unprovoked seizures occur at an interval greater than twenty four hours apart. Seizures were classified as generalized and partial seizures, with underlying etiology investigated with EEG, CT scan in majority of the patients. Follow - up rate, seizure - control and antiepileptic drugs used among 151 children enrolled as on 31 March 2005 were compared with 106 children with new onset epilepsy enrolled as on February 2006. Eight children with breakthrough convulsion after a seizure free period of five to eighteen months were followed up after injection vitamin D. Nineteen children with poor control of seizures receiving polytherapy with newer antiepileptic drugs were assessed with frontline antiepileptic medication of phenobarbital and/or phenytoin. Serum calcium, phosphorus, alkaline phosphatase were done in seventy two consecutive children with seizure disorder.

Results:

During post protocol period good seizure control was achieved in 84.8% as against 80.7% and use of phenobarbital and/or phenytoin increased to 65.11% from 22.87%. Of the 8 cases with breakthrough seizures seven remained seizure free after vitamin D administration and with no dose enhancement of AED medications of the nineteen. Children receiving polytherapy thirteen children could be successfully switched to phenobarbital and/or phenytoin. Forty four (61%) children had hypocalcemia (less than 9 mg%), fifty seven (79%) children had raised alkaline phosphatase levels (more than 270 IU).

Comments:

Phenobarbital and/or phenytoin have been found to be effective frontline AED. Periodic administration of vitamin D plays a supportive role.     

New Horizons in the development of antiepileptic drugs: Innovative strategies

The past decades have brought many advances to the treatment of epilepsy. However, despite the continued development and release of new antiepileptic drugs, many patients have seizures that do not respond to drug therapy or have related side effects that preclude continued use. Even in patients in whom pharmacotherapy is efficacious, current antiepileptic drugs do not seem to affect the progression or the underlying natural history of epilepsy. Furthermore, there is currently no drug available which prevents the development of epilepsy, e.g. after head trauma or stroke. Thus, there are at least four important goals for the future: (1) development of better antiepileptic ("anti-ictal") drugs with higher efficacy and tolerability to stop seizures compared to current medications; (2) better understanding of processes leading to epilepsy, thus allowing to create therapies aimed at the prevention of epilepsy in patients at risk; (3) development of disease-modifying therapies, interfering with progression of epilepsy, and (4) improved understanding of neurobiological mechanisms of pharmacoresistance, allowing to develop drugs for reversal or prevention of drug resistance. The third Workshop on New Horizons in the Development of Antiepileptic Drugs explored these four goals for improved epilepsy therapy, with a focus on innovative strategies in the search for better anti-ictal drugs, for novel drugs for prevention of epilepsy or its progression, and for drugs overcoming drug resistance in epilepsy. In this conference review, the current status of antiepileptic therapies under development is critically assessed, and innovative approaches for future therapies are highlighted.     

Clinical characteristics of psychogenic nonepileptic seizure status in the long-term monitoring unit

Patients with psychogenic nonepileptic seizures (PNES) mimicking status epilepticus (PNES-status) are at risk of iatrogenic complications. Our aim was to assess whether the population of patients with PNES who develop PNES-status are distinguishable. Retrospectively, we identified patients with PNES-status and compared them with patients with PNES without status and with patients with electroclinical status epilepticus (SE). Of 49 patients with PNES, 9 had PNES-status (18.2%) and 40 had PNES only. Compared with patients with PNES, subjects with PNES-status had taken fewer than three antiepileptic medications (P=0.016), had more than one event per week (P=0.026), were more likely to be admitted emergently to the monitoring unit (P=0.007), had shorter long-term monitoring (LTM) stays (P=0.003), and tended to be diagnosed sooner after initial presentation (P=0.058). Use of fewer than three antiepileptic drugs and emergent admission were independent predictors of PNES-status classification on logistic regression. Of 154 patients with epilepsy, 8 had SE during LTM (5.2%), significantly fewer than the proportion with PNES-status relative to PNES (P=0.008); the only clinical variable distinguishing these two groups was a baseline lower seizure frequency among the patients with epileptic seizures (P=0.045). Our results suggest that patients with PNES-status have features that differentiate them from patients with PNES without status and, to a lesser extent, from patients with epileptic seizures.     

Effect of war on the occurrence of epileptic seizures in children

We studied the occurrence of epileptic seizures in 72 children from war-affected and 39 children from non-war-affected areas during and after the 1991-1992 war in Croatia. During the war, children from war-affected areas who had "stable" epilepsy before the war and regularly took antiepilepsy medications had epileptic seizures more often than children from areas not affected by the war. In 2002, all children (n=10) whose first epileptic seizure was related to a stressful event had a "stable" condition, whereas 4 of 10 children whose first epileptic seizure was not stress-related had an "unstable" condition. Typical absence seizures were observed in 6 of 10 children in the stress-related group and none in the non-stress-related patient group. Stressful life events can be provocative factors for the occurrence of epileptic seizures. Typical absence seizures are more likely to be provoked by stress then other types of epileptic seizures.     

Drug-induced seizures: a 10-year experience

Of 53 patients with drug-induced seizures seen in the last decade, 45% had single seizures, 40% had multiple convulsions, and 15% had status epilepticus. Generalized seizures with focal features were common, but simple partial (motor) seizures occurred in only two patients. Isoniazid, insulin, lidocaine, and psychotropic medications were the most common drugs that caused seizures. Forty-nine patients recovered without ill effects, but 4 patients died of cardiovascular complications. The combined cardiovascular toxicity of the convulsants, antidotes, and anticonvulsants was more important than the number or duration of seizures in determining outcome.