Anti-epileptic drugs-induced de novo absence seizures

The authors present three patients with de novo absence epilepsy after administration of carbamazepine and vigabatrin. Despite the underlying diseases, the prognosis for drug-induced de novo absence seizure is good because it subsides rapidly after discontinuing the use of the offending drugs. The gamma-aminobutyric acid-transmitted thalamocortical circuitry accounts for a major part of the underlying neurophysiology of the absence epilepsy. Because drug-induced de novo absence seizure is rare, pro-absence drugs can only be considered a promoting factor. The underlying epileptogenecity of the patients or the synergistic effects of the accompanying drugs is required to trigger the de novo absence seizure. The possibility of drug-induced aggravation should be considered whenever an unexpected increase in seizure frequency and/or new seizure types appear following a change in drug treatment. By understanding the underlying mechanism of absence epilepsy, we can avoid the inappropriate use of anticonvulsants in children with epilepsy and prevent drug-induced absence seizures.     

Antiepileptic Drug-Induced Worsening of Seizures in Children

Summary: Antiepileptic drugs (AEDs) may aggravate preexisting seizures and trigger new seizure types. However, the extent and mechanisms of this problem are unclear, for several reasons. AED trials are not designed to detect worsening of seizures, severe childhood epilepsies may fluctuate in severity, and worsening of seizures may be over-hastily ascribed to the introduction of a new AED. Moreover, the seizure and the epilepsy type may have been incorrectly diagnosed. The problem is identification of true aggravation of epilepsy in the absence of overdosage or toxicity. This is a common and clinically important problem that concerns both established and newer AEDs, but the biologic mechanisms involved are unknown. An increase in seizure frequency due to overdosage has been reported with phenytoin but is rare with other AEDs. Paradoxical reaction has been reported with carbamazepine (CBZ), benzodiazepines, and vigabatrin (VGB). Exacerbation of seizures may also occur during AED-induced encephalopathy or hepatopathy. An inappropriate choice of the AED (i.e., a purely pharmacodynamic mechanism) can induce worsening when CBZ or VGB is used in absence and myoclonic seizures. Further research should determine whether seizure exacerbation is associated with the type of epilepsy or with the type of EEG abnormality. Recent evidence indicates that lamotrigine is inappropriate in severe myoclonic epilepsy. Some childhood epileptic encephalopathies have been affected by certain seizure-worsening mechanisms. Whether this is due to a predisposition in specific syndromes or to an increased risk for adverse effects in patients undergoing multiple AED manipulations is unclear. Furthermore, some syndromes are not the sum of accompanying seizure types but have unique neurobiology.     

Antiepileptic drug discovery: does mechanism of action matter?

This commentary discusses briefly the role of the mechanism of antiepileptic action in discovery of drugs for the treatment of epilepsy. More specifically, two questions are addressed. (1) Has mechanism-driven antiepileptic drug discovery brought us better epilepsy treatment? Although this question is difficult to answer, the short answer is "not yet." Modern antiepileptic drugs with new or modified mechanisms of action do not seem to have substantially improved the efficacy or the safety of epilepsy treatment. In fact, some modern antiepileptic drugs such as progabide, tiagabine, and vigabatrin have been associated with a number of safety issues. (2) Why do drugs with new mechanisms seem to have failed to deliver better treatment? Although it is always difficult to know why something did not occur, one putative explanation may be worthwhile to consider. The past development of new antiepileptic drugs targeted putative mechanisms of seizure generation. As seizures are only symptoms of the underlying epilepsy, blocking seizure generation can provide at best only symptomatic treatment. It may be that the failure in treating drug-resistant seizures is related, at least in part, to the failure of current drugs in targeting the mechanisms underlying epilepsy. In conclusion, continuing to develop new antiepileptic drugs for drug-resistant epilepsy by targeting seizure generation may be futile and one possible explanation of why we do not seem to make substantial progress in the treatment of drug-resistant epilepsy. Developing antiepileptic drugs with antiepileptogenic activity may be a clue to better treatment of presently drug-resistant epilepsy.     

Selection of drugs for the treatment of epilepsy

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.     

Juvenile absence epilepsy exacerbated by valproic acid

Valproic acid is commonly and effectively used in the treatment of idiopathic generalized epilepsies, including juvenile absence epilepsy. Although several adverse effects are associated with this drug, it has only rarely been known to exacerbate seizures. Similar to antiarrhythmic drugs aggravating particular arrhythmias, antiepileptic drugs can paradoxically induce new seizure types or exacerbate existing ones. This reaction is better known with carbamazepine and phenytoin, but is less common with broad-spectrum antiepileptic drugs such as valproic acid. This report describes a case of paradoxical, intravenous valproic acid-induced seizure exacerbation in a child with juvenile absence epilepsy, documented by video-electroencephalography.     

Aggravation of epilepsy by anti-epileptic drugs

The possibility that so-called anti-epileptic drugs (AEDs) may aggravate epilepsy must always be borne in mind by the clinician. Many reports of such aggravation of seizures have been published. Most such reports are anecdotal and speculative, and suggest that many such reactions are idiosyncratic. However, for some there is a sufficient body of evidence to suggest that some AEDs used in certain epilepsies may consistently cause worsening of seizures. Seizure aggravation may include increase in the frequency or severity of existing seizures, emergence of new types of seizure, or the occurrence of status epilepticus. The pathophysiology of seizure aggravation is poorly understood including non-specific effects such as those associated with sedation, drug-induced encephalopathy, and paradoxical or inverse pharmacodynamic effects. For some epilepsies the choice of AEDs may be inappropriate, and although the mechanism of seizure aggravation is not clear, its occurrence may be fairly predictable. This is best documented for the use of carbamazepine in idiopathic generalized and myoclonic epilepsies. Most other AEDs have been reported occasionally to cause seizure aggravation. The lowest risk of seizure aggravation appears to be with valproate. Risk factors for worsening of seizures are epileptic encephalopathy, polytherapy, high frequency of seizures, and cognitive impairment. Advances in pharmacogenomics may in the future enable such adverse effects to be predicted for individual patients. Meanwhile, a systematic approach to reporting AED-induced seizure aggravation should be developed.     

Aggravation of Generalized Epilepsies

Summary: Generalized epilepsies are treatable with a number of antiepileptic drugs (AEDs) that are effective in different seizure types and epilepsy syndromes. The mechanisms of action of these AEDs are incompletely understood but include inhibition of low-threshold calcium currents and of voltage-gated sodium channels and facilitation of GABA_A receptor currents. The mechanisms of aggravation are also unknown but could include elevation of brain GABA, blockade of voltage-gated sodium channels, and idiosyncratic toxicity reactions. Anecdotal reports suggest that aggravation of generalized epilepsy can occur with virtually all AEDs. The best-documented examples are aggravation of absences by carbamazepine and aggravation of symptomatic generalized epilepsies by vigaba-trin. Therefore, the physician must be constantly aware of the problem of aggravation of seizures by AEDs. With careful diagnosis of the epileptic syndrome and an awareness of the problem, aggravation of seizures can be minimized.     

Reducing overtreatment

Although treatment of epilepsy easily evolves into a situation of overtreatment, reversing the process can be difficult and time consuming. Benefits of reducing overtreatment may include a decrease in side effects, better seizure control, a simplification in the medication regimen, improved compliance, and reduced costs. The risks include seizure exacerbation due to withdrawal or due to loss of protection. Reversal of pharmacokinetic interactions may also lead to seizure aggravation or to drug toxicity. When reducing overtreatment, there are three main challenges: to select the drugs that should be eliminated, to choose an appropriate rate of reduction, and to anticipate reversible pharmacokinetic interactions that can have clinically significant consequences. Overall, there is a lack of published data to properly support recommendations for implementing reduction of overtreatment. This is particularly the case in the pediatric population and for the newer antiepileptic drugs.     

Seizure Aggravation in Idiopathic Generalized Epilepsies

Summary:  Seizures in the idiopathic generalized epilepsies (IGEs) usually remit completely with antiepileptic drugs (AEDs). Occasionally, however, they may be aggravated by AEDs. Before attributing exacerbation of seizures to an AED, alternative explanations need to be excluded. These include natural fluctuation of seizures, irregular compliance, maladjustment to the disease, comorbid illness, and development of tolerance. Aggravation may be due to a paradoxical reaction or drug-induced encephalopathy, sedative effects, or inappropriate use of a drug; and this need to be established, as it will guide management. An important caveat is that most data on aggravation of generalized seizures are based on anecdotal case reports or case series. Whether considering efficacy or aggravation, the interpretation of data from uncontrolled studies and case reports must be treated with caution. In practice, despite the fact that clear evidence is lacking, the possibility of seizure aggravation must be considered when treating people with IGEs. Predictive factors for seizure aggravation in a particular patient with a specific drug are yet to be fully defined. It is paramount to classify seizure type correctly in all patients. If this is not possible, a broad-spectrum AED should be used. Drugs that modulate Na⁺-channels and GABAergic drugs seem to be more prone to aggravating seizures, and therefore are best avoided in the initial management of IGE. Further studies are required to elucidate this phenomenon in full. It is interesting to speculate that paradoxical responses to AEDs may have pharmacogenetic value, serving as tools for a more precise and useful characterization of the epilepsies.     

Sleep complaints and epilepsy: the role of seizures, antiepileptic drugs and sleep disorders.

Patients with epilepsy commonly complain of daytime sleepiness and poor sleep quality. These problems are frequently attributed to antiepileptic drugs and seizures. Antiepileptic drugs and seizures have effects on sleep architecture often leading to daytime sleepiness. However, sleep symptoms may also be caused by poor sleep hygiene and primary sleep disorders. Primary sleep disorders should be suspected in patients with persistent daytime sleepiness, particularly those on AED monotherapy or with low serum drug concentrations and well-controlled seizures. Treatment of sleep disorders and improved sleep hygiene may improve seizure control and quality of life.     

Women and epilepsy: review and practical recommendations

Individuals with epilepsy experience a number of sex-specific problems. In women, pregnancy and delivery are obvious issues, fertility problems are more often encountered and they also seem to have a higher frequency of sexual problems. A large number of women with epilepsy experience seizure exacerbation in relation to the menstrual cycle and have higher frequencies of menstrual disturbances and polycystic ovaries. Cosmetic problems affecting skin, hair or weight may also be drug induced. The use of antiepileptic drugs may influence the effect of contraceptives leading to unplanned pregnancies and contraceptives may affect the serum levels of antiepileptic drugs. The care of pregnant women with epilepsy requires attention to a number of guidelines and close cooperation between neurologist and gynecologist is recommended. Although the majority of the women with epilepsy experience normal pregnancies and deliveries, their children have a higher risk of birth defects. At menopause, their seizure pattern may change and some antiepileptic drugs may increase the risk of osteoporosis. The optimal treatment of women with epilepsy should take into account these gender-specific issues in the different stages of life.     

When antiepileptic drugs aggravate epilepsy

Paradoxically, an antiepileptic drug (AED) may aggravate epilepsy. The number of AEDs is steadily increasing, and the occurrence of paradoxical aggravation will probably become a frequent problem. The overall status of the patient treated for epilepsy can be altered due to maladjustment to the diagnosis of epilepsy, to unwanted side-effects, to overdosage and to the occurrence of tolerance. However, the main mechanism of aggravation is the occurrence of an inverse pharmacodynamic effect. The specific effect of the AED is such that it controls epilepsy in most cases and increases seizures in other cases. Idiopathic generalised epilepsies (IGE) are particularly prone to pharmacodynamic aggravation: typical absences are constantly increased by carbamazepine (CBZ), vigabatrin, tiagabine, gabapentin, while phenytoin (PHT) is less aggravating. Juvenile myoclonic epilepsy is often aggravated by CBZ, less constantly by PHT and other AEDs. Generalised tonic-clonic seizures found in IGEs may respond to AEDs that aggravate the other seizure types. In symptomatic generalised epilepsies, patients have often several seizure types that respond differently to AEDs: myoclonias are generally aggravated by the same drugs that aggravated IGEs; tonic seizures in the Lennox-Gastaut syndrome respond to CBZ, which may however aggravate atypical absences. In severe myoclonic epilepsy of infancy, there is a nearly constant aggravating effect of lamotrigine. In some patients with benign rolandic epilepsy, a clear aggravation may be produced by CBZ, with occurrence of negative myoclonias, atypical absences, drop attacks, and at the maximum evolution into a state of electrical status epilepticus during sleep. It is much more difficult to pinpoint specific pharmacological sensitivity in other focal epilepsies, but aggravation clearly occurs. When treating epilepsy, the clinician should act according to seizure type, or, better, to epilepsy type. Patients are usually aware of aggravation before their doctors: we should listen carefully whenever they express a 'dislike' for an AED.     

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.     

Quality of life for patients with epilepsy is determined by more than seizure control: the role of psychosocial factors

Antiepileptic drugs remain the cornerstone of epilepsy treatment for minimizing, if not eliminating, seizures. However, many factors other than the degree of seizure control influence the quality of life for patients with epilepsy. This review focuses on psychosocial factors that have been associated with quality of life in this population, especially mood disorders, stigma seizure worry, self-esteem and self-mastery. Irrespective of their level of seizure control from antiepileptic drugs, patients may also benefit from targeted psychosocial interventions that reduce the negative impact of these factors on their quality of life.     

Epileptic psychoses and anticonvulsant drug treatment

Forty four consecutive patients with epilepsy and psychoses were studied retrospectively for psychotic episodes associated with changes in antiepileptic drug therapy. Twenty seven patients (61%) developed their first episode of psychosis unrelated to changes in their antiepileptic drug regimen. Twenty three of these patients developed psychoses with temporally unrelated changes in seizure frequency. Many patients had chronic schizophrenia-like psychotic symptoms. Seventeen patients (39%) developed their first episode of psychosis in association with changes in their antiepileptic drug regimen. Twelve patients developed psychoses temporally related to seizure attenuation or aggravation. Many of their psychotic symptoms were polymorphic with a single episode or recurrent episodes. No marked differences were found in the various clinical backgrounds between the two groups. In the drug-related group, seven patients developed psychoses after starting add-on therapy with a new antiepileptic drug, six after abruptly discontinuing their drugs, and four after taking an overdose of antiepileptic drugs. Based on the present findings, drug regimens should be changed gradually and compliance should be maintained to prevent epileptic psychoses.     

Animal models of focal epilepsy

Animal models are important in the study of the development and expression of focal seizures as well as in the preclinical evaluation of antiepileptic treatment. Many different models are available, including acute and chronic models for simple partial seizures and models for complex partial seizures. Work on models has revealed that the pathophysiology of seizure disorders includes several neurotransmitter and membrane channel alterations. In addition, epileptogenesis of focal epilepsy has been shown to involve the selective loss of neurons and axonal reorganization. Antiepileptic treatment still hinges on three general themes: modulation of voltage-dependent ion channels involved in spike propagation and burst generation, enhancement of GABA-mediated inhibition, and suppression of excitatory amino acidergic activity. Many antiepileptic drugs have proven efficacy against focal seizures in animal models as well as patients. More recently developed antiepileptic drugs may prove to be superior in the alleviation of intractable partial seizures. The three general themes of antiepileptic drug action still dominate the development of antiepileptic treatment strategies. Too much emphasis on the classical models of focal epilepsy may hamper the development of innovative strategies. On the other hand, continued research on new and existing models may broaden our knowledge of the pathophysiological processes underlying focal epilepsy, and inspire new avenues in antiepileptic treatment development.     

Behaviour, cognition and epilepsy

Cognitive and behavioural impairments have been observed as a consequence even of single seizures. In individuals with high seizure frequency, such impairments may accumulate and have a much greater impact on daily life than hitherto suspected. In addition, the risk of behavioural impairments is increased for some seizure types, such as secondary generalized seizures. Moreover, for all epilepsy types, increased risk is associated with persistent or poorly controlled seizures. Clinical studies show that cognitive impairments induced by seizures are reversible for most seizure types when seizures are controlled adequately. Additionally, for some seizure types there may be a kind of time window within which impairments are reversible. Exceeding the time window may result in irreversible impairment. These studies suggest that antiepileptic drug treatment can thus protect against such secondary behavioural impairments or at least correct these when seizures are controlled. This emphasizes the need to achieve complete and early seizure control. On the contrary, all antiepileptic drugs have a detrimental effect on the central nervous system and may affect cognitive function, behaviour and mood to some extent. Some treatments may undo the beneficial effects of antiepileptic drug treatment by inducing new or other cognitive impairments. This once more illustrates the need for the emphasis of clinical practice to evolve from mere seizure control to a more comprehensive approach, in which the prevention of central cognitive effects and effects on daily life of both seizures and drugs is given due attention. Optimal management requires a careful balance between, on the one hand, the desire to reach early and maximal seizure control and, on the other, the need to avoid tolerability problems related to cognitive and behavioural impairments. This article reviews how this balance can be achieved for older and newer antiepileptic drugs.     

The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies

OBJECTIVE: To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined. METHODS: All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates. RESULTS: 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%). CONCLUSIONS: Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.     

Basic Mechanisms of Epilepsy: Targets for Therapeutic Intervention

Summary: Although a wide variety of drugs are available for treatment of epilepsy, many patients with epilepsy still experience uncontrolled seizures. In addition, there is a need for new drugs that can halt epileptogenesis after brain injury. Mechanisms that underlie seizure processes constitute potential target areas for the development of new antiepileptic drugs (AEDs). An understanding of the underlying mechanisms of interictal spike discharge and seizure spread is critical for the development of AEDs for treatment of partial seizures. Suppression of specific forms of voltage-dependent calcium currents and inhibition of GABA_B receptor-mediated inhibition are two key target areas for new AEDs to treat primary generalized seizures. As researchers gain more understanding of the cellular, molecular, and genetic mechanisms underlying seizure propagation, we should be better able to develop therapeutic agents designed to suppress seizure-provoking mechanisms and to enhance the brain's natural protective mechanisms.     

神经外科患者癫痫反复发作处理分析

目的 探讨神经外科患者出现癫痫反复发作的临床特点、处理原则与方法.方法 回顾性分析沈阳军区总医院神经外科自2011年1月至6月收治的9例癫痫反复发作患者的临床资料,分析其加重的原因、发作特点及治疗方法和结果.结果 9例患者中3例合并胶质瘤、1例蛛网膜囊肿、1例海绵状血管瘤、1例脑软化灶;7例有癫痫病史,2例既往无癫痫病史;7例为额叶癫痫,2例颞叶癫痫.癫痫发作加重的原因:减药3例,新诊断的脑肿瘤2例,手术(颅内电极置入术)1例,原因不明3例.癫痫发作类型包括部分性发作与全面性发作,发作频率从间隔3min至间隔数小时发作一次.患者经给予多种抗癫痫药物联合用药治疗,包括口服与注射给药,癫痫得到控制,其中添加左乙拉西坦口服有较好的疗效.结论 神经外科患者出现癫痫反复发作多呈药物难治性,发作不易控制,其处理应使用对部分性癫痫发作有较好疗效的多种抗癫痫药物联合用药,剂量应高于常规初始剂量,包括静脉注射及肌注给药,以尽快控制癫痫发作.左乙拉西坦因口服吸收快、起效迅速及有较好的抗癫痫作用,对癫痫反复发作有较好的疗效.