Neuropharmacology & Neurotherapeutics
Sep. 05, 2021
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This article includes discussion of secondarily generalized tonic-clonic seizures (SGTCS), complex partial seizures with secondary generalization, simple partial seizures with secondary generalization, and focal seizures evolving to a bilateral convulsive seizure. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Secondarily generalized tonic-clonic seizures involve ictal discharges beginning in a restricted focus and spreading to involve bilateral motor outputs from the brain. Generalized tonic-clonic seizures can occur secondarily in idiopathic or symptomatic focal epilepsies and represent the final common pathway in the ictal progression of most seizure types. In this article, clinical features suggesting lateralization and diagnostic techniques to localize the focus are discussed, and management options are briefly covered.
• Seizures that clinically appear to be generalized may represent activation of specific pathways, dependent on the location of the focus, and may not be truly generalized.
• Cardiac arrhythmias and SUDEP are associated with intractable, secondarily generalized seizures.
• Novel therapies such as responsive intracranial stimulation hold promise for achieving more optimal seizure control.
• Modulation of inflammatory responses in immune-mediated seizures represents an evolving new avenue of treatment of epilepsy and possibly epileptogenesis.
The earliest descriptions of tonic-clonic seizures appear in Egyptian hieroglyphics prior to 700 BC. Partial-onset seizures in which convulsions were restricted to 1 side of the body were systematically described by Louis François Bravais in his 1827 thesis. In a paper published in 1870, John Hughlings Jackson, unlike Bravais, accepted the fact that convulsions that are initially unilateral could spread to the bilateral muscles of both sides of the body. He also believed that loss of consciousness could occur before the convulsion spread to the contralateral side of the body.
The terminology and classification of seizures and epilepsy by ILAE has undergone several revisions since 1970. In the report of ILAE commission on classification and terminology of seizures and epilepsy in 2010, it was recommended that the phrase “focal seizure evolving to a bilateral convulsive disorder” replace the term “secondarily generalized seizure.”
Secondarily generalized tonic-clonic seizures represent ictal discharges beginning in a restricted focus and spreading to involve bilateral motor outputs from the brain. They have been typically divided into specific stages. Marked heterogeneity exists between phase durations and clinical expression, suggesting multiple cortical and subcortical routes of spread. The most commonly described stages are as follows (36).
Aura. Usually an antecedent simple partial seizure, characterized by localized or nonlocalized symptoms, which the patient is aware of, but in the absence of observable signs. When an observable sign is present, the convention is to categorize that phenomena as a partial seizure rather than aura. The most common classification of auras include abdominal, somatosensory, olfactory, gustatory, auditory, or psychic auras. Simple partial seizures may progress to complex partial seizures or directly to generalized tonic-clonic seizures. Complex partial seizures consist of localized signs or symptoms with “alteration of consciousness” and amnesia. Clinically these are often associated with automatisms such as orofacial grimacing, chewing, lip-smacking, fumbling, picking, or repetitive movements of the hands and arms. They may also include unresponsive staring.
Onset of generalization. The transition between the aura or antecedent seizure and remaining phases of generalized tonic-clonic seizures can sometimes be identified. It is often characterized by nonadversive head turn or by vocalization (40). Clonic jerks that are usually irregular and asymmetric may precede the tonic phase.
Tonic phase. The tonic phase begins with a rigid muscular contraction that usually consists of a brief phase of flexion followed by a longer phase of extension. The flexion phase usually begins in the head and trunk and then extends to the extremities and is usually symmetric. The extension phase usually begins with axial muscle contractions, along with laryngeal spasm that may produce an ictal cry and apnea. Autonomic signs such as tachycardia, hypertension, and diaphoresis may begin during this phase. The tonic phase usually lasts for 10 to 30 seconds.
Clonic phase. The tonic phase gives way to clonic convulsive movements, in which rhythmic jerking lasts for a variable period of time. During the clonic phase, muscle relaxation interrupts tonic contraction and produces generalized rhythmic jerks, which slow down until the seizure ends. Deep, often stertorous respiration occurs at the end of the clonic phase, as other muscles relax. Urine incontinence and tongue biting may occur in this phase. The clonic phase usually lasts for 30 to 50 seconds.
Postictal state. The postictal state includes a period during which the patient becomes quiet in deep sleep, begins breathing deeply, and then gradually wakes up, often confused, with some automatic behaviors; the patient may later complain of feeling stiffness, generalized soreness, and headache.
Limited data exist for prognostic factors specifically for secondarily generalized tonic-clonic seizures. The available prognostic data are conflicting because of differing design, classification, duration of follow up in different studies, and etiology of the seizures. However, it is reasonable to assume that factors indicating poor prognosis for epilepsy in general will also hold true for secondarily generalized tonic-clonic seizures. Prognosis for individuals with secondarily generalized tonic-clonic seizures is less favorable than that of patients with most types of idiopathic generalized tonic-clonic seizures.
In 1 of the longest cohorts for seizure prognosis and survival in patients with newly diagnosed epilepsy, the data of 657 people who were followed for a median of 23.6 years was analyzed. There was only slightly more likelihood of recurrence of seizure in people who only had a single seizure at the time of registration versus those with 2 or more unprovoked seizures. Premature mortality in both groups of people with a single seizure and 2 or more unprovoked seizures was increased compared to the general population (02).
Complications that may occur in the ictal or immediate postictal period following a generalized tonic-clonic seizure include:
• Oral trauma
As the relationship between SUDEP, cardiac arrhythmias, and ictal asystole is further clarified, close attention on video-EEG monitoring to cardiac arrhythmias becomes of prime importance (14). A pacemaker may be indicated in some patients with ictal asystole or bradycardia.
Some of the risk factors for SUDEP include increased frequency of generalized tonic-clonic seizures, increased duration of seizures, younger age at onset, and symptomatic etiology (17). There is growing information about the complex genetic interactions predisposing individuals to SUDEP both in genetic and acquired epilepsies (15).
A 45-year-old woman presented following an episode of staring, picking at her clothes, and head version to the left followed by a generalized tonic-clonic seizure lasting about 1 minute. She was treated with lorazepam 2 mg and in the ambulance was noted to be lethargic and confused for 30 minutes following the event. Brain MRI demonstrated only subtle atrophy and increased signal on FLAIR sequencing in the right hippocampus. She recalled awaking sore and with bloody tongue twice in the previous 3 years. She was started on an antiepileptic drug.
Generalized seizures have long been thought to involve the whole brain. Research has indicated that generalized seizures (idiopathic or secondary) may not result in diffuse cortical activation and may activate only specific circuits (18). Although our understanding is still incomplete, a complex model of epileptogenic circuitry involving cortical and subcortical “nodes” may be instrumental in propagation of seizure activity. Although primary generalized seizures may utilize thalamocortical circuits as a primary pathway, secondary generalized seizures may do so less directly or not at all. The pathways utilized to achieve secondary generalization may be dependent on the location of the focus itself.
Several clinical manifestations have been reported to have localizing or lateralizing value for partial seizures. These include ictal speech, post-ictal dysphasia, dystonic limb posturing, unilateral hand automatisms, ictal vomiting, unilateral eyelid blinking, and versive head and eye turning (40). In some cases, particularly in the frontal and parietal lobes, the spread of the ictal discharge is rapid, and localizing features may not be apparent.
For secondarily generalized tonic-clonic seizures, head version has been reported to have reliable lateralizing value in frontal and temporal lobe epilepsies for seizure onset zone contralateral to the direction of head turning, when it is forced and immediately precedes secondary generalization.
Dystonic posturing of the contralateral extremities is a reliable lateralizing sign to the contralateral hemisphere in temporal lobe seizures. Unilateral motor automatisms have less reliable lateralizing value to the ipsilateral hemisphere. Left-sided unilateral motor automatisms without contralateral dystonia are reported to have lateralizing value to the left hemisphere, although right-sided unilateral motor automatisms without contralateral dystonia are reported to have no significant lateralizing value. Asymmetric tonic limb posturing, where 1 elbow is extended while the other is flexed (figure of 4 sign), has been described as a lateralizing sign with a positive predictive value of about 90%. The extended elbow is contralateral to the side of ictal onset.
Postictal paresis is another relatively frequent (13.4%) lateralizing feature that is easy to detect, indicating onset in the contralateral hemisphere. Postictal features can be transient and must be assessed shortly after the seizure.
Reliable localization of dominant versus nondominant hemisphere temporal lobe seizures by postictal reading was well demonstrated by Privitera and colleagues (28). In all 62 seizures originating from the dominant left temporal lobe, patients took more than 68 seconds to read the test phrase correctly; in 42 of 43 seizures from the nondominant right temporal lobe, patients read the test phrase in less than 54 seconds (mean, 19.7 seconds).
Localization or Lateralization
Forced head version
In addition to localizing information, the 1985 and 1989 ILAE epilepsy classification included etiologic classification of epilepsy and epilepsy syndromes. The term idiopathic referred to epilepsy syndromes that occurred in childhood or adolescence in the absence of any apparent cause. Most cases of idiopathic epilepsy were thought to be of a genetic etiology. On the other hand, the term symptomatic referred to epilepsy syndromes that were caused by diffuse, focal, or multifocal brain lesions. The 1989 classification also included the term cryptogenic to describe epilepsy syndromes that were presumed to be symptomatic, but the cause was unknown in specific patients. The revised classification in 2010 suggested uses of the terms genetic, structural-metabolic, and unknown to replace idiopathic, symptomatic, and cryptogenic, respectively. However, this change has not been widely adopted and the need for this change has been disputed (33).
Pathophysiology can be divided broadly into 3 main processes: epileptogenesis, mechanisms of spread, and termination of seizures.
Epileptogenesis. Several broad mechanisms may be involved in epileptogenesis of focal seizures, but basic pathogenesis seems to involve localized breakdown of the balance between inhibition and excitation. The origin is primarily in the cerebral cortex. In some models, neuronal cell loss induces aberrant synaptic reorganization, which enhances excitatory influences. Other models suggest dropout of inhibitory neurons or changes in neurotransmitter receptors may be more significant.
Different mechanisms that have been proposed for tumor-associated epilepsy include altered intrinsic properties of the tumor cell membranes and their ability to generate action potentials, pH disturbances that alter neuronal excitability directly and possibly through secondary effects on the NMDA subclass of glutamate receptors (01), and downregulation of the potassium chloride transporter in the regions around the tumor that can lead to compromise of the GABAergic inhibitory circuits (23).
Research has suggested that blood-brain barrier dysfunction may trigger an immune-mediated inflammatory response that may be instrumental in epileptogenesis (12). A metaanalysis of 66 articles about the role of inflammatory modulators in epilepsy found a significant increase in interleukin (IL)-6 and IL-17 in serum and IL-1β and IL-10 in CSF of patients with epilepsy with various etiologies (08). Modulation of inflammatory responses represents an evolving new avenue of treatment of epilepsy, and possibly epileptogenesis (29).
Mechanisms of spread. Epileptic activity may remain localized to a small area due in part to “surround inhibition” and other less clear mechanisms. With secondary generalization, the epileptic focus propagates through fibers of cortico-cortical networks and multiple brain circuits to reach larger cortex areas and subcortical structures. Spread occurs when the focal seizure is adequately intense and when the surrounding activity is less inhibitory. In a study that analyzed 39 seizures in patients with temporal lobe epilepsy, it was found that all the seizures that became generalized involved the posterior lateral temporal region, suggesting that this region may serve as a gateway that is involved in controlling propagation of temporal lobe seizures (39).
Termination of seizures. One suggested mechanism of seizure termination is that the synchronization toward the end of seizures is paced by intrinsic neuronal oscillations that are initiated by hyperpolarization-activated depolarizing current and then enhanced by Na+ and Ca2+ currents. Activation of hyperpolarizing currents eventually overcomes the depolarizing effects and results in seizure termination in the entire synchronized territory (35).
Other potential mechanisms include synchronization of inhibitory interneurons by synchronized ictal excitation, which leads to inhibitory termination (27), and upregulation of the inhibitory neurons in the seizure onset zone (38).
The role of endogenous adenosine in seizure termination by attenuating depolarization of GABA-A receptor-mediated signaling, which is important in seizure initiation and propagation, has been a focus of research studies in the past few years (04).
There is substantial variability in reported prevalence of epilepsy worldwide. In developed countries, there has been an estimation of about 4 to 7 per 1000 persons and in developing countries estimates have been around 5 to 74 per 1000 persons. This variability can be attributed to methodological differences, age and ethnic characteristics of the studied population, definition of epilepsy, and other biases in recruitment, but risk factors and medical care are likely predominant factors.
Distribution of epilepsy syndromes in newly diagnosed patients has been reported in several studies. One of the largest cohort studies in France reported 47.4% of newly diagnosed epilepsy cases with history of more than 1 seizure to be focal or localization related, including secondarily generalized tonic-clonic seizures, comprising of 13.5% symptomatic, 29.2% cryptogenic, and 4.7% idiopathic, whereas 33.8% were primary generalized, comprising of 27.4% idiopathic and 3.8% cryptogenic or symptomatic (19).
The diagnosis of seizures relies critically on history. Usually it is not difficult to distinguish generalized tonic-clonic seizures from other epileptic disorders. However, it is often difficult to distinguish secondary generalized from primary generalized tonic-clonic seizures. The focal onset is usually recognized when a slow onset with a well-defined partial seizure evolves into generalized tonic-clonic seizures. However, spread of the seizure can be extremely rapid making it difficult to appreciate clinically or even electroencephalographically. A focal onset seizure can sometimes arise from a focus deeper in the cortex or with a dipole orientation not detectable at recording electrodes. Differentiation is then helped by indirect evidence, such as semiology of seizures, focal brain lesions on imaging, or focal interictal epileptiform activity. If needed, other tests such as long-term video EEG monitoring, intracranial monitoring, ictal SPECT, PET, or MEG can be used for further evaluation and localization.
Psychogenic nonepileptic seizures are the most common differential diagnosis. Some of the features suggestive of psychogenic nonepileptic seizures include:
• Triggers that are unusual for epileptic seizures (conditions promoting feelings of anxiety or guilt)
Phenomena strongly associated with psychogenic nonepileptic seizures include gradual onset or termination, pseudo sleep, irregular or asynchronous activity, including side-to-side head movements, pelvic thrusting, opisthotonic posturing, stuttering, weeping, preserved awareness with bilateral motor activity, and persistent eye closure.
In contrast, symptoms in favor of epileptic seizures include occurrence out of sleep, incontinence, significant injuries, tongue bites of the posterior part of the tongue, and postictal confusion. The diagnosis sometimes requires video-EEG monitoring, which is the “gold standard” for diagnosis. Provocative techniques, activation procedures, or induction can be useful for the differential diagnosis of psychogenic nonepileptic seizures, particularly when no spontaneous attacks occur during monitoring, although some controversies in utilization of these techniques exist (07).
Generalized tonic-clonic seizures can occur secondarily in idiopathic or symptomatic focal epilepsies, being the final common pathway in the ictal progression of most seizure types. Common pathological substrates that cause focal epilepsies in adults include:
• Malformations of cortical development
Common idiopathic focal epilepsies causing secondarily generalized tonic-clonic seizures occur mainly in children and include (22):
• Benign childhood epilepsy with centrotemporal spikes
Diagnosis of epilepsy starts with a complete history and physical examination of the patient. A detailed history of the semiology of the seizure can help identify simple or complex partial signs or symptoms prior to generalization. Focal neurologic abnormalities are useful, especially if they correlate with the localization of the initial ictal manifestations. Various diagnostic tools can then be used to confirm location of the epileptic focus or functional deficit, including EEG and imaging studies such as PET, SPECT, MEG, fMRI, and DTI.
Electroencephalogram (EEG). EEG is an important diagnostic tool for diagnosis, localization, and determination of an epilepsy syndrome. The EEG abnormalities that can be observed in secondarily generalized tonic-clonic seizures include interictal, ictal, and postictal patterns.
Interictal pattern. The interictal pattern includes spikes, sharp waves, and, less often, polyspike and spike-and-wave complexes. Up to 40% of patients with epilepsy do not demonstrate any interictal epileptiform EEG findings on initial EEGs; but with repeated studies including sleep-deprived EEG and EEG with additional leads (eg, T1, T2, or subtemporal), the yield approaches 90%.
Ictal pattern. During the tonic phase of convulsion, a progressively higher amplitude and lower frequency discharge pattern is seen simultaneously in cortical hemispheres. This pattern then becomes slower and intermixed with bilateral high-amplitude spikes and a progressively greater amount of rhythmic delta activity. During the clonic phase, progressive repetitive complexes of high-amplitude spike-and-slow waves are observed.
Postictal pattern. EEG generally shows a period of diffusely slow and low-amplitude activities; focal or lateralized slowing indicates partial onset.
Imaging studies. MRI and CT have been used routinely in diagnosis and management of epilepsy. MRI is recommended as the standard of care for patients with suspicion of focal onset epilepsy. Coronal FLAIR, T1 and T2 sequences with 1 to 3 mm cuts should be used to detect hippocampal sclerosis, and 3D volumetric studies including SPGR sequences, with multiple planes of reconstruction, are currently best for detecting cortical dysplasias.
Positron emission tomography (PET). PET scans produce metabolic maps of the brain. The most commonly used tracer is 18F-flourodeoxyglucose (FDG), although flumazenil is also useful. Epileptic foci and surrounding areas may have decreased metabolism during the interictal period, with sensitivities ranging from 30% to 90% depending on location.
Single-photon emission computed tomography (SPECT). Stabilized technetium 99m is most commonly used in focal seizures. Ictal SPECT requires injection during or shortly after the seizure onset, usually during video-EEG monitoring. The isotope distribution is proportional to blood flow, and regions of maximal seizure activity show hyperperfusion.
Magnetoencephalography (MEG). This technique detects the magnetic fields associated with electrical charges in the cortex. It is complementary in detecting some dipoles not seen on scalp EEG.
Functional magnetic resonance imaging (fMRI). Rarely, seizures have been captured during scanning and show clear areas of seizure involvement. The fMRI is usually used in conjunction with neuropsychological testing and invasive cortical stimulation to identify eloquent language areas as well as the sensory and motor cortex to guide electrode placement and to delimit surgical resection.
Diffusion tensor imaging (DTI). DTI is an MRI imaging that allows visualization of white matter anatomy of the brain. This modality has been used in guiding the plan for epilepsy surgery, especially in temporal lobe epilepsies (34).
Therapeutic options of secondarily generalized tonic-clonic seizures include medical therapy and surgery. Along with therapy, management should include counseling of the patient regarding the condition and providing knowledge of standard seizure precautions.
Medical therapy. Medical therapy with a single AED is the initial primary approach to management of secondarily generalized tonic-clonic seizures. The use of a single AED reduces the risks of idiosyncratic and dose-related toxic reactions, the cost of medications, and chances of drug interactions, and it increases the compliance of therapy. The initial drug selection is based on consideration of syndrome and seizure type, potential side effects, cost, comorbidities, and drug interactions. According to the American Academy of Neurology guidelines, gabapentin, lamotrigine, oxcarbazepine, and topiramate are among the newer agents that can be used in initial monotherapy (11). The guidelines published by ILAE in 2006 provide evidence for long-term efficacy or effectiveness of initial monotherapy for patients with newly diagnosed or untreated epilepsy (13). Carbamazepine has generally been considered a first drug of choice in the treatment of SGTCS (30). A large, unblinded, randomized control trial (SANAD) compared carbamazepine with relatively newer AEDs, including gabapentin, lamotrigine, oxcarbazepine, and topiramate (24). The trial found lamotrigine to be significantly better for time-to-treatment failure for any reason (inadequate seizure control or unacceptable side effects). Further analysis showed lamotrigine to be better mainly because of its better tolerability than carbamazepine. Carbamazepine was still slightly better than lamotrigine for the secondary efficacy outcome of time to first seizure.
Rational polytherapy, combining AEDs with different mechanisms of action for better efficacy, is a common practice in refractory epilepsy, although there are no robust guidelines and little evidence-based data for clinicians to follow (06).
Achieving seizure control is inversely correlated with the number of failed drug regimens (05). ILAE proposed a definition for drug resistant epilepsy as failure of adequate trials of 2 tolerated, appropriately chosen and used AEDs (whether as monotherapies or in combination) to achieve sustained seizure freedom (20). Wrong diagnosis, non-compliance, and inadequate or inappropriate treatment are common reasons for pseudo-resistance that need to be identified in cases of drug resistant epilepsy (21). Early identification of patients with drug resistant epilepsy is important in order to consider other modalities to achieve seizure control including vagal nerve stimulation, surgical intervention, and responsive intracranial stimulation.
Vagus nerve stimulation (VNS). Vagus nerve stimulation is used as an adjunctive therapy to intractable seizures. A meta-analysis demonstrated up to 50% reduction in seizure frequency; however, seizure freedom is rarely achieved (10). Vagus nerve stimulation involves repeated stimulation of the left vagus nerve through implanted electrodes. Despite studies in animals and human, which show changes in brain electrophysiology, metabolism, and neurochemistry, the mode of action remains uncertain. Stimulation is delivered via a programmable generator, allowing variation in current, pulse, frequency, and duty-cycle. Adverse surgical outcomes are acceptably low in experienced hands. Stimulation-induced effects, such as hoarseness, cough, and dysphagia, are intensity dependent, diminish over time, and are usually not treatment-limiting. The current generation of VNS devices includes the ability to detect ictal tachycardia and deliver enhanced stimuli to try to interrupt the seizures. Although the rate of rise in heart rate is rapid in seizures, adequate reliability of ictal detection and response must be balanced with tolerability of intermittent stimuli from other instances of rapid tachycardia.
Intracranial stimulation. Direct brain stimulation has received renewed attention in the treatment of epilepsy. A randomized blinded controlled trial with a device that provides responsive, closed-loop focal cortical stimulation has been shown effective as adjunctive therapy in adults with refractory epilepsy with no more than 2 epileptogenic foci, with median 44% reduction in seizures at 1 year and 53% at 2 years (03). Suggested mechanisms involved in effectiveness of direct stimulation include changes in cellular inhibition or excitation, changes in synaptic plasticity, neurogenesis or cortical reorganization.
A study (SANTE) of 110 patients who underwent bilateral anterior thalamic stimulation experienced a median reduction of 41% at 1 year and 69% reduction at 5 years in seizure frequency (31). European regulatory bodies have approved this technique for treatment of patients with medically refractory epilepsy, but the FDA is currently reviewing long-term data.
Surgical therapy. Surgery should be considered as a treatment option in patients with drug resistant epilepsy. Common disorders that can be successfully addressed with surgery include low-grade tumors, vascular lesions, cortical dysplasia, and mesial temporal or hippocampal sclerosis. The key to successful epilepsy surgery is multimodal localization of the seizure focus. Video-EEG recording with scalp, and if needed, intracranial recording, plays a vital role in localization. Several imaging technologies, including PET scans, ictal SPECT, magnetic resonance spectroscopy, fMRI, and DTI are being increasingly used to help in localization and placement of intracranial electrodes. Seizures related to benign tumors and mesial temporal sclerosis respond best to surgery. Surgery is less effective if there is no lesion in the MRI, or if the lesion is in extratemporal location. A randomized trial of early surgical therapy for drug-resistant mesial temporal lobe epilepsy showed 2-year seizure freedom in 11 of 15 surgically-treated patients when compared to 0 of 23 in the medical arm (09).
Less invasive surgical techniques such as stereotactic radiosurgery or laser ablation have been used to target specific epileptogenic foci (26). Laser ablation is undergoing an increasing role in treatment.
Other therapies. Stem cell and gene therapies are making progress and may play a role in treatment of intractable epilepsy in the future. Several neuronal and glial precursor lines can now be synthesized in vitro, and research is ongoing in molding differentiation, survival, and integration of these precursors (25). Grafting primary GABAergic cells in the epileptogenic areas of the brain has shown promising results in animal models (32).
Complete control with anticonvulsants can be achieved in approximately 45% to 55% of patients with secondarily generalized tonic-clonic seizures. The remaining cases have varying response to treatment based on the etiology, location, and modality of treatment.
There are various challenges in medical care of women of childbearing age with epilepsy. There are approximately 500,000 of patients with epilepsy in the United States who are in the childbearing age. Epilepsy is the most common neurologic disorder, and the treatment is not interrupted during pregnancy because of potential harmful effects of seizures on fetus. On the other hand, the teratogenic effects of AEDs are always of great concern to the patient and health care providers.
The rate of remaining seizure free during pregnancy if there has been no seizure at least 9 to 12 months prior to the pregnancy is about 84% to 92%. Pregnancy registries have provided key information that usually guides the counseling and treatment of women with epilepsy in their reproductive years (16).
Major congenital malformation (MCM) rate in the general population is estimated to be around 1.6% to 3.2%. With exposure to AEDs during pregnancy, this rate can increase 2- to 3-fold higher, depending on the specific medication exposure. The available data confirm that the risk of MCM in AED polytherapy is higher compared to AED monotherapy.
Valproate is well recognized to be associated with higher risk of MCMs and adverse effects on cognitive function in offspring of women with epilepsy. This medication has a higher risk of causing spina bifida and hypospadias than other AEDs. The absolute risk of MCM is about 6% to 9% of exposed pregnancies during first trimester, which appears to be dose-related. Therefore, this medication should be avoided in this population of patients as much as possible.
Association of exposure to topiramate in first trimester and risk of facial cleft has been reported from several pregnancy registries and studies. In utero exposure to carbamazepine has been confirmed to be associated with spina bifida with an odds ratio of 2.6% (CI 1.2 to 53). Levetiracetam seems to be associated a low risk of MCMs with rate of about 2.4%.
Data from European and International Registry of Antiepileptic Drug and Pregnancy (EURAP) reveal a close relationship between dose of antiepileptic medications and associated MCMs risk. According to the data, the risk of MCMs for lamotrigine at doses less than 300 mg/day is at 1.7% versus 3.6% at higher doses. This risk for less than 400 mg/day of carbamazepine is at 2% versus 7.7% at doses above 1000 mg/day. Similarly, valproate and phenobarbital were shown to have a direct dose-associated risk of MCMs.
Adverse effect of fetal exposure to some AEDs on the IQ, namely valproate and phenobarbital, has been demonstrated in retrospective and prospective studies. Data about other AEDs are emerging. A review of data about MCMs from the pregnancy registries is provided by Tomson and coworkers (37).
There is evidence that taking folic acid supplementation during pregnancy reduces the risk of MCMs, especially neural tube defect and cognitive disabilities in offspring of women with epilepsy who are taking AEDs. The recommended dose is 4 mg/day.
The blood level of AEDs may decrease during pregnancy due to multiple factors including induced metabolism of some AEDs secondary to hormonal changes. Therefore, frequent monitoring and dose adjustment are of importance in these cases.
Anesthesia-induced seizures are rare. Enflurane, sevoflurane, and etomidate are among anesthetic agents that can induce epileptiform discharges and seizures and, therefore, it is recommended these agents be avoided in patients with epilepsy, if possible.
Robert L Beach MD PhD
Dr. Beach, Director of the Comprehensive Epilepsy Program at SUNY Upstate Medical University, has no relevant financial relationships to disclose.See Profile
Shahram Izadyar MD
Dr. Izadyar of Upstate Medical University in Syracuse has no relevant financial relationships to disclose.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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