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Epilepsy

Diagnosis of Seizures

The selection of a course of treatment and accurate prognostic counseling require correct diagnosis and classification of the epileptic seizure type. Seizures are classified as partial onset or generalized onset by ictal behavior and EEG. The most common diagnostic differential for the adult neurologist is determining whether a paroxysmal, stereotyped neurological event is a primary generalized seizure, a partial seizure, or a nonepileptic event. Nonepileptic events comprise approximately 30% of admissions to our epilepsy-monitoring unit. Although most patients with nonepileptic events have psychogenic seizures, there are other conditions that can be mistaken for epileptic seizures, which are listed in the Table below epilepsy, epalepsy

Differential diagnosis of epileptic seizures

• Syncope of cardiac origin: arrhythmias, congenital heart disease, cardiomyopathy

• Syncope of noncardiac origin: vasovagal, medication induced, orthostatic

• Migraine

• Transient global amnesia

• Cerebrovascular disease

• Metabolic: hypoglycemia, porphyria, renal/hepatic disease, pheochromocytoma

• Psychiatric disease: anxiety/panic disorder, conversion disorder, intermittent explosive disorder

• Sleep disorders: narcolepsy, parasomnias, paroxysmal nocturnal choreoathetosis

• Movement disorders: paroxysmal dyskinesias

• Psychogenic seizures

The history is essential in order to establish the correct diagnosis of a transient, paroxysmal event. Historical details which suggest that the event is a seizure include a warning, absence of pallor or color change, and lack of a postural component. Atypical movements and nonstereotyped behaviors are more usual for the nonepileptic event than are stereotyped, repetitive and well organized tonic-clonic movements, although there are exceptions. Tongue biting, fecal incontinence, and injury are rare in nonepileptic events, but may occur. Precipitating factors for seizures include sleep deprivation, concurrent febrile illness and menstruation. Prior exposure to seizures in a family member, friend, coworker or schoolmate is often found in patients with

Principles of Clinical Use of Antiepileptic Drugs

The goal of pharmacological treatment of epilepsy is to control seizures without adverse medication-related side effects. This goal is not always attained. While primary generalized epilepsies respond well to medication, 45% of patients with partial epilepsies continue to have seizures despite optimal medical management. These patients seek a balance between seizures and medication related side effects.

The established antiepileptic drugs (AEDs) are phenobarbital, phenytoin, carbamazepine, ethosuximide and valproate. Comparative efficacy studies show that simple and complex partial seizures are most likely to be controlled without significant adverse side effects by carbamazepine and phenytoin while secondarily generalized tonic clonic seizures will respond equally well to carbamazepine, phenytoin or valproate. Phenobarbital is equally efficacious but is less well tolerated because of sedative side effects. Nonconvulsive generalized seizures (absence) are well

Because there is overlapping efficacy for individual AEDs, the particular agent is often chosen because the side effect profile is best suited for the individual patient. Although each medication has specific and distinctive side effects, many side effects are common to all the agents. When considering medication toxicity, it is useful to differentiate acute, dose related and idiosyncratic effects. Specific acute and dose-related side effects will be discussed for each agent separately.

Dose-related side effects are common and frequently limit use of a particular AED in an individual patient. While these side effects are associated with higher serum levels, the specific level at which an individual patient will develop signs of toxicity varies. A dose related side effect common to all AEDs is cognitive impairment. This arises in a significant minority of patients and will be described as "slowing", difficulty with concentration, sleepiness and poor memory. Neuropsychological testing reveals prolongation in the time to complete cognitive tasks. Although phenobarbital and other barbiturate medications have the most marked effects in this area, all AEDs are capable of affecting some patients. Behavioral changes such as irritability, poor concentration and depression can arise with any of the AEDs. 

While severe and even sometimes life threatening, idiosyncratic reactions are rare and unpredictable. Idiosyncratic reactions arise with every one of the older AEDs and with Felbamate, and include bone marrow suppression, allergic reactions and gastrointestinal effects.

New AEDs are needed because existing agents are not completely efficacious or tolerated, especially for patients with partial onset seizures. There has been great progress in new drug development. Newly approved AEDs include gabapentin, lamotrigine, and topiramate. These agents offer advantages over the older AEDs in terms of better tolerability, ease of use and, in some cases, broader efficacy.

Gabapentin (Neurontin) was developed as a structural analog to GABA but appears to display very few GABAergic effects. The mechanism of action has not been established. Gabapentin is effective as add-on therapy and also probably as monotherapy for partial and secondarily generalized tonic seizures at doses ranging from 1200-mg day to 4800 mg per day. Gabapentin is not effective for typical absence seizures. The medication is well tolerated with adverse effects principally being somnolence and fatigue that lessens with continued therapy. Lack of drug interactions is one pharmacological advantage of Gabapentin. Less than 3% of the medication is .protein bound and elimination is primarily renal. There are no active metabolites.

Lamotrigine (Lamictal) is a triazine derivative structurally and pharmacologically unrelated to currently used AEDs. The mechanism of action in unknown, although the drug may have an effect on voltage sensitive calcium channels, thus preventing the release of excitatory neurotransmitters. Lamotrigine shows efficacy as adjunctive therapy and in monotherapy for partial seizures, all generalized tonic clonic seizures, and absence seizures. Adverse events include rash, dizziness, ataxia, somnolence and headache. Serious rash leading to hospitalization is more frequent with

Topiramate is a carbonic anhydrase inhibitor that appears to have multiple mechanisms of action. It is effective in treating essentially all seizure types. The most common side effects include cognitive slowing. The drug displays intermediate protein binding and minimal drug interactions. The typical effective dose is 400 mg per day although some patients benefit from doses as high 1200 mg per day.

When to begin AEDs

Whether to begin an AED after a first seizure depends on the risks of further seizures, of seizure related injury, psychological distress, loss of employment and loss of driving privileges. Alternatively, the risk of adverse effects from exposure to AEDs must be considered, as well as the likelihood that medication will be effective. Since these variables differ for each patient, the decision is individualized. For example, patients with simple partial seizures are not at risk for physical injury and can usually continue to drive. However, a GTCS may cause injury, be

Given the above caveats, most patients should not be treated after a first seizure. Some epilepsy syndromes, such as absence and myoclonic seizures, are essentially certain to recur. For the majority of first seizures, however, the risk of recurrence is low. In adults, the risk of a second seizure ranges from 30 to 60% with highest risk for patients with an abnormal EEG and a remote symptomatic etiology. Most seizures recur within the first. In children, the risk of recurrence within 2 years is 35-50% with the highest risk in children who are neurologically abnormal, have complex partial seizures and abnormal EEGs. After the second seizure, the risk of recurrence rises to 80 to 90%. Several studies suggest that AED treatment does not alter the risk of recurrence.

When to Stop AEDs

Many patients who have been seizure free for 2 to 5 years can be successfully withdrawn from AEDs. The benefits associated with discontinuation of AEDs must be weighed against the probability that a seizure will occur and the potential adverse consequences of having a seizure. As many as 75% of children who have been seizure free for two years can be successfully withdrawn. Adults are more likely to relapse than children. In adults, relapse occurs in 26-63% with most relapses within one to two years after medication withdrawal. Predictors of relapseTreating the Medically Intractable Patient

Patients who continue to have seizures despite treatment with appropriate AEDs in monotherapy over six months should be referred to a neurologist. If seizures are not controlled within six months, then referral to a tertiary epilepsy center is indicated. If it is established that seizures are epileptic, then the patient will be a candidate for second line AEDs, for investigational AEDs, or for epilepsy surgery.

Epilepsy Surgery

Identification of Surgical Candidates

Epilepsy surgery is an underutilized therapy that should be considered in patients with localization~related epilepsies that are medically intractable and clinically disabling (NIH Consensus Development Conference, 1990). Medical intractability is defined as failure to achieve seizure control without adverse drug effects on maximal monotherapy. Seizures must be frequent and disabling, ie, complex partial or secondarily generalized. However, disability may be defined differently for each individual. For instance, daytime seizures occurring one or more times a year will restrict driving privileges in most states and may limit employment. Nocturnal GTCS confer less potential for injury than daytime GTCS and even complex partial seizures. Other considerations in candidates for epilepsy surgery include the long-term effects of seizures and of AEDs on cognition, memory and learning. Data in humans is circumstantial but supports the concern that frequent epileptic events may lead to progressive cognitive impairment in some individuals. Children whose seizures begin earlier in life have a tendency to display lower I.Q. Cognitive side effects of AEDs in children are also of concern. Phenobarbital in particular has been associated with diminished cognitive function in the pediatric population.

Psychosocial disability must also be considered. The unpredictable, recurrent nature of seizures can lead to anxiety, depression and low self-esteem. A sense of diminished competence and independence can develop. Children with epilepsy often face parental over-protectiveness. The final consequence of uncontrolled seizures is limited social, educational and vocational potential.

The Evaluation for Epilepsy Surgery

Data obtained from extracranial electrophysiological monitoring forms the basis of the noninvasive evaluation for epilepsy surgery. The goal of the evaluation is to record several of the patient's typical behavioral seizures. By identifying the precise anatomic region of seizure onset, the epileptogenic region may be defined.

Successful localization of the epileptogenic region is further confirmed by tests of brain structure (MRI) and function, including neuropsychological testing, the intracarotid amytal test, single photon emission computed tomography (SPECT) and positron emission tomography (PET). Neuropsychological testing evaluates I.Q., memory, visual-spatial and language function in order to identify deficiencies in a restricted brain region that might correspond to areas believed to represent the epileptogenic region. This testing also allows comparison of pre and post-operative cognitive function. The intracarotid amytal test (Wada test) assesses hemispheric lateralization of language and memory after intracarotid injection of amytal, a short-acting anesthetic. This procedure establishes the safety of surgery in terms of preservation of language and memory and is used to confirm localization of a temporal lobe epileptogenic region by detecting asymmetries in memory function.

SPECT measures regional cerebral blood flow, an indicator of local cerebral metabolic rate. The sensitivity and specificity of interictal SPECT scans is not sufficiently high to be an accurate tool for localization of the epileptogenic region. However, at the time of a seizure, the SPECT scan shows extensive hyperperfusion of the region from which the seizures arise, particularly with seizures arising from the temporal lobe.

PET provides another means to obtain functional brain images. A variety of tracers are available and can be selected to portray blood flow, blood volume, tissue pH, oxygen metabolism or neurotransmitter metabolism. The radioisotope most commonly used is 18F-flurodeoxyglucose (FDG) which reflects glucose metabolism. PET scanning is a valuable tool in identifying the region from which seizures arise. 70% of patients with partial seizures demonstrate an area of hypometabolism interictally, which correlates .highly with the epileptogenic region. PET can identify the epileptogenic region in some very young children with intractable seizures, such as infantile spasms.

While each center has its own protocol, in general, a minimum number of tests must localize the epileptogenic region concordantly. Most centers have developed testing protocols that allow some patients to go directly to surgery after the initial noninvasive evaluation, bypassing implantation with intracranial electrodes.

If the epileptogenic region can not be adequately localized during the noninvasive evaluation, or if the epileptogenic region involves essential cortex, then the patient may require evaluation with intracranial electrodes. There are a variety of electrode types which can be placed in the epidural or subdural space, or stereotaxically within the brain parenchyma. In most centers, different types of electrode may be combined within an individual patient. All intracranial electrodes can be used acutely (in the operating room) or chronically, for periods up to 4 to 6 weeks. The electrodes are used for electrographic monitoring as well as mapping of brain function. Intracranial electrodes are not subject to many of the artifacts that confound recordings with scalp electrodes, such as muscle and movement, and are in close proximity to neural generators of the EEG signal. However, intracranial electrodes sample from a restricted area of cortex (6 mm2), are costly, and carry a small (<3%) risk of infection, hemorrhage and injury to brain structures.

Epilepsy Surgeries

The goal of epilepsy surgery may be to control seizures by resection of the epileptogenic lesion or region. In patients who are not candidates for cortical resection, surgery may be considered for palliation, as with 

85% of partial epilepsies arise from the temporal lobe and therefore the most common resective procedure is the anterior temporal lobe resection. This is performed as an en bloc resection, generally extending 4.5 cm from the temporal tip in the language dominant hemisphere and 5.5 cm in the nondominant hemisphere, or as a modified procedure involving a less extensive lateral temporal resection or selective removal only of the amygdala and hippocampus. Seizures remit in between 65-85% of patients treated with temporal lobe resection, depending on the seizure etiology, the epileptogenic region and the precise surgical procedure performed. Extratemporal resections are most commonly performed when the epileptogenic region coincides with a structural lesion. Outcome after lesional surgery is quite good (75 to 90% seizure free), although nonlesional extratemporal procedures are less successful (Van Ness, 1992). Complications of cortical resective surgery for epilepsy include hemiparesis (0.5-2%), homonymous hemianopsia and

Corpus callosum section limits the ability for localization related seizures to spread to the contralateral hemisphere and can be a useful procedure for patients with atonic, tonic or convulsive seizures who are not candidates for cortical resection. Disconnection syndromes arise in some patients undergoing a complete callosal section but are less prevalent with the newer staged procedure in which the anterior two-thirds of the callosum is sectioned in a first surgery. Corpus callosotomy can lead to a reduction in injurious seizures in 75% or more, but can also increase simple and partial seizures in

Outcome

Cognitive outcome is good after temporal lobectomy. There is no global cognitive decline after epilepsy surgery, although there may be relatively minor difficulties in specific areas, such as memory. Overall intelligence does not decline after surgery, and may even show a modest increase, particularly if the surgery occurs in the non-dominant hemisphere. Declines in verbal memory may occur after left temporal lobe resection but no consistent deficits in visual-spatial memory have been demonstrated after right temporal lobectomy. The most common language deficit is dysnomia after dominant temporal lobe resection. This risk can be lessened by intraoperative or extraoperative language mapping and by altering the extent of resection if language cortex is felt to be

Surgery can lead to improvement in vocational and psychosocial status, particularly when good seizure control is achieved. Patients may attain their first or better employment. Children undergoing epilepsy surgery are less frequently absent from school and are often able to attend regular, rather than 

Specific, directed rehabilitation efforts may be needed to improve psychosocial, psychiatric and vocational outcome in patients after epilepsy surgery. Patients may need help in the form of counseling, education, structured experience and vocational and occupational rehabilitation in order to learn new psychosocial and vocational skills. If rehabilitation of the patient with epilepsy can be accomplished in this broadest sense, then there will be tangible benefits to surgical therapy for the individual and 

Epilepsy is a heterogeneous condition which adversely affects many aspects of life, including psychosocial function and occupational achievement. The sudden unpredictable nature of seizures often leads to psychological distress, feelings of vulnerability and a sense of diminished competence. Seizures may not be completely controlled in nearly half of those with localization related epilepsy and many others will be troubled by side effects from AEDs. Medication response is optimized when the seizure type, epilepsy syndrome and common medication side effects are considered. Monotherapy is usually as effective as polytherapy and is better tolerated. Surgery is an important treatment option in patients with localization related epilepsy which is medically