10 Evaluation of the Patient with Medically Refractory Epilepsy

Gregory L. Holmes

Department of Neurological Sciences, University of Vermont, Burlington, VT, USA

Introduction

Epilepsy treatment is directed towards preventing seizures and achieving control early in the illness. While most individuals with epilepsy respond well to antiepileptic drugs (AEDs), approximately one-third continue to have seizures, despite trying multiple medications, and are considered medically refractory, also termed medically intractable. The operational definition of refractory epilepsy requires failure to control seizures after trying two or three seizure medications (whether as monotherapies or in combination) appropriately chosen and used. The die is cast rather early in the course of the disorder; even failing the first AED results in a significantly increased risk of experiencing adverse health outcomes. Unfortunately, the mechanisms of refractory epilepsy remain uncertain.

SCIENCE REVISITED

The biological basis of medically refractory epilepsy is unknown. Recent basic research has suggested two postulated mechanisms for refractory epilepsy. According to one postulated mechanism, plasticity of AED targets, with a concomitantly decreased sensitivity to AEDs, leads to medical intractability. The hypothesis proposes that pharmacoresistance involves an upregulation of multidrug transporters at the blood–brain barrier. Upregulation of these transporters limits the concentration of AEDs to the brain parenchyma, thus resulting in a reduced drug concentration at the respective drug target. The second postulated mechanism is that the molecular targets of AEDs are modified and thus are less sensitive to these drugs in chronic epilepsy.

Refractory epilepsy often has significant adverse effects on the physical, psychological, cognitive, social, educational, and vocational state of the patient. It results in a higher risk for a shortened life expectancy, injury, neuropsychological and mental health impairment, and social disability. Individuals with refractory epilepsy have high risks of comorbidities including attention deficit disorder, depression, and anxiety. Underachievement in school, unemployment, and underemployment are common in individuals with refractory epilepsy.

Refractory epilepsy is clearly an important public health issue, and clinicians need to make every attempt possible to control seizures. However, aggressive treatment of refractory epilepsy does not mean that medications should be used at any cost to suppress seizures. As discussed later in this chapter, overtreatment can actually result in increased seizures. In addition, using high doses or multiple AEDs increases the risk of side effects such as headache, fatigue, bone loss, irritability, and cognitive impairment and also increases monetary costs.

Diagnosis of refractory epilepsy

An early step in evaluating individuals with refractory epilepsy is to be certain they have epilepsy. Misdiagnosis is common due to the myriad of signs or symptoms seen in this complex disorder. Accurately diagnosing epilepsy is challenging because clinicians rarely have the opportunity to observe seizures. Therefore, the diagnosis is typically based on the patient’s self-report or the family member’s description of seizures and the medical history. There are many conditions in children and adults that mimic epilepsy. Unfortunately, a significant number of patients with disorders such as REM sleep behavior disorder, night terrors, and psychogenic nonepileptic seizures are being misdiagnosed and then treated unsuccessfully with AEDs for months to years.

TIPS AND TRICKS

Psychogenic nonepileptic seizures may present as chronic epilepsy. When eliciting history, ask if eyes were open or closed during the event. Most patients with epileptic seizures have their eyes open during an epileptic seizure, whereas in psychogenic nonepileptic events, the eyes are tightly closed. In addition, asynchronous movements, pelvic thrusting, side-to-side head or body movement, ictal crying, and memory recall and absence of postictal confusion are signs of psychogenic nonepileptic seizures rather than epileptic seizures. The presence of postictal stertorous breathing is indicative of an epileptic generalized tonic–clonic seizure and is rarely, if ever, seen following a nonepileptic seizure.

To avoid prolonged use of ineffective AEDs, the epilepsy diagnosis should be reconsidered for any patient who does not respond to therapy. This process begins with a detailed history in which the “seizures” are described in detail. While the patient’s account of the event is important, it is critical that a parent, spouse, or caregiver who witnessed the event also provide a description. Details about time of occurrence, duration, and precipitating factors are important. As discussed in the following text, the history should include a description of the behavioral features of the seizure. This information should be obtained at every visit of a patient with refractory epilepsy.

Electroencephalography can be an important tool when diagnosing patients with epilepsy. While there are no legitimate reasons for repeating EEGs at every visit when the patient is doing well, repeating the EEG when the patient continues to have seizures can be helpful in assisting with seizure classification and syndrome identification. To gain the maximum amount of information, the EEG should be recorded during wakefulness, drowsiness, and sleep along with hyperventilation and photic stimulation. Recording an actual event is ideal, so continuous video–EEG monitoring, lasting from hours to days, should be done if questions about the diagnosis remain. If the individual has frequent events, ambulatory EEG may be helpful. However, if AEDs are withdrawn in the attempt to induce an event, it is usually safer to do the monitoring in the hospital. Video–EEG monitoring is particularly helpful in distinguishing epileptic from nonepileptic events.

With the ready availability of cell phone cameras, digital cameras with video capabilities, and video monitoring in home settings, family members can record events on video as they occur. This information can be invaluable in differentiating seizures from nonepileptic behaviors. With the patient’s or family’s permission, these video clips can be shared with colleagues to assist in diagnosis.

Determining seizure type

One possible cause of refractory epilepsy is the use of the incorrect drug for the seizure type. Seizures are classified into two broad categories: (1) focal seizures (seizures beginning in a limited location in the brain) and (2) generalized seizures (seizures that are bilaterally symmetric and without focal onset). The pathophysiological mechanisms of focal seizures and generalized seizures are different, although the common endpoint, such as a generalized tonic–clonic seizure, can be quite similar. Similarly, AEDs are broken down into two categories: AEDs that are effective in focal seizures and those effective in generalized seizures. Certain AEDs that are effective in both seizure types are considered broad spectrum. Treating a patient with the wrong AED for his or her seizure type may not only not control the seizures but could actually exacerbate the condition. For example, treating a patient with a primary generalized epilepsy with carbamazepine could make seizures such as myoclonic, absence, and generalized tonic–clonic seizures worse. Likewise, ethosuximide, a highly effective drug for absence seizures, has limited efficacy against other seizure types.

The first step in determining the correct seizure type is to obtain a detailed description of seizure semiology. While the diagnosis of a generalized tonic–clonic (convulsive) seizure is rarely difficult, determining whether the seizure has a focal onset may be more difficult. Asking about auras and lateralized features at onset, such as eye or head deviation, may help identify a focal onset. Distinguishing between absence and focal seizures with altered awareness can be difficult but is essential in picking the correct AED. Compared to focal seizures with altered awareness (formerly termed complex partial seizures), absence seizures are shorter (<15 s) and have an abrupt onset and offset. Absence seizures result in a “blank” facial appearance with upward eye deviation and may be accompanied by eye blinking. Individuals with focal seizures with altered awareness often have an aura and appear confused and disoriented. Also, automatisms are common, and most patients have some degree of postictal impairment. In both children and adults, absences but not focal seizures are readily induced by hyperventilation.

The interictal EEG can be very helpful in distinguishing focal seizures from generalized seizures (Chapter 7). Typically, focal seizures have focal EEG abnormalities, whereas generalized seizures have generalized discharges. However, generalized discharges on the EEG may have a subtle focal onset followed by rapid generalization. In addition, seeing occasional focal spikes in a patient with generalized epilepsy is not uncommon.

Capturing the patient’s seizures using long-term EEG video monitoring can be quite helpful in correctly classifying seizure type (Chapter 7). The use of this technique allows correlation of behavior with EEG changes and is very useful in determining if the seizure has a focal or generalized onset, which has major implications in drug treatment.

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