Frontiers in Imaging Markers for Epileptogenesis

Solid information about the causes and underlying mechanisms of epilepsy is as jumbled as the disorder itself. This is partially because so many diverse events can cause localized or diffuse clusters of nerve cells to fire abnormally, triggering an epileptic seizure.

Contributing to the problem is the relative unreliability of EEG tracings recorded from patients during the interictal period. Although these tracings can reveal certain abnormalities that are characteristic of epilepsy, such as spikes, they tend to be relatively nonspecific. Interictal spikes, for instance, occur inconsistently; they are present in some persons who do not have epilepsy and absent in others who do. For this reason, they have no value for predicting the onset of a seizure. Furthermore, the magnitude of these spikes does not necessarily correlate with the severity of the patient's epilepsy.¹

A noninvasive, accurate electrophysiological or neuroimaging marker would be of tremendous value for profiling a patient's risk, diagnosing epilepsy, developing new treatments, planning treatment, and monitoring the response to that treatment. A clinically accessible surrogate marker that reliably predicted seizures also could help a patient manage his or her life to minimize the impact and potential damage of epileptic episodes or, better yet, thwart or blunt an impending attack.

EPILEPSY

Epilepsy can develop in any person at any stage of life. Children appear to be at greatest risk for developing new-onset epilepsy until about the age of 10 years.² After that, the potential for epilepsy stabilizes until it increases again around the age of 55 to 60, when the incidence of strokes, brain tumors, and Alzheimer disease starts to escalate. Risk factors for epilepsy are summarized in Table 1.^2,3

Epilepsy is among the most common disorders of the brain and CNS.^2,3 Perhaps this is because any condition or event that causes neurons to fire abnormally—and there are a lot of them—can cause epilepsy (Table 2).^2,3

In about 70% of persons, no cause for seizures can be found.⁴ In others, the most likely cause can vary with the patient's age. Epilepsy in infants and young children, for example, is likely to be related to genetic factors, the presence of birth defects, oxygen deprivation during delivery, or infection. In young adults, epilepsy usually follows severe head trauma.⁴ In middle-aged and old persons, stroke, tumors, and injuries are the most common causes of epilepsy. It can take years after a triggering event for epilepsy to become clinically evident.⁴

MARKERS FOR EPILEPTOGENESIS

EEG tracings and imaging techniques are the cornerstones of epilepsy evaluation. The EEG recordings help confirm the diagnosis and differentiate subtypes of epilepsy. Typical findings include spikes, epileptiform discharges, and postseizure slowing.

During a seizure, the EEG will exhibit progressive increases and decreases in the frequency and amplitude of rhythmic, repetitive epileptiform activity.⁵ Video-EEG monitoring, during which the patient wears an EEG transmitter connected to a wall outlet as he performs usual activities, allows EEGs to be recorded over a prolonged period (typically, 6 to 8 hours when performed on an outpatient basis, or 24 hours on an inpatient basis); electrographic changes can be directly correlated with clinical events.⁶

EEG tracings and neuroimaging techniques not only are used in daily practice but also are being explored in research settings to determine their utility as markers for epileptogenesis.

EEG epileptiform spikes. Early efforts to identify reliable markers of epilepsy focused on the interictal EEG epileptiform spike. Spikes are commonly categorized as being either red or green; however, attempts to differentiate the 2 types of spikes based on morphology (rise time, sharpness, afterwaves), patterns of recurrence, or response to medications have been unsuccessful.

Recent findings suggest, however, that EEG spikes with high-frequency oscillations (250 to 600 Hz) may be somewhat of a fingerprint for epilepsy, unique to structures that generate spontaneous seizures in persons with mesial temporal lobe involvement.^7-9 Some slower oscillations (100 to 200 Hz) also may be abnormal epileptiform events and may occur early after a triggering insult but well before an actual seizure. The take-home message here is that high-frequency oscillations—so-called red spikes—are a surrogate marker for epileptogenicity as well as for epileptogenesis.⁷

Epileptic seizures can originate spontaneously or be propagated secondarily. Evidence suggests that the mechanisms underlying the interictal EEG spikes associated with each type of seizure are different.¹ This discovery has prompted interest in researching whether higher-resolution noninvasive EEG or magnetoencephalography can identify high-frequency epileptogenic oscillations.^10,11

Positron emission tomography (PET). PET appears to hold some promise as a technique for identifying seizure-generating brain tissue. One study of patients with tuberous sclerosis found that a-methyl tryptophan (AMT) accumulated in tubers that generated spontaneous seizures.¹²