Is Epilepsy a Progressive Disease

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Is Epilepsy a Progressive Disease?

William H. Theodore, M.D.

Several lines of evidence suggest that persistent seizures can injure the brain. A number of observers have found that seizures become harder to treat as their number increases (1-2). However, the process has been hard to document statistically, and not all investigators have recognized this phenomenon (3). Seizure frequency rather than absolute number, as well as the epilepsy syndrome classification, may be a better indicator of epilepsy severity, and predictor of prognosis (4). Studies of cognitive function have generally found deficits in patients with epilepsy that correlate with underlying brain pathology, seizure frequency, and the effects of antiepileptic drugs. The worst affected patients, such as children with the Lennox-Gastaut syndrome, may be difficult to test, and the underlying severity of the condition make detection of progressive impairment exiguous. However, neuropsychological studies indicate that cognitive function declines over time in adults with temporal lobe epilepsy, and the decline seems to occur more rapidly than in normal controls (5).

Traditional EEG methods, including long-term video-EEG monitoring, have not been useful for showing progression of epilepsy, as there is little correlation between clinical course and EEG fluctuations (6). It is possible that the advent of digital methods will facilitate the quantitative studies necessary for such a task, but the lability of EEG will make the task of demonstrating statistically significant evolution difficult.

Transcranial magnetic stimulation has been used in patients with epilepsy to evaluate underlying cortical excitability, the effects of antiepileptic drugs, and for cognitive and therapeutic studies (7,8). Longitudinal studies of cortical excitability could potentially show progressive alterations, but would be difficult to control for the effects of AEDs, random alterations in seizure frequency, and other transient factors.

Imaging studies, including positron emission tomography (PET) and magnetic resonance imaging (MRI) offer a quantifiable approach to measuring the possible progression of epilepsy. Both, particularly in patients with complex partial seizures of temporal origin, have been shown to be reliable indicators of static brain dysfunction. Hippocampal (HF) atrophy, one of the imaging hallmarks of mesial temporal sclerosis (MTS) is a reliable marker of the epileptogenic zone (9-11). Factors associated with the presence and severity of HF atrophy include a history of complex or prolonged febrile seizures (12-16). Some studies have not found a strong effect of febrile seizures on HF atrophy, or a specific association with temporal lobe seizures, as opposed to epilepsy in general (17-21).

HF atrophy increases with increasing epilepsy duration (14-16). The total number of generalized tonic clonic (GTCS) and perhaps complex partial (CPS) seizures, in patients with a long duration of epilepsy, were associated with increasing HF in some but not all studies (14-15, 22). Volume reduction was also present in some children with only infrequent clinical seizures (23). Thus, either underlying disease, or a subclinical ‘epileptogenic process,’ in addition to overt seizures, might contribute to neuronal injury.

There have been several case reports suggesting development of hippocampal sclerosis in patients with febrile or non-febrile status epilepticus (24-27). A recent study of new-onset epilepsy detected no volume loss on repeat scans over several years, whether or not patients had persistent seizures (28).

Focal hypometabolism is an excellent predictor of outcome after temporal lobectomy (29). Reduced CMRglc in temporal lobe epileptic foci probably is due to a combination of neuronal loss and superimposed functional factors (30-32). In patients with temporal lobe epilepsy, we found increasing relative hypometablism in the mesial temporal region ipsilateral to the epileptic focus in association with increasing epilepsy duration. In addition, the mismatch between blood flow and metabolism in patients with temporal lobe epilepsy has been reported to increase with epilepsy duration, suggesting progressive functional impairment (33). The combined effect of epilepsy duration and febrile seizures suggests that, after an initial insult, progressive HF damage may occur in patients with persistent seizures.

In a study of children within one year after their third unprovoked partial seizure, we found that children with new onset partial seizures are less likely to have abnormalities of glucose utilization than adults with chronic partial epilepsy (34). These FDG-PET results are consistent with reports that only 10 % of patients with newly diagnosed seizures had hippocampal sclerosis on MRI (35). It is likely that a higher percentage of these patients will go on to develop uncontrolled epilepsy, suggesting that MRI abnormalities will also increase in frequency. In a one year follow-up, 8% of the patients showed evidence of increased HF volume loss (36).

It is possible that the progress of metabolic or pathologic abnormalities in patients with temporal lobe epilepsy may not be altered by adequate seizure control. The presence of an epileptic focus might be associated with progressive neuronal injury even in clinically “well-controlled” patients.

Atrophy and hypometabolism may extend to extratemporal structures., particularly thalamus and cerebellum (37-41). Phenytoin, although associated with cerebellar toxicity, made only a small contribution to the reduction of CMRglc (37). Patients with temporal lobe epilepsy and a history of complex or prolonged febrile seizures may have reduced whole brain volume as well (23, 42-43).

Taken together, the volumetric MRI and FDG-PET studies suggest that, after an initial insult, possibly related to early status epilepticus or CFS, increasing epilepsy duration leads to progressive volume loss. Frequent GTCS probably exacerbate the process, which may extend beyond the region of the epileptic focus, and have variable effects on other brain structures. There may be regional differences in the effects of both initiating events (febrile seizures) and epilepsy itself on imaging parameters. Structural volume and glucose metabolism may be independent measures of neuronal integrity, and of progressive damage in patients with persistent seizures. However, it is also possible that patients with HF atrophy at seizure onset will be more likely to develop uncontrolled epilepsy, which would be consistent with the recent observations of Berg and Shinnar (4), as well as with the data available from imaging studies so far.

However, the longitudinal studies that have been discussed have several major limitations. The data are nearly all cross-sectional, except for a few case reports. We can at best infer a relation between epilepsy duration, or in some studies, seizure number, and progressive structural loss or functional impairment. The patients studied generally were not selected from the population at large, but rather from among those referred to centers for the treatment of intractable epilepsy. The association between long epilepsy duration and greater HF atrophy or hypometabolism could represent the severity of the underlying epilepsy syndrome, rather than simply an effect of persistent seizures. Moreover, we do not know the effect of prolonged antiepileptic drug treatment on brain volumes.

Functional imaging parameters such as CMRglc may be affected by a number of clinical factors, such as antiepileptic drugs, and time since the most recent seizure (44-45). Several studies have reported that abnormalities in CMRglc can revert toward normal after successful temporal lobectomy, in both contralateral mesial temporal structures, ipsilateral frontal cortex and thalamus (46-47). MRS data also suggests that reduced NAA/Cr, thought to be a marker of neuronal number, may also be a functional marker that could tend to become normal if seizures remit. Serles et al (48) reported that NAA/Cr increased after surgery and was significantly higher in seizure-free than in non-seizure free patients. Although volume measurements sound more stable, recent demonstration of new neuronal growth in the adult mammalian brain suggests that volumetric MRI measurements may be mutable as well. In addition we do not know the time frame for development of progressive neuronal injury from persistent epilepsy. The cross-sectional studies have included patients with seizures for decades. In contrast, the prospective studies will have a time frame of five years or less. Negative results from these will not rule out the possibility of an effect that could take longer to develop or detect.

The data suggests that underlying features of the epileptic disorder, including etiology, location, severity, and duration, have the most important effect on outcome (see table). It is clear, however, that at least some forms of epilepsy are progressive, including common syndromes, such as mesial temporal lobe epilepsy with hippocampal sclerosis. These patients may develop progressive neuropsychological dysfunction, and their seizures may become more difficult to treat over time. Moreover, children with mesial temporal lobe epilepsy experience scholastic and social difficulties, particularly as they grow into adolescence, that can have serious and persistent effects on their adult lives. Temporal lobectomy has been shown to be more effective than continued drug treatment for these patients, and should be used when treatment with two AEDs has failed (50). Additional drug treatment is unlikely to be effective, while surgery can lead to seizure freedom and significant improvement in quality of life (3, 49).


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