Mesial temporal sclerosis (MTS) is characteristic of intractable temporal lobe epilepsy (TLE).95–99 Long-term cognitive deficits have been associated with pathologic findings involving the hippocampus. In one study, 59 patients with TLE underwent neuropsychological testing before surgical resection of mesial temporal lobe structures.100 After resection, volumetric cell densities were determined for several hippocampal subfields:
Verbal memory impairment was found to be significantly correlated with hippocampal neuronal loss in CA3 and the hilar area for patients with left temporal seizure foci. Verbal intellectual ability and language skills, however, were not correlated with pathologic change.
The role of an initial precipitating injury (IPI) in producing anatomic changes was studied by examining hippocampi in resected temporal lobes.101 The precipitating injuries were divided into three groups:
These groups were compared with hippocampi from patient with no IPI (i.e., idiopathic TLE).
Neuronal loss was significantly less prominent in those with idiopathic TLE than in those with IPI. Patients in whom the IPI was not associated with seizure were older at age of injury, had a longer latent period between injury and seizures, and showed more modest neuronal loss in Ammon’s horn, CA1, and the presubiculum than did patients whose IPI initially produced seizures. An IPI that produced repetitive, nonprolonged seizures showed the shortest latent period, earliest age of TLE onset, and less CA2 damage than did other categories of IPI. CA1 and presubiculum neuronal losses were greater in patients with TLE of longer duration. An IPI after the age of 4 years was associated with shorter latent periods than an IPI occurring before the age of 4.
Correlation of pathologic findings and cognitive impairment has several methodological limitations:
Lencz et al.102 compared quantitative MRI in patients with refractory TLE and normal controls. They found that the left and right hippocampi were symmetric in the controls but the hippocampus was smaller on the side of the focus in patients with seizures. Additionally, the affected temporal lobe was smaller in patients with seizures than in normal controls. Neuronal densities were proportional to the ipsilateral-contralateral MRI volume ratio for every hippocampal subfield except CA2. Cognitive testing showed significant correlation between MRI measurement of the left hippocampus and logical memory retention scores and between the left temporal lobe volume and verbal memory testing.
The progressive nature of intellectual disability is also supported by MRI studies. In a case report of a 28-year-old patient with complex partial and secondary generalized seizures, a progressive decrease in the left hippocampal volume on MRI scans obtained 4 years apart was associated with moderate decline in verbal learning and memory functions and mild decline in visuospatial memory functions.103
Patients with status epilepticus (SE) have demonstrated MRI abnormalities including cytotoxic and vasogenic edema, hyperperfusion of the epileptic region, and alteration of the leptomeningeal blood-brain barrier.104 The changes were reversed on subsequent MRI, but these follow-up studies also showed subtle signs of atrophy, evidence of irreversible change. Other evidence indicating that recurrent seizures cause ongoing hippocampal damage include the observation that prolongation of ipsilateral T2 relaxation time in the body of the hippocampus correlated with the total number of both partial and generalized seizures and with the duration of TLE symptoms.105
Several MRI studies have found evidence that SE can cause neuronal loss in the hippocampus. A 32-month-old child with an episode of SE was a subject for study of the progression of MTS.110 Initial MRI demonstrated an increased T2 signal of the right hippocampus but no atrophy. Serial MRI performed at 2 months and then 13 months later demonstrated progressive hippocampal atrophy with resolution of the increased T2 signal. This study demonstrates the progressive changes induced by epilepsy. In an adult patient with generalized tonic-clonic SE, MRI scans showed bilateral hippocampal atrophy on initial evaluation.111 Progressive hippocampal atrophy was detected in follow-up studies.
MRI studies also demonstrated that repeated seizures correlate with progressive neuronal loss. This additional loss is small, usually occurs over long time intervals, and is found in limited subfields including granule cells, CA1, and the presubiculum.106 This radiologic evidence is consistent with the cascadic model of deterioration, in which most cognitive change occurs early in the course of the disorder, followed by later stabilization of function.24 Autopsies of patients who had seizures of 30 years’ duration or patients with frequent generalized seizures showed greater neuronal losses than were seen in patients with fewer years of seizures.107
To evaluate the progressive neuronal losses that take place in TLE, Tasch et al.108 evaluated patients using the neuron marker N-acetyl aspartate and MRI measurement of hippocampal volume. These researchers found that duration of epilepsy was negatively correlated with N-acetyl aspartate concentration bilaterally and hippocampal volume ipsilateral to the seizure focus. The number of complex partial seizures was not correlated with any radiologic measurement, but the number of generalized tonic-clonic seizures, like seizure duration, was negatively correlated with N-acetyl aspartate measurements bilaterally and hippocampal volume ipsilaterally. These findings suggest that early fixed injuries can cause temporal lobe damage and that progressive neuronal losses also can result from multiple generalized seizures.
van Paesschen et al.109 studied the hippocampus within 1 year of new onset of partial seizures, to identify possible change. Of 36 patients, 4 had MTS at onset and 32 had no changes on MRI. Between the time that the baseline and follow-up MRI scans were obtained, 23 experienced seizures. Of the four patients with MTS, one had increased T2 relaxation time, suggesting progressive hippocampal damage. None of the 32 patients with negative MRI progressed to MTS, but two had significant hippocampal changes. The authors hypothesize that these hippocampal changes were the result of inflammatory swelling or edema after seizures were controlled.
Using quantitative MRI, Baxendale et al.112 found a significant association between global memory impairment and an abnormal proportion of gray to white matter. Patients with this structural abnormality did not have a WAIS-R score that differed significantly from that of normal patients. Extrahippocampal structural abnormalities were associated with further disruptions of memory in patients with MTS.
FDG-PET (fluorodeoxyglucose–positron emission tomography) measurement showed that prefrontal glucose hypometabolism is associated with lower verbal and performance intelligence scores.113,114
Reviewed and revised May 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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