A proper neuropathologic definition of temporal lobe epilepsy (TLE) continues to be an important endeavor in understanding the causation and maintenance of seizures in this disorder. The hippocampus, located in the mesial temporal lobe, is commonly regarded as the locus of seizure origin in TLE because depth electrode studies show seizures to originate from this area, and surgical removal of the hippocampus produces good seizure control. Beginning in the early 1800s, several investigators contributed important insights into the understanding of hippocampal pathology in TLE [reviewed in (1)].
The earliest pathological descriptions were based on macroscopic examination of autopsy brain specimens and described the hippocampus as hardened (indurated) and small (atrophied) (2). This condition came to be known as Ammon's horn sclerosis. The first microscopic examination and description of the epileptic hippocampus was published by Sommer (3). He observed that pyramidal neurons were lost in the hippocampus not diffusely but preferentially in a portion of the hippocampus that has come to be called Sommer's sector and corresponds to area CA1 (4). Sommer briefly noted that some neurons were lost in the hilus of the dentate gyrus as well.
In 1899, Bratz (5) provided a more detailed description of the TLE hippocampus. While confirming the loss of pyramidal neurons in area CA1, he observed that neurons were preserved in the subiculum, presubiculum, stratum oriens, and the granule cell layer of the dentate gyrus. He also described a smaller loss of pyramidal neurons in the hilus (“end folium”) of the dentate gyrus, and in a region corresponding to CA2 that “resists destruction the longest.” Bratz further described an abundance of blood vessels in the atrophic sectors, their patency, and a lack of any pathologic alterations in their walls [see discussion in (1)]. This latter feature has received little attention in recent studies. The term hippocampal sclerosis was therefore originally used to describe a shrunken and hardened hippocampus, which histologically displayed preferential neuronal loss with secondary astroglial proliferation (6). This pathology has been reported in 20–80% of hippocampi in autopsy series of brains from those with epilepsy [Table 2 in (6)], and in 50–70% of hippocampi surgically resected from patients with TLE [Table 10 in (6)].
|Type||Gender||Age at surgery |
|Age at first seizure |
|Seizure duration |
|Autopsy (n = 26)||13F:13M||30.5 ± 9.0 (14–50)||NA||NA|
|PTLE (n = 18)||10F:8M||32.5 ± 9.5 (15–50)||9.4 ± 6.8 (0.2–19)||22.7 ± 12.8 (5.8–47)|
|MaTLE (n = 42)||16F:26M||27.8 ± 9.7 (11–53)||14.7 ± 11.4 (0.1–48)||13.7 ± 8.2 (0.12–33)|
|MTLE (n = 72)||34F:38M||29.9 ± 9.0 (7–51)||4.4 ± 7.1 (0.3–36)||25.8 ± 10.8 (2.0–48)|
|MTLE/DYN− (n = 10)||3F:7M||28.1 ± 7.8 (18–47)||6.5 ± 9.0 (0.1–28)||21.5 ± 6.7 (10–29.3)|
|CA1 group (n = 9)||3F:6M||37.8 ± 13 (10–53)||7.9 ± 8.8 (0.1–28)||29.9 ± 14.3 (6–48)|
Several studies have attempted to define hippocampal sclerosis further by neuron counts (7–11). The correlation of these quantitative studies with the qualitative patterns observed microscopically has been difficult, mainly because of the pronounced interindividual variability of neuron loss and the absence of an agreed-on quantitative measure of “sclerosis.” Bruton (12) identified three degrees of neuronal loss recognizable by qualitative microscopy. “Classic” Ammon's horn sclerosis is characterized by a severe to total loss of neurons in areas CA1 and the hilus (CA4), with lesser loss in the granule cell layer, and least in CA2. “Total” Ammon's horn sclerosis is characterized by a “global” destruction of hippocampal neurons (i.e., a pronounced loss of neurons in all fields of the Ammon's horn and dentate gyrus). “End folium sclerosis” involves neuron loss only in the end folium (hilus). Babb (13) pointed out the difficulty of correlating cell counts with these three types. The different quantitative criteria (percentage of cell loss) chosen to define sclerosis resulted in different classifications of the same group of patients. This was especially true for hippocampi other than those with end folium sclerosis. Kim (14), opting for a statistical approach, chose as a quantitative definition of sclerosis a neuronal density of <60% of the control group mean. This percentage represents the control mean value minus two standard deviations averaged throughout all CA fields.
More recently, immunohistochemical studies of hippocampi, removed in the surgical treatment of drug-refractory TLE, examined changes in chemically defined neuron systems within the hippocampus. These studies were reviewed recently (15). In particular, immunohistochemical studies on the localization of the peptides neuropeptide Y (NPY), somatostatin (SOM), substance P (SP), and dynorphin (DYN) in the TLE hippocampi show distinct patterns among patients (16,17). The loss of populations of peptidergic neurons in the subgranular zone of the dentate hilus and sprouting of several peptidergic axons into the dentate molecular layer (a cluster of features taken as evidence of “reorganization”) seem to be associated with hippocampi that also show sclerosis. Do such reorganizational features define the epileptogenic hippocampus better than the presence of hippocampal sclerosis, or do they together help to provide better criteria for classification of hippocampal pathology? The electrophysiologic properties of the dentate granule cells in surgically removed hippocampal specimens provide another functional index for the characterization of hippocampi in TLE patients (18). The goal of the present study was to examine hippocampi from a large population of patients with intractable TLE to determine the relations between immunohistochemical characteristics, neuronal densities, granule cell excitability, and surgical outcome. Such an analysis will facilitate the discussion of whether intractable TLE is a single entity or one with several subtypes, and help provide further insight into the pathophysiologic mechanisms underlying TLE.