Do these pathological abnormalities correlate with cognitive

There are a number of pathological abnormalities that have been investigated in TLE and considered in relation to the neuropsychological functioning of the patient. These are the presence of specific lesions, the presence or extent of HS, or

hippocampal volume as a continuous variable.

4.3.1 Findings from pre-surgical patients

Many studies assessing neuropsychological performance in relation to pathological abnormalities have been conducted on pre-surgical patients, so that the pathological abnormalities can be assessed on the resected tissue. This has the benefit of allowing for accurate identification of pathology, but at the same time limits the population studied to those with medically refractory epilepsy. Comparisons have been made using neuronal cell loss, cell densities in different parts of the hippocampus and also the number and architecture of granule cells of the dentate gyrus, as well as the presence of HS.

It is generally proposed that the left hippocampus is more important for verbal memory and the right for non-verbal memory. Studies have shown that there is significant correlation between left HS or neuronal cell loss in the hippocampus and presurgical verbal memory impairment in patients with left temporal lobe foci (Sass, Spencer et al. 1990; Sass, Sass et al. 1992; Miller, Munoz et al. 1993; Rausch and Babb 1993; Saling, Berkovic et al. 1993; Pauli, Hildebrandt et al. 2006). This correlation is sometimes task specific, for instance it has been found that left HS is associated with impaired learning and recall of word pairs but not of a logical memory story (a story read to a patient thus recalled by them) (Rausch & Babb,

has been suggested that the recall of prose may be more associated with the lateral component of the left temporal lobe, as there was a relationship found between prose recall and lateral temporal lobe resection but not mesial temporal lobe resection (Ojemann & Dodrill, 1985). In this context, HS or neuron loss is most commonly associated with impaired delayed recall (Miller et al., 1993; Rausch & Babb, 1993; Saling et al., 1993) or percent retention measures, while generally not associated with general cognitive ability, language competency (Sass et al., 1992), attention, recognition memory or immediate memory (Miller et al., 1993).

Findings of a relationship between HS and non-verbal memory are less consistent. Impaired delayed recall of a complex figure has been associated with HS, although this was found across left and right HS groups so is not demonstrative of a material specific deficit (Miller et al., 1993). It has been proposed that this lack of a clear relationship between right-sided pathology and visual memory may be due to the way people verbalise even non-verbal information for storage and recall.

Studies have also tried to further clarify more precisely whereabouts neuron loss correlates with memory impairment. Rausch found that damage to neurons in either the anterior or posterior part of the left hippocampus was not sufficient to severely impair memory performance, extensive damage is required (Rausch, 1987). However, correlation has been found between percent retention of logical memory story and neuron loss in region „CA3‟ and the hilar region of the hippocampus in left TLE patients (Sass et al., 1992). The internal limb of the dentate gyrus has also been found to be particularly well correlated with measures of memory (Pauli et al., 2006), as well as the degree of granule cell loss and abnormality of granule cell architecture in the dentate gyrus (Blümcke et al., 2009).

Comparing patients with different types of left temporal lobe pathologies (HS, mesial tumour, lateral tumour), Helmstaedter and colleagues proposed that, due to surgical outcome data, patients with hippocampal pathologies were more likely to be impaired in delayed recall of a word list, while patients with lateral temporal

lobe lesions were expected to be worse at immediate recall and working memory. The „hippocampal effect‟ was found in patients with HS who were more impaired in delayed recall of a word list (than patients with lateral tumours and also mesial tumours), but no „lateral effect‟ (worse immediate and working memory with lateral lesions) (Helmstaedter et al., 1997).

4.3.2 Findings from MRI investigations

A unilaterally small hippocampus and increased T2-weighted signal seen on MRI have been shown to be effective at identifying HS (Jackson et al., 1990; Lencz et al., 1992) and side of seizure onset (Jack Jr et al., 1990; García-Fiñana et al., 2006). This would suggest that, as well as by assessing patients‟ pathological abnormalities at surgery, quantitative MRI can also be used to assess temporal lobe or hippocampal damage in patients who don‟t need surgery. It also indicates that assessing the relationship between MRI abnormalities and neuropsychological status can give an idea of the relationship between pathological abnormalities and neuropsychological status.

MRI volumetrics have identified atrophy in TLE patients in the hippocampus (Jack Jr et al., 1992; Quigg et al., 1997; Woermann et al., 1998; Tasch et al., 1999; Daley et al., 2006; García-Fiñana et al., 2006; Oyegbile et al., 2006), mesial temporal structures such as amygdala (Kälviäinen et al., 1997; Martin et al., 1999), fornix (Kuzniecky et al., 1999; Martin et al., 1999), and entorhinal cortex (Bernasconi et al., 1999) as well as basal ganglia and thalamus (DeCarli et al., 1998; Tuchscherer et al., 2010).

Extrahippocampal temporal regions (Moran et al., 2001) and extratemporal regions such as cerebellum (Ney et al., 1994; Specht et al., 1997; Bohnen et al., 1998; Sandok et al., 2000) have also been found to be abnormal in TLE. MRI volumetrics have also been used in TLE patients to assess the whole brain, finding a relatively diffuse pattern of cerebral volume loss (in frontal, parietal and temporal but not occipital lobes (Hermann et al., 2003)) or reduced total brain volume (Oyegbile et al., 2006),

with white matter reduced more than grey matter (Hermann et al., 2003; Oyegbile et al., 2006).

The relationships of hippocampal and temporal lobe volumes to memory have been investigated. The volume of the left (dominant) hippocampus has been shown to be correlated with delayed recall or retention of verbal information, including a logical memory story (Lencz et al., 1992) and also verbal paired associates, with a weaker and less consistent correlation with immediate recall (Griffith et al., 2003). This is consistent with the post-surgical findings discussed demonstrating that

hippocampal pathology correlated better with delayed than immediate recall (Miller et al., 1993; Rausch & Babb, 1993; Saling et al., 1993). Volume of the left temporal lobe has also been shown to correlate with verbal recall of a word list (Lencz et al., 1992). This is in conflict with the aforementioned pre-surgical findings, that patients with hippocampal pathology are more impaired at word list recall, whereas logical memory story recall might be more related to the lateral temporal lobe (Rausch & Babb, 1993; Saling et al., 1993). No reliable relationships have been found between right hippocampal volume and visual memory measures, a finding consistent with previous studies (Griffith et al., 2003).

For people with epilepsy, abnormalities outside the temporal lobes also exist. Therefore it is unsurprising that cognitive abnormalities often extend beyond the field of memory. Neuropsychological impairment in patients has been found to correlate with total brain volume (Oyegbile et al., 2006). The reduction in white matter raises the idea of reduced cortical connectivity in TLE and this is a model for the diffuse cognitive dysfunction which is seen (Hermann et al., 2003). The cause of the widespread volume abnormalities is unclear, but it could be due to the effects of seizures or their treatment on brain growth and cognitive development, the

progressive adverse effects of longstanding epilepsy on brain structure and function, or discrete cerebral insults antedating or related to the onset of the focal epilepsy. Animal studies might suggest that white matter is particularly vulnerable to seizure activity, particularly in immature rat brains (Dwyer & Wasterlain, 1982).

In summary, findings from both MRI studies and pre-surgical patients show a number of abnormalities in TLE that correlate with various cognitive measures, largely in the temporal lobe and hippocampus as well as more diffuse volume abnormalities. Left hippocampal volume or HS correlates with retention or delayed recall of verbal information. More diffuse white matter changes, total brain volume reduction and diffusely reduced cortical thickness correlate with more extensive cognitive and executive dysfunction. It would seem clear that pathological changes in epilepsy have a significant detrimental effect on neuropsychological functioning.