Quantitative Histology
ASPECTS OF SPATIAL MEMORY TEST: Administration
I'm going to show you some pictures and I want you to look very carefully at each one and answer some questions.
Present the 'Food' stimuli. Note the time
Ask the 10 questions. If a subject gets one wrong, ask them again. If they get it wrong again, give the right answer*. At the end of the 10 questions ensure that the subject has looked at the picture for at least 1 minute. If there is time remaining, ask them to continue to study at the picture for the remaining time.
Repeat with the 'Desk' and 'Zoo' stimuli.
Administer the AMIPB information processing subtest.
'Now I'm going to show you some more pictures. Some will be the same as the ones you saw earlier and some will be slightly different but the differences might be quite small. I want you to have a good look at each one and tell me if its the same or different to the ones you saw earlier. Remember, some will be the same and some will be different. I want you to answer as quickly as you can BUT I can only take your first answer so I want you be sure before you say anything. So be quick, but you must be accurate. Do you understand?
Check the subject understands the instructions. Present picture 1.
Now is this the same or different to the one you saw earlier?
Record the time it takes for the subject to answer and the response. If the subject indicates that the picture is different ask them how it differs. Ensure that they identify the right change. Go on to the next item.
Now is this the same or different to the one you saw earlier?
Repeat the instructions for each item as necessary. Sometimes the subject will tell you about the difference before they say 'same' or 'different'. Remind them that they only need to say 'same' or 'different' until asked for further information, and continue with the test.
* It is very unusual for a subject not to be able to answer the initial questions. The results of the memory test are probably not valid if the subject is unable to complete this part of the test and it is probably best to discontinue the task.
Scoring
The test yields 6 scores: 1. The overall number o f scenes correctly classified as the same or different from the original (Max. 60). 2. The number o f identical scenes correctly recognised (Max. 12). 3. The number o f figurative detail changes correctly identified (Max. 12). 4. The number o f ‘filled space’ changes correctly identified (Max. 12). 5. The number o f ‘location’ changes correctly identified (Max. 12). 6. The number o f ‘orientation’ changes correctly identified (Max. 12). The total time taken to complete the test and the cumulative total taken to classify each o f the five categories o f scene were also calculated, (Identical, Figurative Detail Changes, Filled/Unfilled Space Changes, Spatial Location Changes, Orientation Changes). See Appendix 4 for an example o f the AoSMT score sheet.
Quantitative Measures o f Hippocampal Pathology
Bilateral MRI hippocampal volume measurements, corrected for intracranial volume were available for 38 o f the patients. Hippocampal T2 relaxation times were available for 59 o f the patients. Small hippocampal volumes and high HCT2 relaxation times have been associated with extensive neuronal loss and gliosis on histopathological examination o f resected specimens. The procedures used to derive the measures used in this study are described in detail in Chapter 8.
Statistical Analyses
Multivariate analysis o f variance evaluates differences among centroids (average on the combined dependent variables, DVs) when there are two or more levels o f an
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independent variable, IV (groups). MANOVA has a number o f advantages over ANOVA. By measuring several DVs instead o f only one, the likelihood o f
discovering the important variables is improved. A second advantage o f MANOVA over a series o f ANOVAs when there are several DVs is protection against inflated Type I error due to multiple tests o f correlated DVs (Tabachnick & Fidell, 1996)^^\ Differences between the RTLE, LTLE and normal control group on the Aspects o f Spatial Memory Test scores were therefore examined using multivariate analyses o f variance. Once reliable differences were found, univariate F tests with Bonferroni adjustment were used to test the importance o f the individual DVs.
Pearsons correlations were used to examine the relationship between the AoSMT scores and the quantitative measures o f hippocampal pathology.
Norms from the AMIPB manual are quoted in the Table 9.2 to simply facilitate appreciation o f the clinical significance o f the raw scores achieved by the RTLE and LTLE groups on the memory tests for readers who may not be familiar with the tests. Two sets o f norms are presented: 1) Form I, age range 18-30, and 2) Form I, age range 31-45. These ranges were chosen as the most representative as 94% o f the sample in this study were between the ages o f 18 and 45.
RESULTS
Group Differences
There were no significant differences between any o f the groups (RTLE, LTLE, Normal controls) in their scores on the information processing task from the AMIPB (F= 1.39, p>0.05). The multivariate analyses o f variance revealed a significant effect o f laterality o f seizure focus (RTLE vs. LTLE) on the AMIPB memory test scores (F=2.1, p=0.04). Univariate F tests revealed that the RTLE group obtained
significantly lower scores than the LTLE group on the design learning task and on the complex figure recall task See Table 9.2. Although there were no significant
differences between the RTLE and LTLE groups on the story recall and list learning tasks, the mean scores o f both groups below the 25th percentile o f published norms (Form I, age ranges 18-30 and 31-45).
Table 9.2: Baseline Neuropsychological Test Scores fo r the RTLE and LTLE Groups
Test RTLE Group
mean (s.d.) LTLE Group mean (s.d.) Normals* mean (s.d.) List Learning 45.3 (8.4) 45.3(10.4) a 57.3 (7.6) P 52.9(7.8) List Recall 9.2 (2.8) 8.8 (3.2) a 12.5 (2.3) P 11.7(2.5)
Story: immediate recall 24.7(10.7) 23.5(10.1) a 39.2(10.5) P 33.0(10.1)
Story: delayed recall 21.5(12.1) 20.5(10.7) a 37.5 (10.6) P 30.9(10.5)
Story % retained 82.4(19.3) 84.0 (24.3) a 95.7 (10.9) P 92.8(10.4)
Design Leamingt 29.6 (9.6) 35.6 (6.9) a 36.8 (6.7) P 32.0(7.7)
Design Recall 6.5 (2.7) 7.2 (2.2) a 7.9 (1.9) P 6.7(2.6)
Figure: immediate recallt 69.2 (21.3) 80.6(11.3) a 89.6 (15.4) P 78.6(19.4)
Figure: delayed recallt 65.9 (20.8) 79.1 (11.7) a 87.2 (17.5) P 76.0(19.3)
Figure: % retained^ 92.7(14.8) 98.1 (6.4) a 97.0 (9.9) P 98.0(15.3)
* From the AMIPB test manual, t P<0.01 t P<0.05
a Form I, age 18-30 (page 57) P Form I, age 31-45 (page 58)
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The MANOVA analyses revealed a significant group effect on the scores from the AoSMT (F=3.6, p<0.001). Post hoc multiple range tests revealed that overall the RTLE patients correctly classified significantly fewer items than the LTLE group (f=4.1, p=0.01). Taking each class o f change individually there were no significant group differences in the number o f identical items accurately identified, or the number o f filled/unfilled space or spatial location changes correctly identified by each group. However the RTLE group identified significantly fewer figurative detail changes than both the LTLE group and the control group (F=5.7, p=0.004). There were no
significant differences between the two patient groups in the number o f orientation changes each identified. However the LTLE group identified significantly more
orientation changes than the normal controls (F=3.7,p=0.02). See Figure 9.6.
Overall the RTLE group took significantly longer than the LTLE group and the control group to complete the test (F=12.7, p<0.001). There were no significant differences between the RTLE and LTLE groups in the time taken to classify the identical items or the changes in spatial location. However the RTL group took significantly longer than the normal control group to identify both types o f change (identical items; F=6.7,p=0.001, spatial location; F=6.1 ,p=003). The RTLE group took significantly longer than both the LTLE group and the normal controls to identify figurative detail changes (F=23.8, p<0.001) changes in orientation (F=6.9, p=0.002) and changes in the filled/unfilled space o f a composition (F=8.75, p<0.001). See Figure 9.7. (Full details o f the all the statistical analyses are presented in Appendix 4).
Figure 9.6 Total number o f changes identified in each category fo r the RTLE & LTLE groups (max. =1 2 )
Normals RTLE Group M ean (s.d) LTLE group M ean (s.d) N orm al controls g M ean (s.d) Total Score 46.5 (6.5) 50.1 (4.9) 48.8 (3 .8 ) Orientation 6.7 (2.2) 7.2 (2.2) 5.8 (2.0) Figurative detail 8.8 (1.9) 1 0 .0 (1 .6 ) 1 0 .3 (1 .6 )
Sam e/no change 9.3 (2.4) 1 0 .2 (1 .8 ) 10.2 (2.0)
Filled/unfilled space 1 0 .9 (1 .3 ) 1 1 .3 (1 .0 ) 11.4 (0.8)
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Figure 9.7 Total time taken to classify the 1 2 pictures in each category fo r the RTLE & LTLE groups.
I
i
(0
Normals
RTl£
Tim e (seconds) RTLE Group
M ean (s.d) LTLEgrcMip M ean (s.d) Norm al controls % M ean (s.d) " Total Tim e 3 2 3 .7 (1 1 1 .4 ) 2 6 7 .1 (6 3 .1 ) 228.3 (46.8) Orientation Tim e 73.6 (33.4) 5 7 .9 (1 8 .9 ) 52.9 (1 4 .9 )
Figurative detail Tim e 5 6 .7 (1 2 .5 ) 4 5 .8 (1 0 .4 ) 39.3 (6.5)
Sam e/no change Tim e 95.1 (54.9) 79.5 (27.1) 63.1 (17.8)
Filled/unfilled space Tim e 50.6 (22.0) 4 0 .9 (1 3 .3 ) 34.7 (8.6)
Sensitivity and Specificity o f the AoSM T
In clinical practice every test has a set o f characteristics that reflect the information expected in patients with and without the ‘disease’. These test characteristics lead to two fundamental questions: 1) If the disease is present, what is the likelihood that the test result will be positive? 2) If the disease is not present, what is the likelihood that the result will be normal? The answer to the first question determines the sensitivity o f the test, and that o f the latter addresses its specificity (Griner et al, 1981)'^"*. These characteristics are displayed in Figure 9.8.
Figure 9.8 Receiver Operating Characteristics o f a Clinical Test fo r Lateralised
Temporal Lobe Dysfunction.
RTLE focus present
RTLE focus not present
Score below cut off A B Score within normal range C D Sensitivity Specificity False negative rate False positive rate
True positive results (A)
Total patients with RTLE (A+C) True negative results
m
Total patients without RTLE (B+D) False negative results I Q Total patients with RTLE (A+C) False positive results______ IB) Total patients without RTLE (B+D)The process o f confirming the laterality o f a seizure focus requires a test whose specificity is high. When a test is used either for the purpose o f screening or to exclude a diagnostic possibility, it must be sensitive. The ideal test is one in which
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there is no overlap in the range o f patients with and without the ‘disease’ in question. However such a test is rare in neuropsychology, and in most tests there is some overlap in scores between patients with and without the lesion in question. When a test is developed for clinical use, it is customary to define the normal range as within two standard deviations o f the mean. This range encompasses approximately 95% o f the test results o f normal subjects with approximately 2.5% o f subjects falling either above or below this range. However whilst this stringent cut-off results in high specificity, the sensitivity o f a test is often considerably reduced at this level. Such a cut-off point may be appropriate to confirm a suspected diagnosis but cannot be used to exclude suspected dysfunction because o f its low sensitivity. Each cut-off point defines a set o f operating characteristics for the test in question. Generally as sensitivity is increased, specificity falls and vice versa.
A graph can be constructed that correlates true and false positive rates (sensitivity and 1 minus specificity, respectively) for a series o f cut o ff points for any test. Such a graph is known as the Receiver Operating Characteristics (ROC) o f a test. The graph can be used to decide the optimum cut-off point according to the purpose o f the test. In addition, when two or more tests are available to pursue a diagnostic consideration, a comparison o f the ROCs o f each will often show where one has an advantage over the other. As the criteria for an abnormal score are made more stringent, the curves move down and towards the left (greater specificity, lower sensitivity). If the purpose o f the test is to confirm a strong clinical suspicion these stringent criteria would be appropriate. Conversely, as the criteria for an abnormal score are made more liberal, the curves move up and to the right (greater sensitivity, lower specificity). If the