The medial temporal epilepsy syndrome should logically include neurobehavioral features: memory problems/complaints as well as the inter ictal behavioral syndrome of Gastaut-Geschwind & Blumer There may be differential roles for different key structures in engendering neurobehavioral symptoms

1. Mesial Temporal Structures And
Epilepsy Related Psychopathology
Where Is The Nexus?
Dr. Ennapadam.S. Krishnamoorthy
MD., DCN, PhD (Lond), FRCP (Lond, Glas, Edin), MAMS (India)
Founder Director
TRIMED I NEUROKRISH
www.trimedtherapy.com I www.neurokrish.com

2. Inter-ictal behavioral syndrome of
Temporal Lobe Epilepsy
Syndrome described by Gastaut & Geschwind
and characterised by
• intensified and labile emotionality
• viscosity (orderliness, excessive attention to
detail and persistence)
• hyposexuality
• religiosity
• hypergraphia

3. Sensory- Limbic Hyperconnection- an
explanation for the behavioral features
increased electrical activity-temporal lobe

enhanced connection between sensory input
and limbic processing

sensory experience suffused with emotional
coloration

4. Laterality & inter-ictal behavioral
syndrome
RIGHT SIDED FOCUS
(EMOTIVE)
emotionality
elation and sadness
Tendency to ‘polish’
image
LEFT SIDED FOCUS
(IDEATIVE)
sense of personal
destiny
philosophical interests
Tendency to ‘tarnish’
image

5. • Described by Kraeplin- Verstimmungen: mood, anxiety, somatic and
psychotic components identified
• Concept revoked by Blumer
• Pleomorphic pattern with eight symptoms: irritability, depressive
moods, anergia, insomnia, atypical pains, anxiety, and euphoric
moods
• Occur at various intervals- last from hours to two/three days; may on
occasion last longer
• Some symptoms may be present continually at a baseline-intermittent
fluctuations occur
• The presence of at least three symptoms generally coincides with
significant disability

6. The Spectrum of Psychopathology in Epilepsy
Features of the Affective
Somatoform spectrum
Features of the
Geschwind syndrome
Psychotic features
specific to epilepsy
Changes in the structure
Of the AHC
AEDs
Seizures
Neuropsychological
Symptoms

7. The Medial Temporal Lobe Epilepsy
Syndrome
(Trimble, 1998)
• Simple/ Complex partial seizures with or without secondary
generalisation
• EEG with temporal lobe focus
• MRI demonstrating MTS pathology
• Memory complaints and/or disorder
• Characteristic Psychopathology: Dysphoria,
anxiety/agitation/aggression, psychotic symptoms,
personality features described by Gastaut & Geschwind
• Religiosity, emotional viscosity, hypergraphia, hyposexuality,
peculiar ethical concerns

8. The Mesial Temporal
Structures in Epilepsy- I
• Subjects with localisation related epilepsy
show reduced mean hippocampal volume
when compared to subjects with newly
diagnosed partial seizures and normal controls
(Everitt, 1998; Kalviainen 1998)
• Progressive Hippocampal Sclerosis- reported in
patients with recurrent partial & secondary
generalised seizures (O’Brien, 1999), & status
(Wieshmann, 1997)
• Van Paesschen (1998)- significant loss of HV in
8% of patients scanned a year apart

9. The Mesial Temporal
Structures in Epilepsy- II
• Atrophy on volumetry correlates well with
mesial temporal sclerosis and neuronal loss on
post-operative histopathology (Jack, 1992;
Cendes, 1992;1993)
• Number of studies have shown change in MTS
volumes (Bernasoni, 2003a); entorhinal cortex
involvement (Bernasconi, 2003b; Bartlomei,
2005); involvement of hippocampus, amygdala
and entorhinal cortex and progressive but
differential volume loss (Bernasconi, 2005);

10. The Mesial Temporal
Structures in Epilepsy- III
• However, Liu (2001) failed to demonstrate
significant differences in mean volumes in 53
community based subjects followed up over 3.5
years
Chicken or Egg?
• Does chronic epilepsy result in smaller MTS
volumes?
• Do reduced MTS volumes determine intractability of
epilepsy?
• The jury is still out!

11. The Mesial Temporal
Structures in Schizophrenia-I
• MRI in Schiz- well researched- 193 peer reviewed
papers from 1988 to mid 2000
• Ventricular enlargement- 80%
• MTS involved in 74% of studies and temporal
neocortex in 100%
• Combined grey and white matter of superior
temporal gyrus- 67%
• Parietal and frontal abnormalities- 60%
Shenton ME, Schizophrenia Shenton ME, Schizophrenia RReesseeaarrcchh 2 2000011; ;4 499: :1 1-5-522

12. The Mesial Temporal
Structures in Schizophrenia-II
• 61% of MRI studies, report smaller temporal
lobe volume in Schizophrenia
• Studies examining laterality- all reported
right>left whole temporal volume- consistent
with population data
• AHC volume reductions seen in both chronic
and first episode schizophrenia
• STG volume reduction seems specific to
schizophrenia spectrum/ may be reversible
Shenton ME, Schizophrenia Shenton ME, Schizophrenia RReesseeaarrcchh 2 2000011; ;4 499: :1 1-5-522

13. The Mesial Temporal
Structures in Schizophrenia-III
• Study and follow up of high risk individuals
- Diminished gray matter in medial temporal, lateral
temporal and inferior frontal cortex on the right side
in those at high risk
- Reduction in gray matter in the left parahippocampal,
fusiform, orbitofrontal and cerebellar cortices and
cingulate gyri in those who developed psychosis on
follow up
Pantelis C, Velakoulis D, McGorry PD. The Lancet
2003; 361: 281-288

14. The Mesial Temporal
Structures in Schizophrenia-IV
• Study comparing ultra high risk individuals, first
episode psychosis and chronic schizophrenia
- Normal baseline amygdala and hippocampal volumes in ultra
high risk individuals whether or not they developed a psychotic
illness
- Left hippocampal volume reduction in first episode psychosis
without schizophreniform symptoms
- Normal hippocampal volumes in other first episode psychosis
groups
- Bilateral hippocampal volume reduction in chronic
schizophrenia
- Increased amygdala volumes only in non-schizophrenic
psychosis
- No treatment effects on structural volumes Velakoulis D. Arch.
Velakoulis D. Arch.
Gen. Psych. 2006; 63:
139-149
Gen. Psych. 2006; 63:
139-149

15. Imaging In Affective Disorders- Findings
From Early Studies
• Enlarged VBR; enlarged sulci/ cerebellar vermis
atrophy (Elkis, 1995)
• Progressive enlargement of VBR (Woods, 1990)/ 
neuropsychology (Coffey, 1993)
• Smaller frontal lobes/ Basal Ganglia (Krishnan,
1992/93); cerebellum/ brain stem
• WML scattered in the peri-ventricular WM, deep
WM, BG & Pons (Videbech, 1997)
Videbech P. MRI findings in patients with affective disorder: a meta analysis. Acta Psychiatr Scand Videbech P. MRI findings in patients with affective disorder: a meta analysis. Acta Psychiatr Scand 1 919979:79:69;6 1; 5175-71-61868

16. The Mesial Temporal Structures
in Affective Disorder- Hippocampus
• Early studies: Decreased hippocampal volumes in
Bipolar (Altshuler, 1991) and Unipolar depression
reported
• An emerging and more consistent literature on the
importance of hippocampal volume loss in major
depression (Bremner, 2000; Frodl, 2002 for example)
• Hippocampus is a key region of interest in
Depression (Mayberg- 6th INA Congress)

17. The Mesial Temporal Structures
in Affective Disorder- Amygdala
• Amygdala also appears to undergo structural and functional
changes- however the direction of change reported is variable
(Caetano, 2004)
• Both amygdala enlargement (Altshuler, 1998) and over-activation
(Drevets, 1992) have been linked with depression
• Many reports suggest preservation or even increase in
amygdala volume in depressed patients and those with
affective psychosis
• Whether the changes in the amygdala are a gender specific
trait, more commonly observed in women has been
questioned (Tebartz van Elst, 2001)

18. Mesial Temporal Structures and
Epilepsy Related Psychopathology

19. Aims
• To investigate independent associations
between hippocampal integrity, amygdala
integrity and co-morbid psychopathology in
epilepsy
• In particular to study differential associations
between MTS integrity and generic versus
epilepsy specific psychopathology

20. Methodology-1
• MRI; 1.5T GE Signa Horizon Scanner
• T1-weighted inversion recovery prepared volume
acquisition; slice thickness 1.5 mm
• Images transferred to SUN workstation- measured
using interactive software program Mrreg
• Images zoomed/ magnified: Amygdala & HS
outlined manually using a mouse driven cursor
and established protocol (Watson, 1992, 1997)
• MTS volumes corrected for total brain size by
division from IC volume (Cendes, 1993)

21. Methodology
MRI based
Amygdala volumetry
MRI based
quantification

22. MTS, Epilepsy & Psychopathology
Epilepsy with Interictal Aggression:
• No evidence for amygdala sclerosis
•Hippocampal sclerosis significantly less
Epilepsy with Dysthymia:
Amygdala volumes bilaterally enlarged*
Amygdala volumes/ BDI scores positively correlated*
Tebartz van Elst; 1. Brain 2000;123:234-243. 2. Biol Psych 1999;46:1614-
1623 *statistically significant
Tebartz van Elst; 1. Brain 2000;123:234-243. 2. Biol Psych 1999;46:1614-
1623 *statistically significant

23. Psychoses of Epilepsy (POE)
2100
2050
2000
1950
1900
1850
1800
1750
1700
1650
1600
1550
CONTROL
RAV
LAV
• TBV significantly smaller
in POE compared to
controls and TLE-NP
p<0.000)
• Both RAV and LAV  in
POE- even after
correcting for potential
confounders
• Trend of increasing
amygdala volumes
Tebartz van Elst, Tebartz van Elst, B Brarainin 2 2000022; ;1 12255(1(1):) :1 14400-1-14499

24. MTS Volumes in Psychoses of
Epilepsy
CON (SE) TLE-NP (SE) POE CON (SE) TLE-NP (SE) POE (S (SEE) ) SSiginginfiicfiacnacnece
TBV 1214,82
(25,5)
1168,34
(22,7)
1056, 51
(23,5)
**
RHV 2,695
(0,082)
2,621
(0,116)
2,923
(0,151)
LHV 2,516
(0,075)
2,324
(0,14)
2,509
(0,116)
RAV 1, 749
(0,048)
1,798
(0,051)
2,065
(0,069)
**
LAV 1,756
(0,047)
1,826
(0,058)
2,067
(0,054)
**
*** *p <p <0 .00.10 1a fatfetre rb obnofnefrerrornoin ci ocrorrercetciotinon

25. Epilepsy And Co-morbid Anxiety: Trend Of Increase
In Amygdala Volumes
2400
2200
2000
1800
1600
1400
1200
Rt.Amyg. Lt.Amyg.
Group I
Group II A
Group II B
• 8 anxiety, 8 no
psychopathology;15
controls
• Groups matched for age
and gender
• Anxiety Group- earlier
onset of epilepsy (p<0.05)
and longer course
(p<0.001)
• Patients with clinically
significant anxiety had
larger Right MTS*
Group-I: No psychopathology; Group-IIA- anxiety symptoms; Group IIB- Group-I: No psychopathology; Group-IIA- anxiety symptoms; Group IIB- a naxnixeiteyt yd idaigangonsoissis
SSaatitsishhcchhaannddrara P P e et ta al,l ,J J N Neeuuroroppssyycchhiaiatrtyry C Clilnin N Neeuurorosscci.i .2 2000033 F Faalll;l1;155(4(4):)4:45500-2-2..

26. Mean amygdala & hippocampal volumes
(cubic mm)
NNAA AANNXX CCOONNTT
RAV 1714
(255)*
2039
(369)+
1904
(206)
LAV 1843
(164)
2042
(467)
1928
(203)
RHV 2066
(595)*
2508
(383)
2481
(256)
LHV 2337
(447)
2450
(314)
2553
(234)
* difference compared to control volume, p< 0.05; + difference compared to * difference compared to control volume, p< 0.05; + difference compared to N NAA v ovloulmume,e p, <p <0 .00.505

27. Hippocampus and Geschwind’s triad
• 33 subjects (23 men) with
refractory partial seizures
completed NBI
• Patients scoring high and
low on patient and carer
NBI sub-scales assessed
• Groups were matched for
frequency/ severity using
NHSSS
• Hyper-religiosity inversely
associated with right
hippocampal volume
• We compared epilepsy
patients with very severe
BHA (>3 SD) and those
with no BHA
• High psychiatric co-morbidity
in both groups-no
statistical difference
• Group with BHA-self
ratings emotions, fear,
guilt, sadness; carer
ratings: hyposexuality,
hypergraphia,
dependency
Wuerfel et al, JNNP 2004; 1. 75
(4); 640-2.
Wuerfel et al, JNNP 2004; 1. 75
(4); 640-2.
Tebartz van Elst L. Epi & Behav
2003: 4; 291-7
Tebartz van Elst L. Epi & Behav
2003: 4; 291-7

28. Supportive Literature
• Baxendale, 2005 has reported greater
hippocampal symmetry in patients with
epilepsy and depression
• Velakoulis et al, 2006 have reported increased
amygdala volumes in first episode psychoses
and in non-schizophreniform psychosis

29. What’s Good About These Studies?
• Well defined populations assessed by experts- homogenous
• Standardised techniques of volumetric measurement- good
intra-rater reliability
• Clinical raters blind to MR findings and MR raters blind to
clinical diagnosis
• Consistent & robust trend in results

30. What are the Limitations?
• Small sample sizes
• Variable clinical seizure definition
• Inter-rater reliability of MR volumetry technique
unknown at the time of study: established later
• NBI- not a validated measure of epilepsy specific
psychopathology

31. Reasons For Differential Involvement
Of The Amygdala And Hippocampus
¨ Amygdala:
- Generator/ processor of emotional impulses
- Dysfunction leads to de novo psychopathology
- Is this reflected in enlarged volumes
• Hippocampus:
- Comparator of amygdala outflow (and storehouse of
memories)
- Dysfunction leads to extreme manifestations of normal
behaviors
- The neurobiological basis of the MTE syndrome
of Trimble?

32. Explanatory Hypotheses
1. Regional Specificity:
• Do the amygdala and hippocampus have different roles to
play in the development of psychopathology?
• Are they responsible for specific forms of psychopathology:
schizophrenia- hippocampus; affective disorders- amygdala;
major depression- hippocampus and so on
2. Cause versus effect:
¨ Are the changes observed the cause of psychopathological
dysfunction?
¨ Do they influence the direction or outcome of dysfunction?
¨ Are they the consequence of psychopathology?

33. Explanatory Hypothesis
3. Is it simply that the mesial temporal structures are crucial for
the evolution and course of both epilepsy and various
psychiatric disorders?
4. Do they indicate a specific nexus between epilepsy, MTS and
certain forms of psychopathology?
- For example it has been postulated that epilepsy and
depression have a bi-directional relationship

34. Potential Confounders in this Area of Research
• Constant improvements in imaging technology
•
• Variance in imaging methodology: scanner resolution, slice
thickness, AHC vs. A & H
• State versus trait issues in the assessment of psychopathology
• Also categorical versus dimensional approaches to the assessment
of psychopathology in imaging research
• Difficulties in carrying out prospective work
• Population variance in brain size- age, sex, socio-economic status,
nutritional factors- relative absence of normative data

35. Conclusions
• The medial temporal structures have a role in the genesis of
psychopathology
• The medial temporal epilepsy syndrome should logically
include neurobehavioral features: memory
problems/complaints as well as the inter ictal behavioral
syndrome of Gastaut-Geschwind & Blumer
• There may be differential roles for different key structures in
engendering neurobehavioral symptoms
• Prospective hypothesis driven studies using standard
protocols and other versatile techniques fMRI/ PET/MRS are
necessary

36. Acknowledgements
Fellow Investigators:
Baumer, Brown, Koepp, Lemieux, Samuel, Satishchandra,
Selai, Tebartz van Elst, Thompson, von Gunten,
Woermann, Wuerfel
(Group lead by Professor Michael Trimble)
• Raymond Way Neuropsychiatry Research Group,
Department of Clinical and Experimental Epilepsy,
Institute of Neurology, Queen Square
• MRI Unit, National Society for Epilepsy, Chalfont St.
Peter, Buckinghamshire
• Paul Hamlyn Foundation
• Dr. R Muthuram- TS Srinivasan Fellow in
Neuropsychiatric Imaging

37. Thank You
email: research@neurokrish.com