mesial temporal structures and epilepsy related psychopathology
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Mesial Temporal Structures And Epilepsy Related Psychopathology
Where Is The Nexus?
Dr. Ennapadam.S. KrishnamoorthyMD., DCN, PhD (Lond), FRCP (Lond, Glas, Edin), MAMS (India)
Founder Director
TRIMED I NEUROKRISH
www.trimedtherapy.com I www.neurokrish.com
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
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
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
• 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
The Spectrum of Psychopathology in Epilepsy
Features of the Affective Somatoform spectrum
Changes in the structureOf the AHC
Features of the Geschwind syndrome
Psychotic features specific to epilepsy
AEDs
Seizures
NeuropsychologicalSymptoms
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
• 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
The Mesial Temporal Structures in Epilepsy- I
• 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);
The Mesial Temporal Structures in Epilepsy- II
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!
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 Research 2001; 49: 1-52Shenton ME, Schizophrenia Research 2001; 49: 1-52
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 Research 2001; 49: 1-52Shenton ME, Schizophrenia Research 2001; 49: 1-52
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 upPantelis C, Velakoulis D, McGorry PD. The Lancet 2003; 361: 281-288
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. Gen. Psych. 2006; 63: 139-149
Velakoulis D. Arch. Gen. Psych. 2006; 63: 139-149
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 1997:96; 157-168Videbech P. MRI findings in patients with affective disorder: a meta analysis. Acta Psychiatr Scand 1997:96; 157-168
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)
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)
Mesial Temporal Structures and Epilepsy Related Psychopathology
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
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)
Methodology
MRI based Amygdala volumetry
MRI based quantification
MTS, Epilepsy & Psychopathology
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
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*
155016001650170017501800185019001950200020502100
CONTROL
RAVLAV
• 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, Brain 2002; 125(1): 140-149Tebartz van Elst, Brain 2002; 125(1): 140-149
Psychoses of Epilepsy (POE)
MTS Volumes in Psychoses of Epilepsy
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)
**
CON (SE) TLE-NP (SE) POE (SE) SignificanceCON (SE) TLE-NP (SE) POE (SE) Significance
** p< 0.01 after bonferroni correction** p< 0.01 after bonferroni correction
Epilepsy And Co-morbid Anxiety: Trend Of Increase In Amygdala Volumes
1200
1400
1600
1800
2000
2200
2400
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- anxiety diagnosisGroup-I: No psychopathology; Group-IIA- anxiety symptoms; Group IIB- anxiety diagnosis
Satishchandra P et al, J Neuropsychiatry Clin Neurosci. 2003 Fall;15(4):450-2.Satishchandra P et al, J Neuropsychiatry Clin Neurosci. 2003 Fall;15(4):450-2.
Mean amygdala & hippocampal volumes (cubic mm)
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 NA volume, p< 0.05* difference compared to control volume, p< 0.05; + difference compared to NA volume, p< 0.05
NA ANX CONTNA ANX CONT
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
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
• 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
What’s Good About These Studies?
• 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
What are the Limitations?
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?
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?
Explanatory Hypotheses
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
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
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
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
Acknowledgements
