Transcript No Slide Title

EPILEPSY AND MEMORY
David M. Treiman, M.D.
Barrow Neurological Institute
Phoenix, Arizona
“. . . The commonest failure is loss of memory
and that this, if regarded in all degrees, is more
frequent than the integrity of that faculty.”
- J. Russell Reynolds, 1861
Epilepsy: its symptoms, treatment and
relation to other chronic convulsive
diseases. London: John Churchill
Epileptic Seizure
A clinical manifestation of a transient, usually
hypersynchronous, abnormal electrical
discharge in the brain, consisting of sudden and
transitory abnormal behavioral phenomena
(alterations of consciousness, motor, sensory,
autonomic, or psychic events).
Epilepsy
A neurological disorder characterized by
recurrent non-provoked epileptic seizures.
Epileptic Seizure
Generic description
• Abrupt onset
• Impaired consciousness during event
• Amnesia for the event and part of the
post-ictal period
• Post-ictal depressed consciousness, with
gradual recovery
Epilepsy & Memory
Issues for consideration
• Ictal amnesia & fugue states
• Post-ictal amnesia
• Inter-ictal memory deficits
Hx. of Concepts of Memory
• Unitary memory
• Multiple memory systems
– Franz Joseph Gall & phrenology
– Maine de Biran
» Representative memory - recollection of ideas & events
» Mechanical memory - acquisition of habits & skills
» Sensitive memory - memory for feelings
– 19th C neurologists - memory centers
• 1st half of 20th C - back to unitary memory
• Post WWII - multiple memory systems again
– Much of renewed interest stimulated by case of H.M.
Case of H.M.
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27 yo motor winder, hs grad, szs since age 10
Possible TBI age 9, nl PEG x2, EEGs non-focal
9/53 bilateral MT resections, posterior to 8 cm
Post-op no neuro deficit, except memory:
– little ability to retain & recollect new information
across a delay
– no difficulty with immediate or short term retention
– could learn new motor skills
– remote memories retained
– FSIQ 112 (vs 104 pre-op)
• Szs persisted, but much less severe & frequent
Scoville & Milner, J Neurol Neurosurg Psychiat 20:11, 1957
Post-op MRI from H.M. & Control
H.M.
A amygdala
cs calcarine sulcus
EC entorhinal cortex
Corkin et al., J Neurosci 17:3964, 1977
Control
H
hippocampus
MMN medial mammillary nucleus
PR perirhinal cortex
Human Memory Systems
Declarative or explicit memory: recall
• Episodic memory (remembering)
– the explicit recollection of incidents that occurred at
a particular time and place in one’s personal past
– mesial TL damage: impairs new acquisition
– prefrontal cortex: impairment of recall of temporal
order and of source (when, where)
• Semantic memory (knowing)
– general knowledge, not linked to time or place
– mesial TL damage: impairs new acquisition
Human Memory Systems
Nondeclarative or implicit memory:
unconscious, no active recall
• Perceptual Representation System
– Identification of words and objects based on their
form and structure, but not their meaning.
– Presemantic - not involved in associative or
conceptual information, i.e., meaning or function.
– Three major subsystems:
» visual word form
» auditory word form
» structural description - relations between parts that
determines global structure (what it is).
– Not mediated by mesial temporal lobe
Human Memory Systems
Implicit
• Procedural memory
– Acquisition of skills and habits (knowing how)
– Acquired gradually through repetitive practice (e.g.,
athletes, musicians
– Not dependent on mesial temporal structures
– Cortical striate system critical (HD patients poor at
learning new motor skills, altho intact explicit mem.)
– Cerebellum necessary for sequences of movements
Human Memory Systems
• Working memory
– short term retention over a period of seconds
– way of holding information on-line in service of
comprehending, reasoning, problem solving
– Three components:
» phonological loop - allows recycling of speech-based
information - left parietal supramarginal gyrus
» visuaospatial sketch pad - short-term retention of visual
and spatial information - several sites right hemisphere
» central executive or limited capacity work space prefrontal cortex
Summary of Memory
• Explicit memory systems (both episodic and
semantic memory) require intact temporal lobe,
and thus are at risk in temporal lobe epilepsy.
• Implicit memory systems (perceptual
representation system, procedural memory,
working memory) are localized outside of the
mesial temporal lobe, and thus not at risk in
temporal lobe epilepsy.
What is the evidence for memory
impairment in temporal lobe epilepsy?
Interictal memory deficits
• Physician impression
– Russell Reynolds’ observation (1861)
– Lennox (1942): “…the patient finds it hard to recall
events and names, especially those learned recently.”
– Loiseau et al. (1988): “…memory deficits in epileptic
patients merit special attention since they seek help
for these more frequently than for other mental
impairments.”
• Self-reports of patients
• Neuropsychological testing of memory
– Many reports, especially in TLE
Factors that may increase risk
Summary of older studies
• Identified etiology (risk from underlying
disorder)
• Seizure type (TLE for reasons already cited)
• Age of onset/duration of epilepsy
• Frequency and severity of seizures
• “Ictal time”
• Highly disordered EEG
• Antiepileptic drugs
Is neuronal damage progressive in
chronic intractable epilepsy?
Impairment of hippocampaldependent spatial memory after SE
• Abundant evidence from experimental studies
– Scoville & Milner 1957, Morris et al. 1982, Holmes et
al. 1988, Stafstrom et al. 1993, Nissinen et al 2000
• Rutten et al 2002 studied development of SEinduced cognitive dysfunction in immature rats
– SE induced by Li/pilo age P20
– Water maze performance at P22,P25, P30,P50
– P50 rats exposed to nonenriched or enriched envir.
– Water maze performance compared between control
and SE rats and in SE rats between environments
Water maze escape latencies
SE at P22, testing P22-50
Rutten et al. Eur J Neurosci 16:501, 2002
* P<0.05; **P<0.01; ***P<0.001
Enriched Environment
Toys, moving objects, classical music
Rutten et al. Eur J Neurosci 16:501, 2002
Effect of enriched environment on
water maze escape latency
Rutten et al. Eur J Neurosci 16:501, 2002
* P<0.05; **P<0.01
SE-induced hippocampal damage
CA3 cell
loss
Control, P30
Supragranular
sprouting
Rutten et al. Eur J Neurosci 16:501, 2002
SE rat, P30
To what extent is memory taskspecific in the MT lobes?
Correlations with task specific
declarative memory (L > R)
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Hippocampal sclerosis
Hippocampal neuronal density
Hippocampal volume
Hippocampal N-acetylaspartate/creatine ratios
NAA/Cr better correlated than volume
MRI, Cr/NAA, Verbal Memory
Sawrie et al., Epilepsia 42:1403, 2002
LM% - logical memory percentage retention
Cr - creatine
NAA - N-acetylaspartate
Memory & MRI volumes
Pegna et al., Eur Neurol 47:148, 2001
Surgical Treatment of Epilepsy
• Types of procedures:
– ATL; selective amygdalohippocampectomy
» 70% to 90% seizure free
– Focal cortical resections
– Corpus Callosotomy
– Hemispherectomy
• Evaluation:
– Scalp vido-EEG monitoring to localize seizure onset
– Invasive monitoring
» depth wire electrodes
» intracranial grid electrodes
Risk of TL Surgery to memory
• Case of H.M. (cited 1744 times through 2001)
• Two cases w/ right MTL EEG s and amnesia
after LT lobectomy w/ lg hippocampal removal
– Penfield & Milner, 1958
• Right MTL pathology verified at autopsy
– Penfield & Mathieson, 1974
• Subsequent reports by others of memory
deficits after unilateral TL lobectomy with
contralateral pathology
Corkin Nat Rev Neurosci 3:153, 2002
Intracarotid Na+ Amobarbital
Wada Test
• Wada (1949) used intracarotid Amytal to assess
lateralization of speech dominance
• Milner et al. (1962) modified Wada test to study
memory competence
• Now used routinely for pre-operative
assessment of patients in whom TL lobectomy
or selective amygdalo-hippocampectomy is
planned
IAP Protocol
• Transfemoral cerebral angiogram to evaluate
vascular anatomy/degree of cross-flow
• Arms are elevated, patient counts backward
from 20
• Amytal injected by hand (usually 100-125 mg)
until contralateral arm drops and slowing is
seen on EEG
• Memory items presented and patient asked to
name them to assess language
• Memory tested after drug effect is gone,
assessed by normalization of behavior & EEG
UCLA IAP Experience
IAP result
Positive
Negative
Amnesia
No
# of
present amnesia surgeries
1
0
0
214
1*
214
* A total of four patients had positive IAP results, but
only one underwent hippocampal removal
Rauch Epi Res Suppl 5:77, 1992
Risk to verbal memory after ATL
SRB scores in patients with R & L HS
Left ATL
N = 68
Right ATL
N = 47
Martin et.al., Arch Neurol 59:1895, 2002
Lateralized topographic & memory
deficits in temporal lobectomy patients

Left ATL (N= 13)

Spiers et al., Brain 123:2476, 2001
Right ATL (N = 17)
Comparison of IAT & fMRI in
memory lateralization
Golhy et al., Epilepsia 43:855, 2002
Memory-activated fMRI lateralizes TLE
Mean left-right asymmetry ratios
Jokeit et al, Neurology 57:1786, 2001
Memory-activated fMRI lateralizes TLE
Mean # activated voxels in controls & TLE
Jokeit et al, Neurology 57:1786, 2001
Memory-activated fMRI lateralizes TLE
Scatterplot # activated pixels L MTL vs R MTL
 RIGHT TLE
 LEFT TLE
Jokeit et al, Neurology 57:1786, 2001
Memory-activated fMRI lateralizes TLE
Representative examples L TLE & R TLE
31 yo F w/
left HS
34 yo M w/
right T/L
cavernoma
Jokeit et al, Neurology 57:1786, 2001
Follow-up on HM
• Now 76 years old
• Continues to be unable to acquire new memories
• Intelligence normal and no deficits in perception,
abstract thinking, reasoning
• Language ok: can repeat & transform sentences
with complex syntax, get the point of jokes, even
those turning on semantic ambiguity
• Social behavior appropriate & courteous
• Original 1957 paper cited 1744 times thru 2002
• Physically still in good health, except mobility
markedly reduced from osteoporosis as a
complication of chronic long-term PHT
• Brain will be examined when H.M. dies
SUMMARY
• Memory problems associated with epilepsy have been
recognized for > 150 years
• Unitary vs multiple memory systems considered; case
of HM renewed interest in multiple memory systems
• Current thinking:
– Explicit memory systems (both episodic and
semantic memory) require intact temporal lobe, and
thus are at risk in temporal lobe epilepsy.
– Implicit memory systems (perceptual representation
system, procedural memory, working memory) are
localized outside of the mesial temporal lobe, and
thus not at risk in temporal lobe epilepsy.
SUMMARY
• Many reports of memory deficits in TLE
• Suggestion of progressive deficits, but evidence is
limited
• Abundant animal data, especially from SE studies
• Memory deficits may be at least partially task-specific
• Unilateral temporal lobectomy 70% - 90% success, but
need to avoid disasters of memory impairment
• Wada test useful in lateralizing language, memory
• fMRI shows promise to replace Wada test (IAT)
• Suggestion of progressive deficits emphasize
importance of early consideration for TL, if TLE is
refractory to AEDs