epilepsy and memory david m. treiman, m.d. barrow neurological institute phoenix, arizona
TRANSCRIPT
“. . . 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
Epilepsy
A neurological disorder characterized by recurrent non-provoked epileptic seizures.
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).
Epileptic SeizureGeneric 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 & MemoryIssues 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.• 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
Corkin et al., J Neurosci 17:3964, 1977
H.M. Control
A amygdala H hippocampuscs calcarine sulcus MMN medial mammillary nucleusEC entorhinal cortex PR perirhinal cortex
Human Memory SystemsDeclarative 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 SystemsImplicit
• 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.
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 riskSummary 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
Impairment of hippocampal-dependent 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 SE-induced 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 latenciesSE at P22, testing P22-50
Rutten et al. Eur J Neurosci 16:501, 2002 * P<0.05; **P<0.01; ***P<0.001
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
Rutten et al. Eur J Neurosci 16:501, 2002
Control, P30 SE rat, P30
CA3 cell loss
Supra-granularsprouting
Correlations with task specific declarative memory (L > R)
• Hippocampal sclerosis
• Hippocampal neuronal density
• Hippocampal volume
• Hippocampal N-acetylaspartate/creatine ratios
• NAA/Cr better correlated than volume
Sawrie et al., Epilepsia 42:1403, 2002
MRI, Cr/NAA, Verbal Memory
LM% - logical memory percentage retention Cr - creatineNAA - N-acetylaspartate
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
Intracarotid Na+ AmobarbitalWada 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 Amnesia No # ofpresent amnesia surgeries
Positive 1 0 1*
Negative 0 214 214
* 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 ATLSRB scores in patients with R & L HS
Martin et.al., Arch Neurol 59:1895, 2002
Left ATL N = 68
Right ATL N = 47
Lateralized topographic & memory deficits in temporal lobectomy patients
Spiers et al., Brain 123:2476, 2001
Left ATL (N= 13)
Right ATL (N = 17)
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
Jokeit et al, Neurology 57:1786, 2001
RIGHT TLE LEFT TLE
Memory-activated fMRI lateralizes TLE Representative examples L TLE & R TLE
Jokeit et al, Neurology 57:1786, 2001
31 yo F w/left HS
34 yo M w/right T/Lcavernoma
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