DISORDERS OF MEMORY

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CHAPTER 4 DISORDERS OF MEMORY

Peter J. Nestor

DEFINITIONS AND TERMINOLOGY

Declarative and Nondeclarative Memory

In general, when patients speak of memory complaints, they are referring to the recollection of information for which there is conscious awareness. In neuropsychological terminology, this is called declarative, or explicit, memory. The corollary is nondeclarative, or implicit, memory, which refers to phenomena such as motor skill learning, priming and classical conditioning (Table 4-1). For instance, with appropriate training, a tennis player can be seen to “learn,” as evidenced by improved performance; however, in the course of a rally, the player is not consciously recollecting the motor sequence required to execute each shot. Priming refers to a situation in which prior exposure leads to altered performance and can be shown experimentally in language tasks such as naming and lexical decision making. For example, imagine being presented with words on a computer screen and being asked to read them as soon as they appear; the latency between exposure and response (reaction time) is shorter if a related, as opposed to a nonrelated, item is presented immediately before the test item (e.g., a subject will respond faster to the word tiger if it is preceded by lion rather than house). Highlighting the dissociation between declarative and nondeclarative memory is the fact that patients with Alzheimer’s disease have marked declarative deficits and yet may respond even faster with priming (hyperpriming) than control subjects. Although nondeclarative memory is crucial for many functions, it is not what patients usually mean when they report memory symptoms and is not discussed further.

TABLE 4-1 Classification of Memory Types

Nondeclarative (implicit) memory

Motor skill learning

Priming

Classical conditioning

Working memory

Declarative (explicit) memory

Episodic memory

Semantic memory

Episodic and Semantic Memory

Declarative memory is further subdivided into context-specific and non–context-specific types known as episodic and semantic memory, respectively. Episodic memories are unique in that they are recollections of an individual’s own past experiences, and therefore each is specific in time and space. In contrast, semantic memory refers to knowledge of universal facts and does not require evocation of the circumstances in which such information was acquired. Furthermore, factual knowledge is typically not learned from a single episode but rather is encountered in many contexts over time. To illustrate these definitions, an individual is retrieving semantic memories when he or she recalls that Paris is the capital of France and is home to the Louvre and Eiffel Tower. When the individual recollects specific events from his or her own visit to Paris, this virtual reconstruction of the event constitutes an episodic memory—regardless of how fragmentary the events recalled may have become. This ability to travel mentally in time is sometimes referred to as autonoetic (self-understanding) consciousness, which emphasizes the critical position of self-awareness in the recollective process. It is characteristically multimodal (e.g., visual scenes, sounds, verbal narrative).

Declarative memory is also considered in terms of encoding, storage, and retrieval. In other words, a neurophysiological change takes place during learning (encoding); this change must leave some enduring trace (storage), and there must be a mechanism by which this trace can be reactivated, at will, to lead to the subjective experience of remembering (retrieval). Often, these processes cannot be disentangled in the clinic; for instance, a patient with no recall of new information on formal neuropsychological testing may have a deficit at any or all of these stages. Nevertheless, neuropsychological tests can, to some extent, tease these stages apart by varying task demands. For example, a patient who requires an excessive number of learning trials to reach a criterion and yet retains a lot of this information after a delay can be considered as having an encoding problem. This profile is often indicative of an attention disorder rather than a true amnesic syndrome. Storage problems may be suggested by an accelerated decay in recall performance between two time points (e.g., immediately and 30 minutes after encoding). However, it is important to realize that a degree of decay is seen under normal circumstances; therefore, interpretation requires comparison with demographically matched norms. Retrieval deficits can be investigated by comparing free recall (“What did I ask you to remember?”) with recognition memory (“Which of these did I show you earlier?”). Recognition is typically tested by either forced-choice questions—in which target answers and foils (incorrect alternatives) are presented simultaneously in pairs and the patient has to choose those that he or she has seen before—or by asking for yes/no responses as targets and foils are presented in a random sequence. Because the patient is presented the previously studied material, retrieval demands are minimized, and hence a retrieval deficit is suggested where there is disproportionate impairment of free recall in comparison with recognition memory. Recognition is, however, an easier task than is free recall, and so this dissociation also needs to be assessed by comparison with control norms. It is likely that the neural systems responsible for these processes partially overlap, in that some brain areas such as the hippocampus may be necessary for all aspects, whereas other areas may be differentially engaged at a specific stage. For example, functional activation studies of changes in cerebral blood flow suggest greater engagement of the left and right prefrontal cortices during encoding and retrieval, respectively.¹

Amnesia

Amnesia is the generic term for loss of memory. An inability to establish new memories after the pathological event is called anterograde amnesia, whereas the inability to recall memories that had been established before the pathological event is called retrograde amnesia (Fig. 4-1). The fact that the distinction between anterograde and retrograde is referenced to the pathological insult is important. Students often think erroneously that retrograde amnesia refers to memory loss for past events, whereby “past” is loosely defined as any time before the clinical consultation. This leads to the absurd situation of testing for retrograde deficits by asking the patient what they did “yesterday,” which makes the distinction from anterograde deficits meaningless, as it becomes referenced to the ever-changing present. Patients with dense amnesia, especially in the acute phase, may confabulate: that is, fill in memory gaps with false statements.

Figure 4-1 Schematic representation of different profiles of amnesia.

The episodic/semantic memory distinction is inconsistently defined with regard to the term amnesia. In popular usage, the term amnesic syndrome denotes severe loss of episodic memory with preservation of working memory and general semantic memory (i.e., word meanings, object knowledge). The most sensitive marker is loss of autonoetic awareness. A patient may produce what sounds like a specific episodic memory (e.g., “When I was ten, I fell off a horse and broke my arm”) but, when asked to elaborate, is unable to do so in a manner that offers convincing evidence of mental time travel, rather than mere repetition of an overlearned statement.

The situation becomes more ambiguous with regard to factual semantic knowledge (public events, famous people), including personal semantic facts (e.g., names of schools attended, name of employers). Variable degrees of impairment in factual semantic knowledge are usual in amnesia, and this information can be objectively dated in time (in contrast to an individual’s episodic recollections, which are more difficult to date or verify). As a consequence, evidence for temporal gradients in memory impairment is typically compiled from these datable facts. For instance, a patient with a new-onset pathological process who knows that the Berlin Wall was pulled down, that apartheid ended, and that Iraq invaded Kuwait but does not remember a tsunami killing hundreds of thousands, the World Trade Center being destroyed, or Princess Diana dying has evidence for a retrograde amnesia extending back to the early to mid-1990s. It should be noted that the distinction between episodic and semantic memory—the degree of “semanticization”—becomes blurred at this point, inasmuch as some facts may be recalled from the specific context in which they were encountered—as so-called “flashbulb” memories. In addition, the frequency of exposure to particular facts varies between individuals. For example, the average American has most likely had many more encounters with stories about the World Trade Center than with stories about the Berlin Wall, and this will bias successful recollection towards the more recent, semantically reinforced event.

Working Memory

An important concept to distinguish from both episodic and semantic memory is working memory, frequently referred to by experimental psychologists as short-term memory. This refers to information that, at any given moment, is held “on-line” by the brain—that is, in consciousness—and that is not recollected after a distraction period (unless incidental episodic encoding of the material has also taken place). This faculty is exemplified by the ability to keep a telephone number in the mind in the interval between looking it up the telephone directory and dialing the number. Models of working memory posit auditory-verbal and visuospatial components that are coordinated and manipulated by a central executive system.² A highly distributed network of cortical and subcortical areas supports working memory, although the dorsolateral prefrontal cortex appears to be particularly important for the executive component. It is therefore unsurprising that working memory is most vulnerable to diffuse insults such as those found in metabolic encephalopathies and closed head injury. It can be dissociated from the long-term declarative memory systems described previously; patients with even the densest amnesia can still have intact working memory.

It is important for clinicians to understand the difference between this true short-term memory system and what patients (and many clinicians) may colloquially refer to as short-term memory. The latter, incorrect usage indicates memory for recently experienced events or exposures and therefore actually refers to recently acquired episodic memory.

NEUROBIOLOGY OF LEARNING AND MEMORY

Cellular Mechanisms

From a theoretical perspective, a neural system responsible for learning must be adaptive; in its most elementary form, a sensory event leads to an alteration in behavior at a later time. Put another way, biological events corresponding to learning must take place at the initial experience, and some outcome from these events must remain stable over time. In everyday experience, evidence for this adaptation is illustrated through the sense of familiarity experienced when a related sensory stimulus is subsequently encountered. However, in neurobiological terms, this process can be generalized to any alteration of behavior that is a consequence of a prior experience. Therefore, learning and memory in the broadest sense can encompass phenomena that are far removed from the recollection of an individual’s previous life events, such as the habituation of a blink reflex in response to a recurring visual stimulus.

The relevance of this to the neurobiology of memory is that these more fundamental phenomena—forms of nondeclarative memory—are much more accessible to direct experimentation, not least because they can be studied in organisms with much simpler nervous systems. Important insights into the neural basis of learning and memory have been gleaned from studies in organisms as diverse as invertebrates, such as the Drosophila fruit fly and the Aplysia sea slug, and mammalian species, including nonhuman primates. These models indicate that activity-dependent changes can occur in the efficacy of synaptic transmission; in other words, certain physiological stimuli can give rise to synaptic plasticity. This plasticity is often referred to as a Hebbian synapse, after Donald Hebb, who postulated in 1949 that if a given neuron is repeatedly involved in provoking a second neuron to fire, then the efficiency with which this process takes place will increase. Support for Hebb’s postulate was subsequently explored and developed in a large body of neurophysiological experimentation. The basic observation is that after a brief repetitive stimulation, the amplitude of the excitatory postsynaptic potential is enhanced, and this enhancement can be shown to persist for hours or days. This phenomenon is referred to as long-term potentiation (LTP) and is initially facilitated through modifications to existing proteins at the synapse. A further level of complexity in the dynamics of synaptic transmission is that with certain neurons and stimulation protocols, the converse process, long-term depression (LTD), may occur. Clearly, long-term memory as it is known in humans requires neural changes that persist over much longer periods. By studying very simple nervous systems such as that of Aplysia, neuroscientists have demonstrated, in behaving organisms, that synaptic plasticity in response to classical conditioning gives rise to changes in gene expression and consequently to alterations in protein synthesis.

Glutamate is the principal excitatory neurotransmitter in the central nervous system, and LTP has been demonstrated to occur through agonism of ionotropic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. LTP can be induced by agonism of NMDA receptors, whereas maintenance of LTP, including modulation of gene expression, occurs through AMPA receptors. The relevance of this to clinical practice is that perturbation of glutamate transmission has become a target for pharmacological intervention to enhance mnemonic function. It is already recognized that certain manipulations can impair function; for instance, the NMDA antagonist, ketamine, causes dose-dependent impairments in episodic memory. Another excitatory neurotransmitter implicated in some forms of LTP is acetylcholine. Loss of cholinergic neurons in the basal forebrain is a recognized feature of Alzheimer’s disease, in which memory impairment is the most salient feature. Cholinesterase inhibitor therapy for Alzheimer’s disease is now standard; unfortunately, although these agents offer some symptomatic benefit for attention deficits and behavioral disturbances, their ability to improve memory performance is, at best, modest.

These observations suggest that the transmission properties of existing synapses can be modified by usage, but it is notable that the “hard wiring” of the nervous system is also dynamic. The dendritic spines, the sites of synaptic connections in the neuronal dendritic arbor, also display plasticity over time, which suggests that the neural networks themselves may be adaptive.³ Technical developments, enabling dendritic spines to be labeled and studied in real time, have shown that changes in structure, including the generation of new dendritic spine protrusions, can be triggered by LTP-inducing activity. Conversely, some LTD-inducing stimuli have been shown to cause loss of dendritic spines. It must be acknowledged, however, that although these morphological and physiological findings suggest mechanisms by which learning and memory may be supported, the precise relevance of these specific processes to memory in vivo is far from established in the mature brain.

For further reading on these topics and other current issues in the neuroscience of memory, the excellent essays by Dudai (2002) are recommended.

The Topography of Memory

Experimental manipulations of individual synapses are also considerably removed from an understanding of what constitutes a “memory trace”; this shorthand term is often used to indicate the neural representation of an individual memory. Lesions studies indicate that several brain regions have a critical role in supporting declarative memory. Amnesia characteristically arises with lesions to limbic areas that are subsumed within the anatomical network, often referred to as either the circuit of Papez or the Delay and Brion system. This network includes the mesial temporal lobe (including hippocampus and adjacent entorhinal cortex), the fornix, the diencephalon, and the posterior cingulate region (see Fixed Memory Disorders section, Strategic Lesions subsection).

Between synaptic plasticity and the topographical anatomy of regions implicated in amnesia, the precise nature of the memory trace remains difficult to delineate. As already discussed, the information that constitutes episodic memory comprises multiple sensory modalities. The prevailing hypothesis is that structures such as the hippocampus do not “store” this information, but rather act to bind the disparate components that constitute a memory trace. To illustrate this model, consider an episodic memory of a specific conversation comprising, for simplicity, an auditory component (the dialogue) and a visual component (the scene). At the time of encoding, visual and auditory inputs contemporaneously activate a neural network in the isocortex, including auditory and visual association cortex, as well as the mesial temporal lobe. The temporospatial firing pattern that represents the memory trace can then be subsequently reactivated via the hippocampus. The traditional view (Fig. 4-2) is that with time, this neural representation gradually becomes independent of the hippocampus: so-called consolidation. This is the explanation for the Ribot effect, a temporal gradient in retrograde amnesia in which amnesia is most dense for the time immediately before the pathological insult and is progressively less dense for earlier periods. This view is almost certainly an oversimplification; many amnesic patients do not exhibit a Ribot effect but, rather, a flat profile of memory loss extending back over their whole life. Furthermore, when it is found, the temporal gradient often extends back over several decades, which suggests that consolidation is an implausible entity in evolutionary terms, inasmuch as it implies that in old age, the brain is still consolidating memories from early adult life.⁴

Figure 4-2 Schematic representation of the “classical” model of memory consolidation. At encoding, the sensory percept activates a network of isocortical neurons in concert with the hippocampus. Reactivation of this “memory trace” (corresponding to conscious retrieval of the memory) initially requires hippocampal input; however, in time, the memory trace maybe be reactivated independently of the hippocampus. Although this model can account for some features of the amnesic syndrome in some cases, there are many inconsistencies and controversies. In summary, the concept of memory consolidation remains a hotly debated subject.

Another hotly debated topic is whether the distinction between semantic and episodic memory is meaningful in biological terms. Evidence for two separable memory systems comes from the observation that individuals with episodic memory amnesia have preservation of general semantic knowledge. Furthermore, neuropsychological studies have shown that patients with hippocampal amnesia, including those with damage sustained in infancy,⁵ can acquire new semantic knowledge in spite of the amnesia. This suggests that semantic memory, including its acquisition, can be supported independently of the hippocampus. The opposing view is that the acquisition of both semantic and episodic memory is dependent on a unitary system. Evidence for this comes from the observation that although acquisition of semantic knowledge may occur in patients with hippocampal amnesia, it is not completely normal.⁶ Whereas each episodic memory is unique in time and space, semantic facts are experienced in multiple contexts. This means that there is an enormous encoding advantage for the latter, which may explain the dissociation.

In addition to the interaction of the hippocampus and isocortical sensory association areas in sustaining declarative memory, the amygdala and prefrontal cortex merit mention. The amygdala is involved in emotional processes, such as recognition of fear in other’s faces, but with regard to memory, it is thought to reinforce encoding of emotionally salient events. Clearly, people do not recollect their entire life experience as a bland, continuous narrative. The fact that some experiences are forgotten but others are remembered is related in part to their differing emotional significance, and it is thought that encoding of emotionally significant events is facilitated by an interaction of the amygdala with other mesial temporal structures.⁷ The prefrontal cortex is thought to have a “meta” role in mnemonic processing, being involved in focusing attention for encoding, forming retrieval strategies, and monitoring output.⁸ For instance, when a person is asked to produce a list of animals, performance is enhanced if the list is clustered into semantic categories (“category clustering”) such as zoo animals, farm animals, and domestic animals. The prefrontal cortex is specifically engaged in this type of processing, but not in storing the memories per se. Consequently, frontal lesions can cause deficits in free recall with relative preservation of recognition, because the latter does not require an active retrieval strategy.

ASSESSMENT OF MEMORY

Clinical Assessment

Wherever possible, a history should be obtained from a close relative of the patient to cross-reference to the patient’s account. After the clinician explains the procedure to the patient and obtains his or her consent, the informant should be seen alone, to allow frank discussion without fear of embarrassment. A common mistake in assessing patients with memory symptoms is failure to examine memory adequately. There is often insufficient time in a general clinic to test delayed recall over a long interval; however, new learning can be informally assessed by giving the patient some material to encode and then testing recall and recognition after a 5-minute distraction period filled with other elements of the examination. A seven-item name and address recall can be assessed without any special equipment; this test yields indices of encoding, recall, and recognition (Fig. 4-3). Asking the patient to copy abstract designs, followed by testing of spontaneous recall and recognition, can help assess nonverbal memory.

Figure 4-3 Bedside test of name and address recall. Scoring: Each encoding trial (T1 to T3) is scored on a 7-point scale (1 point for each item). Delayed recall (DR) is tested after five minutes. Recognition can be assessed by presenting the name and address on paper with two foils of similar structure.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(See Mathuranath PS, Nestor PJ, Berrios GE, et al: A brief cognitive test battery to differentiate Alzheimer’s disease and frontotemporal dementia. Neurology 2000; 55:1613-1620.)

Remote autobiographical memory is best evaluated in the clinic by probing for facts about the patient’s life, such as place of birth, schools attended, occupational history, residences, marriages, children, and grandchildren. This provides personal semantic facts that can be checked against the informant’s account. Remote episodic memory can be assessed by asking for specific anecdotes from different life periods (e.g., “Tell me something that happened to you at secondary school”). This, of course, raises the problem of how the veracity of these memories is confirmed, particularly as even a spouse may be unable to confirm some events. When possible, prompts to events that include the informant can circumvent this problem (e.g., “Tell me something that happened on your wedding day”; “Tell me about a family holiday when the children were young”). In pragmatic terms, false memories seldom pose a problem because the usual response with organic memory impairment is failure to produce any memory (real or otherwise). In a clinical setting, in contrast, memory impairment in confabulators is typically apparent without the use of such probes.

Semantic memory for facts can be tested by knowledge of famous people and events, but these must be tailored to the expected knowledge of the local population. For instance, in a U.K. clinic, the clinician might ask, “Who is the prime minister?” “Who was the woman prime minister?” “Which member of the Royal family died in a car accident in Paris?” “Which members of the Beatles are still alive and which are not?” and so forth. Family informants offer a ready-made, reasonably well-matched source for gauging control performance.

General semantic knowledge can be assessed by category fluency tasks (naming as many animals as possible in 1 minute), picture naming, definition (“What is a caterpillar?”), naming according to definition (“What is the large gray animal with a trunk called?”), object knowledge (asking patient to demonstrate use of a stethoscope, corkscrew, stapler, and so forth). The important detail in testing general semantic memory is to ensure that a range of low-frequency items is included; asking the patient to name a “watch” and a “pen,” as in the Mini-Mental State Examination, will only identify very advanced impairments.

Neuropsychological Assessment

The neuropsychologist also documents the patient’s history, including the demographic information necessary for test interpretation (age, education, handedness). Memory performance also needs to be interpreted in the context of general cognitive abilities; thus, the assessment is never restricted to memory alone. A vast array of tests are available that probe various aspects of memory: encoding, retrieval, and recognition; verbal and nonverbal memory; remote memory; and so on. Some of the memory tests in common usage are listed in Table 4-2. Reliable interpretation of neuropsychological performance requires that the tests be administered under standardized conditions by an appropriately trained examiner. Ad hoc incorporation of neuropsychological tests into the bedside examination is therefore best avoided.

TABLE 4-2 Selected Neuropsychological Tests of Memory

Test	Description	Reference or Source
New Learning
Rey Auditory Verbal Learning Test (RAVLT)	Word list encoding, free recall, and recognition	Rey A: L’Examen Clinique en Psychologie. Paris: Presses Universitaires de France, 1964
California Verbal Learning Test (CVLT)	Word list semantic clustering, encoding, free recall and recognition	Delis DC, Kaplan E, Kramer J, et al: California Verbal Learning Test (CVLT-II) Second Edition—Adult Version. San Antonio, TX: The Psychological Corporation, 2000
Story Recall (Logical Memory)	Story free recall ± recognition	Wechsler D: Wechsler Memory Scale—Revised. San Antonio, TX: The Psychological Corporation, 1987.
Recognition Memory Test (RMT)	Face and word recognition	Warrington, EK: Recognition Memory Test. Windsor, UK: NFER-Nelson, 1984
Doors and People Test	Verbal and nonverbal recall and recognition	Baddeley A, Emslie H, Nimmo-Smith I: Doors and people. Oxford, UK: Thames Valley Test Company, 1994
Rey-Osterrieth Complex Figure^*	Nonverbal recall ± recognition	Osterrieth PA: Le Test de Copie d’Une Figure Complex [Complex Figure Copy Test]. Arch Psychol 1944; 30:206-356.
Paired Associates Learning (PAL)	Object/spatial location recall	Cambridge Neuropsychological Test Automated Battery. Cambridge, UK: Cambridge Cognition, Ltd.
Rivermead Behavioural Memory Test (RBMT)	Various tests including some “real-life” memory tasks	Wilson BA, Cockburn J, Baddeley A: Rivermead Behavioural Memory Test (RBMT-II). Oxford, UK: Thames Valley Test Company, 2003
Remote Memory
Autobiographical Memory Interview (AMI)	Personal semantics and episodes from childhood, early adulthood, and recent past	Kopelman M, Wilson B, Baddeley A: The Autobiographical Memory Interview (AMI). Oxford, UK: Thames Valley Test Company, 1990
Galton-Crovitz cue-word test	Specific autobiographical episodes generated to word prompts	Crovitz HF, Schiffman H: Frequency of episodic memories as a function of their age. Bull Psychonom Soc 1974; 4:517-518
General Semantic Memory
Category fluency	Generation of exemplars to a target category
Boston Naming Test	Picture naming	Kaplan E, Goodglass H, Weintraub S: Boston Naming Test. Philadelphia: Lea & Febiger (Also published by Psychcorp and LWW.), 1983
Graded Naming Test	Picture naming	McKenna P, Warrington EK: The Graded Naming Test. Windsor, UK: NFER-Nelson, 1993
Pyramids and Palm Trees Test	Word and picture forced-choice associative knowledge	Howard D, Patterson K: Pyramids and Palm Trees Test. Oxford, UK: Thames Valley Test Company, 1992
Factual Semantic Memory
Variations on tests of famous people, news events, etc.^†

* See Figure 4-9

† These tests are typically used to assess the temporal extent of amnesia; however, because knowledge of such events varies greatly between communities, these tests are typically devised by individual neuropsychology laboratories.

SYNDROMES OF MEMORY DISTURBANCE

Transient Memory Disorders

Transient Global Amnesia

Transient global amnesia (TGA) is a syndrome of sudden onset, occurring in late middle or old age. An affected patient is characteristically densely amnesic and appears confused, repeatedly asking questions such as “Where am I?” or “What are we doing?” The event typically lasts for several hours, and during this time there is both anterograde and retrograde amnesia, although knowledge of personal identity is maintained. After the acute attack resolves, the patient is left with a period of amnesia for the time of the episode. The cause is uncertain, with suggested possibilities including a vascular transient ischemic attack, a seizure, or migraine. In single photon emission computed tomography images, transient perfusion defects in the mesial temporal lobe are evident during the episode,⁹ which highlights the presence of hippocampal dysfunction even if not identifying the underlying cause. Although TGA has an acute onset, it is seldom confused with more dangerous causes of acute amnesia such as viral limbic encephalitis, because the patient is otherwise alert, well and, more often than not, already in the recovery phase by the time of assessment. TGA typically occurs only once, and although cases of recurrent TGA are described, repeated episodes should alert the clinician to the possibility of transient epileptic amnesia (TEA).

Transient Epileptic Amnesia

Temporal lobe epilepsy is an increasingly recognized cause of transient memory impairment in middle-aged and elderly persons. The diagnosis is most secure when amnesic attacks are associated with a history of temporal lobe epilepsy or electroencephalographic evidence of temporal lobe discharges—which may be evident only on a during-sleep recording—and when the frequency of episodes is unequivocally improved by anticonvulsant therapy. Typical attacks of TEA differ in several ways from those of TGA, although the syndromes may be impossible to differentiate on the basis of the retrospective clinical account of an individual episode. The most useful distinguishing features of TEA are that the amnesic attacks are often briefer than those of TGA (less than 1 hour) and may occur on waking from sleep.¹⁰ In contrast to TGA, the patient may remember that he or she was unable to remember during the episode. It is not clear whether TEA results from an ictal or postictal state.

In addition to discrete attacks of TEA, some patients with temporal lobe epilepsy appear to have accelerated forgetting of new episodic memories. These patients do not have evidence of an anterograde amnesia over the half-hour period usually employed to test delayed recall during neuropsychological assessment. However, episodic memory recall over longer periods appears to be impaired.¹¹ Typically, the problem becomes apparent to the patient when the patient is discussing specific events with family members, such as the details of a particular outing, or while he or she is looking at holiday photographs. Although the family members confirm that the patient appeared normal at the time the particular event took place, the patient subsequently claims no recollection of the episode. It is speculated that subclinical temporal spike activity—particularly during sleep—may interfere with long-term consolidation of these memories.

Fixed Memory Disorders

Strategic Lesions

Mesial temporal lobe

Lesions that damage the hippocampus and adjacent areas provide the archetypal substrate for amnesia. Possibly the most famous (or notorious, depending on one’s perspective) case in 20th century neuropsychology is that of H.M., a man who underwent bilateral mesial temporal lobectomy to control intractable epilepsy in the 1950s and was found postoperatively to have profound episodic memory impairment.¹² Since H.M., numerous cases of hippocampal amnesia have been studied. Such cases typically have dense anterograde amnesia with variable retrograde amnesia. The degree of retrograde amnesia is approximately proportional to the extent of mesial temporal lobe lesions, whereas damage restricted to the cornu ammonis 1 field of the hippocampus may be associated with an almost pure anterograde amnesia.¹³

The hippocampus is particularly susceptible to anoxic damage; hence, bilateral focal hippocampal lesions are typically seen after resuscitation from cardiac arrest, carbon monoxide poisoning, and other states of hypoxemia or hypotension that cause inadequate cerebral perfusion. The blood supply of the hippocampus is predominantly via temporal branches of the posterior cerebral artery and, consequently, emboli to the vertebrobasilar system can also cause bilateral infarction. Unilateral infarcts (Fig. 4-4) from the same source tend to cause material-specific deficits; left- and right-sided lesions cause disproportionate verbal and visual memory deficits, respectively. The latter are usually evident in spatial memory tasks, although there is controversy regarding whether a lesion restricted to the right hippocampus is sufficient to cause the deficit. There is evidence to suggest that right parahippocampal damage may play a crucial role.¹⁴ Unilateral infarcts of the hippocampal head can also arise from anterior choroidal artery occlusion. Aside from vascular disease, the other major causes of focal mesial temporal lobe damage are viral and immune system–mediated limbic encephalitides (see sections on Immune System–Mediated Limbic Encephalitis and Viral Limbic Encephalitis).

Figure 4-4 Right-sided mesial temporal lobe infarct (related to atrial fibrillation) in a patient with a material-specific nonverbal memory deficit.

Fornix

The fornix is the principal projection from the mesial temporal lobe to the mamillary body and thalamus. Most reports describe a relatively pure, anterograde amnesia. Iatrogenic lesions caused by surgical division in the course of removing colloid cysts from the third ventricle,¹⁵ as well as tumors and trauma, are recognized causes.

Diencephalon

The fornix, both directly and via the mamillary body, projects to the rostral thalamic nuclei and particularly to the anterior thalamic nucleus. Lesions in this region can cause dense anterograde and retrograde amnesia. Posteromedial central branches from the posterior cerebral arteries supply the anterior nuclei, and hence infarction caused by emboli in the vertebrobasilar system can cause bilateral lesions. This bilateral vulnerability is further increased because the central artery of Percheron, which arises from one or other posterior cerebral artery, divides to supply both mesial thalami; thus, a single vessel occlusion can lead to bilateral infarction. Bilateral lesions can also result from anoxic damage (deep watershed infarcts). As with mesial temporal lesions, unilateral thalamic lesions are associated with material-specific deficits. It is difficult to prove that amnesia may be caused by focal mamillary body lesions, but this seems the most parsimonious explanation in some cases.¹⁶ Patients with diencephalic amnesia may also have a degree of executive impairment, caused by disruption of frontostriatal networks.

Basal forebrain

Cases in which lesions in the region of the septal nuclei, the diagonal band of Broca, the nucleus basalis of Meynert, the substantia innominata, and the nucleus accumbens are associated with amnesia have been described. It is speculated that this may be a consequence of damage to cholinergic projections originating in the diagonal band of Broca and projecting to the hippocampus,¹⁷ although the specific anatomical mechanism is far from certain. Although this area lies in close proximity to the diencephalon, several reports indicate that the latter may be spared in such cases. The typical pathological process is rupture of an aneurysm in the anterior communicating artery.

Retrosplenial cortex

As the name suggests, the retrosplenial cortex lies immediately adjacent to the splenium of the corpus callosum (Fig. 4-5). This cause of amnesia is rare, because focal lesions of the retrosplenial cortex are seldom encountered. Nevertheless, there have been several case reports in which amnesia was associated with damage to this area. Material-specific deficits are typical with unilateral lesions.¹⁸ Interestingly, the neural connections of the retrosplenial cortex are to the mesial temporal lobe and the dorsolateral prefrontal cortex, which place it in what is potentially a pivotal point in relation to structures involved in episodic memory processing. The usual pathological process is hemorrhage related to an underlying vascular malformation. Tumors of the splenium itself have also been reported to cause amnesia,¹⁹ and it may be that this is a consequence of retrosplenial cortex compression; however, the fornix lies subjacent to the ventrorostral surface of the splenium, so that damage to this structure may also be relevant to the genesis of the amnesic syndrome.

Figure 4-5 Lesion sites associated with amnesia in humans.

Korsakoff’s Psychosis

Korsakoff’s psychosis (or syndrome) is a severe, diencephalic amnesia caused by thiamine deficiency. It is typically seen in alcoholic patients with very poor diets, but it is important to remember that the critical factor is the dietary deficiency, rather than the alcohol. Thus, Korsakoff’s psychosis may occur in any disorder in which there is failure to maintain thiamine intake, such as gastrointestinal disorders (including gastric restriction surgery) and hyperemesis gravidarum. It usually follows from Wernicke’s encephalopathy, which consists of the classic triad of ataxia, ophthalmoplegia, and delirium, although presentation with delirium alone is common. It is therefore also referred to as Wernicke-Korsakoff syndrome. Korsakoff’s psychosis can be prevented at this encephalopathic stage by high-dose parenteral thiamine (given in combination with empirical multi–vitamin B group supplements, because multiple deficiencies may be present). Thiamine levels can be assessed by assay of erythrocyte transketolase activity, but this is seldom appropriate, because empirical therapy is straightforward and should not be delayed. Wernicke’s encephalopathy can be precipitated by glucose infusion in incipient thiamine deficiency. Of importance is that Mg²⁺ is a cofactor for thiamine activity, and patients may be resistant to thiamine therapy until concomitant magnesium deficiency is corrected.²⁰ Unfortunately, if the patient has amnesia without delirium, which suggests that Korsakoff’s psychosis has already ensued, the prognosis for recovery is very poor. Nevertheless, suspected Korsakoff’s psychosis and limbic encephalitides (see next section) represent the most urgent management problems among the memory disorders, and thiamine deficiency should always be considered in cases with acute or subacute amnesia (Table 4-3).

TABLE 4-3 Checklist of Emergency Management of Management and Investigation of Acute Amnesia

CSF, cerebrospinal fluid; EEG, electroencephalogram; FDG-PET, fluorodeoxyglucose–positron emission tomography; HSV, herpes simplex virus; HSVE, herpes simplex virus encephalitis; IV, intravenous; Mg, magnesium; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; VGKC-Ab, voltage-gated potassium channel antibodies.

Korsakoff’s psychosis typically causes a severe global amnesia. Anterograde amnesia is profound and accompanied by a severe retrograde amnesia. If the retrograde amnesia is temporally graded (worse for more recent retrograde memories) rather than complete, it usually spares only very remote memory. Typically, there is an associated dysexecutive syndrome. Neuronal loss is found in the mamillary body, the mediodorsal nucleus, and anterior thalamic nucleus; damage to the anterior thalamic nucleus appears most specific for Korsakoff’s psychosis–related amnesia.²¹

Immune System–Mediated Limbic Encephalitis

Paraneoplastic limbic encephalitis causes the subacute onset of amnesia, typically over days to weeks. Like other paraneoplastic neurological syndromes, antibodies raised in response to the tumor are thought to cross-react with neuronal epitopes. Patients typically present with memory impairment in association with confusion and, not infrequently, seizures. Because of these additional features, it is difficult to make appropriate generalizations about the type of memory deficit, but marked impairment of free recall of new information is typical. The electroencephalogram may show focal temporal lobe discharges. Magnetic resonance imaging (MRI) in the acute phase may reveal high signal in the hippocampi on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. The presence of antineuronal antibodies in serum—most commonly anti-Hu—is supportive, but a negative result should not deter a search for malignancy if suspicion is high, particularly if there is a cerebrospinal fluid (CSF) pleocytosis.²² A two-pronged management strategy offers the best chance of improvement: treatment of the acute neurological disorder and definitive management of the tumor. Anecdotal reports suggest that immunomodulatory therapy (steroids, gamma globulin, or plasmapheresis) may be helpful in some cases and should be tried. The most commonly associated malignancy is small-cell lung cancer, with gonad, breast, and non-Hodgkin lymphoma also likely possibilities. Imaging of chest, abdomen, pelvis, and breasts should be performed. Paraneoplastic phenomena are often associated with very early tumors; therefore, if these investigations yield negative results, a full-body fluorodeoxyglucose positron emission tomographic scan to look for metabolic hot spots can increase yield. Cases in which hippocampal atrophy ensues have a poor prognosis for recovery. However, some patients with hippocampi that appear preserved on MRI may recover memory, although prognosis for such recovery is unpredictable (Fig. 4-6).²³

Figure 4-6 Two cases of limbic encephalitis and underlying small cell lung cancer—one with preserved hippocampi (left) whose amnesia responded to therapy and the other with severe hippocampal destruction (right) whose amnesia persisted.

(From Bak TH, Antoun N, Balan KK, et al: Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes. J Neurol Neurosurg Psychiatry 2001; 71:40-47. Reproduced by permission from the BMJ Publishing Group.)

Nonparaneoplastic limbic encephalitis has a clinical onset and memory symptoms that may be indistinguishable from those of paraneoplastic limbic encephalitis.²⁴ Temporal lobe seizures and confusion may also occur. The key feature is the presence of voltage-gated potassium channel antibodies (VGKC-Ab) in the serum, as are found in neuromyotonia, a condition that may coexist with the limbic encephalitis. Imaging studies indicate abnormal signal in the hippocampus on MRI scanning (Fig. 4-7), whereas the CSF is usually acellular.²² Anecdotal reports suggest that immunomodulatory therapy can improve amnesia and that the VGKC-Ab titer may be correlated with disease activity.

Figure 4-7 High signal intensity (arrows) in hippocampi on coronal magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) in voltage-gated potassium channel antibodies (VGKC-Ab)–associated limbic encephalitis.

(From Vincent A, Buckley C, Schott JM, et al: Potassium channel antibody–associated encephalopathy: a potentially immunotherapy response form of limbic encephalitis. Brain 2004; 127(3):701-712. Reproduced by permission of Oxford University Press.)

Viral Limbic Encephalitis

Limbic encephalitis also occurs with herpes simplex virus encephalitis (HSVE); typically, herpes simplex virus (HSV) type 1 is the causative organism, although HSV type 2 can produce the same illness. The clinical features are similar to those of immune system–mediated limbic encephalitis, with memory impairment, confusion, and seizures, although the presentation is typically more fulminant. There is a significant mortality rate, and memory sequelae are common in survivors. HSVE is a medical emergency, in that the best chance for full recovery is with early treatment. Empirical acyclovir should be commenced in all suspected cases as first-line management (i.e., before the diagnostic workup is started; see Table 4-3). Cerebral imaging with MRI, to look for signal changes and hemorrhage in the rostral temporal lobes, often provides supportive evidence. If MRI is unavailable, computed tomography can be utilized, although it is considerably less sensitive.²⁵ Periodic temporal lobe discharges on electroencephalography also provide good supportive evidence. The CSF study shows a lymphocytic pleocytosis, but a very high erythrocyte count—suggestive of a traumatic tap—may also result from cortical hemorrhagic necrosis. Definitive diagnosis is usually established by demonstration of a positive CSF polymerase chain reaction assay for HSV.

In the acute phase, memory assessment is usually superfluous because patients are typically delirious, often requiring sedation and mechanical ventilation. Various combinations of semantic and episodic memory impairments are seen in survivors, depending on the precise location and extent of cerebral damage. Mesial temporal damage is associated with anterograde amnesia, and because the distribution of pathological process is often asymmetrical, material-specific deficits are common. Variable degrees of retrograde amnesia may occur in association with the anterograde memory deficit, and HSVE can occasionally give rise to a relatively focal retrograde amnesia.²⁶ This phenomenon appears to occur when there is disproportionate temporal isocortical damage (as opposed to hippocampal and entorhinal lesions). Temporal isocortical damage can also cause semantic memory impairments. Unlike semantic dementia (see later discussion), these are often quite patchy, giving rise to what are referred to as category-specific deficits.²⁷ Semantic knowledge can be considered in categories defined by their semantic relatedness. For instance, varieties of land animals, breeds of dogs, varieties of birds, body parts, tools, and musical instruments can all be considered as belonging to definable semantic categories and tested for accordingly. The commonest reported category-specific deficit is the dissociation of synthetic artifacts from living creatures, but various other permutations are also described. Category-specific deficits are of research interest because they offer insights into the neural structuring of semantic memory. The basic principle is that as the degree of similarity between semantic exemplars increases, so too does the overlap in the neural networks that represent the items. The attributes of an item give rise to a stable neural representation—or “attractor” in computational models—that identifies it as a specific, nameable entity. For semantically related items (e.g., land animals), these attractors share common features and thus may share common vulnerability if part of the network is damaged. See Rogers and Plaut (2002) for a detailed review of lesion evidence, computational models and proposed theories of category-specific deficits.²⁸

Progressive Memory Disorders

Alzheimer’s Disease

Alzheimer’s disease is the commonest cause of memory impairment. In established Alzheimer’s disease, the diagnosis is usually straightforward: Patients have severe impairment of episodic memory with variable degrees of impairment in other cognitive domains, including semantic and working memory. However, the insidious onset and slowly progressive nature of the impairment make early diagnosis more difficult because, in contrast to the disorders already discussed, patients do not start out with a dense amnesia. It is increasingly recognized that relatively isolated episodic memory impairment can precede full-blown dementia by several years.²⁹ Because the clinical diagnostic criteria for Alzheimer’s disease include impairment in multiple cognitive domains, early symptomatic cases that have not crossed this threshold cannot be labeled “Alzheimer’s disease” if the consensus diagnostic criteria are strictly applied.³⁰ This had led to the introduction of the term amnestic mild cognitive impairment (MCI_a) to describe isolated impairment of episodic memory.³¹ In spite of the current vogue for “diagnosing” MCI_a, it must be emphasized that this term does not denote a pathological entity but rather a degree of severity. If symptomatic Alzheimer’s disease begins with isolated episodic memory impairment, why not revise the diagnostic criteria so that MCI_a is called Alzheimer’s disease? The problem is that in the clinic, the more subtle the cognitive impairment, the less certain it is that symptoms will progress. Many patients with what appears to be isolated memory impairment may have a psychiatric illness or simply have “a bad memory” that will not worsen over time. Annual progression rates from the MCI_a stage to probable Alzheimer’s disease are usually reported to be in the vicinity of 15% per annum. However, there is considerable variability in progression rates between cohorts, which most likely relates to differences in clinical features at baseline; within the designation of MCI_a, there is scope for inclusion of cases that vary from minimal impairment to being on the cusp of a consensus classification of Alzheimer’s disease. Therefore, it is not surprising that MCI_a patients who exhibit features suggestive of Alzheimer’s disease—such as subtle non-mnestic cognitive deficits, hippocampal atrophy visible on MRI, and temporoparietal hypometabolism evident on positron emission tomography—are at highest risk of early deterioration to dementia.

The key to clinical assessment is to disentangle “sinister” memory symptoms from more benign lapses. To this end, three factors in the clinical assessment are essential. The first is always to document history from an informant who knows the patient well. Although the patient usually acknowledges memory lapses, sinister lapses are particularly evident to the informant. In contrast, patients with nonsinister memory symptoms often complain vociferously of the problem, but an informant states that the symptoms have little or no effect. The second is to note the quality of the symptoms. Attention lapses, which can be exacerbated by stress or depression, occur in the normal population and cause people to misplace their keys, forget why they just opened the refrigerator (the “fridge door” effect), miss prearranged appointments, and so on. On the other hand, forgetting an appointment or passing on a phone message but then subsequently having no clear recollection of the appointment’s being made or the conversation’s occurring in the first place is a far more ominous symptom. Likewise, getting temporarily lost in an unfamiliar place is of little significance, whereas forgetting how to get about in one’s usual neighborhood is a more serious matter. Another helpful way to examine these issues objectively is to take a detailed autobiographical history. Many patients with early Alzheimer’s disease present very well if allowed to take the lead in the consultation. However, patients can be taken out of their “comfort zone” by being asked for specific details of major life events (e.g., schools attended, full employment history, residences, marriages, birth details of children and grandchildren), and their answers can often expose major problems that would otherwise be missed. The final assessment is to examine memory formally, both in the clinic and with formal neuropsychological measures. In the early stages, patients with organic memory impairment resulting from Alzheimer’s disease exhibit good registration of new information but profound deficits in delayed free recall. Of note is that the widely used Mini-Mental State Examination contains little to expose this deficit. The only delayed-recall task is three-item word recall, which is usually conducted after a delay of only a few seconds. Intelligent patients can often hold this information in working memory; hence, a perfect score on the Mini-Mental State Examination does not exclude the possibility of a significant episodic memory deficit.

The cause of the episodic memory deficit in Alzheimer’s disease is complex. Early neurofibrillary tangle deposition (one of the hallmarks of Alzheimer’s disease) in the mesial temporal lobe suggests that memory impairment may be underpinned by damage to this area. However, although structural imaging may reveal hippocampal atrophy in many individuals (Fig. 4-8), there is considerable overlap in this feature between Alzheimer’s disease and healthy aging. Likewise, although cholinergic depletion is well recognized in Alzheimer’s disease, pathological³² and cholinergic ligand-based functional imaging studies³³ suggest that this is not a major feature of the very early stage of the disease. Positron emission tomography suggests that the deficit may result from the combined effect of a degeneration of the functional network, including the mesial temporal lobe, diencephalon, and retrosplenial/posterior cingulate cortex.³⁴

Figure 4-8 Hippocampal atrophy (arrows) in a man with mild Alzheimer’s disease (Mini-Mental State Examination score = 22/30).

Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is probably the second commonest cause of dementia in elderly persons, after Alzheimer’s disease. It is characterized by fluctuating confusion, hallucinations (typically of the formed visual type), spontaneous extrapyramidal features, and a neuropsychological profile of prominent working memory and visuoperceptual deficits.³⁵ Nevertheless, the presenting complaint is often stated to be “memory problems.” The key difference from Alzheimer’s disease is that for the degree of episodic memory impairment, there is disproportionate impairment of the aforementioned domains. The memory impairment itself is also qualitatively different from that seen in Alzheimer’s disease and, indeed, from amnesic syndromes in general. In keeping with the working memory deficit, patients have marked deficits in encoding. For instance, in three-trial learning of a seven-element name and address, many patients with very mild Alzheimer’s disease can repeat all seven elements after the first trial and, if not, performance generally improves over the subsequent trials. In contrast, DLB patients tend to have marked impairment of registration after the first trial and little or no improvement over subsequent trials. However, whereas delayed recall in early Alzheimer’s disease is markedly impaired in spite of good registration (e.g., learning trial scores are 6/7, 7/7, and 7/7; delayed-recall score is 0/7), many patients with DLB recall a large proportion of what they managed to encode (e.g., learning trial scores are 3/7, 4/7, and 4/7; delayed-recall score is 3/7).

DLB is associated with a marked cholinergic deficit and, although cholinesterase inhibitors were introduced primarily for Alzheimer’s disease, it appears from anecdotal reports and small trials that they are more useful in improving cognition in DLB.³⁶ In addition to the positive effects that these drugs have on the neuropsychiatric features of DLB, they seem particularly helpful in improving working memory and the related encoding deficit.

Frontotemporal Dementia

There are three clinical presentations of frontotemporal dementia: a neuropsychiatric syndrome, nonfluent progressive aphasia, and semantic dementia.³⁷ Of these, semantic dementia is of most interest with respect to impainment of declarative memory.³⁸ As the name suggests, these patients have progressive semantic memory impairment (factual knowledge, word meanings, and object knowledge), which gives rise to comprehension deficits and fluent aphasia. Unlike post-HSVE cases, significant category-specific deficits in semantic knowledge are rarely encountered, possibly because HSVE is more likely to result in a patchy distribution of cortical damage. In fascinating contrast to amnesic syndromes, patients with semantic dementia have relative preservation of episodic memory, as evinced by their often remarkably rich ability to recount anecdotes from the recent past. An important caveat for the neuropsychological assessment of episodic memory in semantic dementia is that the semantic knowledge deficit confounds performance on verbal memory tasks. Word-list learning or story recall is aided under normal circumstances by the ability to make semantic associations; if semantic knowledge is degraded, then word-list learning is analogous to normal subjects’ learning a list of unfamiliar foreign-language words. Nevertheless, because degeneration is usually maximal in the left temporal lobe, a degree of verbal episodic memory impairment is difficult to rule out. However, on nonverbal tests that minimize semantic associative knowledge (e.g., the Rey-Osterrieth Complex Figure Copy Test [Fig. 4-9]), delayed recall scores are often within the normal range.

Figure 4-9 Rey-Osterrieth Complex Figure Copy Test.

The remote memory profile also provides an interesting contrast to that seen in classic amnesic syndromes. Recent episodic memory (dating back weeks to months) is relatively preserved in comparison with memory from more remote time periods,³⁹ a finding that is also true of semantic facts that can be dated to a specific time period (such as knowledge of famous people and events).⁴⁰ These findings suggest that remote autobiographical memories may actually be supported by similar mechanisms to those involved in semantic memory.

The distribution of degenerative change in semantic dementia is typically asymmetrical and involves the anterior temporal lobes (especially the poles and inferior surfaces) (Fig. 4-10). The preservation of episodic memory was initially thought result from sparing of the hippocampi; however, volumetric MRI has shown that hippocampal atrophy in semantic dementia is at least as severe as that seen in Alzheimer’s disease, which suggests that the amnesia in the latter may be more a consequence of damage to other areas. A final contentious issue in semantic dementia is whether the asymmetrical atrophy of the temporal lobes can give rise to material-specific semantic memory deficits. Some authors have suggested that patients with greater right-sided atrophy have more problems with nonverbal semantics ⁴¹ (such as prosopagnosia for famous faces). The alternative view is that semantic knowledge is bilaterally distributed but naming is lateralized to the left. Consequently, verbal semantics are more impaired with greater degrees of left temporal atrophy, because this weights word-processing ability.