465 Conferences and Reviews

Amnesia in Medical Practice

Discussant JAMES A. TULSKY, MD

This discussion was selectedfrom the weekly staffconferences in the Department ofMedicine, University ofCalifornia, San Francisco. Takenfrom a transcription, it has been edited by Nathan M. Bass, MD, PhD, Associate Professor of Medicine, under the direction ofLloyd H. Smith Jr, MD, Professor ofMedicine and Associate Dean in the School of Medicine.

(Tulsky JA: in medical practice. West J Med 1993;1 59:465-473)

HOMER A. BOUSHEY, MD*: The topic chosenfor discus- peared preoccupied. His nurse feared he was having a sion in this conference involves the impairment ofmem- and called an internist who worked in a nearby of- ory, a common problem among the elderly. The disorder fice. He did not examine the patient but reassured the that James A. Tulsky, MD, will discuss differsfrom most nurse that everything was probably OK and asked that she fonns ofmemory loss in the abruptness ofits occurrence call him back if this behavior continued. and its reversibility. At the end of the day the patient left his office and went to retrieve his car at the parking garage. One of the JAMES A. TULSKY, MDt: To introduce a discussion of am- attendants found him wandering aimlessly, for he could nesic syndromes, I present an illustrative case: not recollect where he had parked. His wife drove down- Case Presentation town, helped him find his car, and took him home. By this time, he was acting normally. His personal physician ex- The patient, a 71-year-old male physician without any amined him two days later and found no abnormalities. serious medical problems, awoke one morning to a world Two years later a similar episode occurred. This time that seemed "unreal." Despite this feeling of detachment, the physician was giving a lecture to a group of internal he went to the hospital, entered the operating room, and medicine residents. He last remembers walking into the performed a scheduled vaginal hysterectomy. He com- conference room and seeing someone "with a beard." Al- pleted the procedure in 45 minutes and without complica- though he does not giving the talk, he did receive a tions. He dictated his operative report and then looked in complimentary thank you note a week later. When he ar- on several patients. Although no mishaps occurred, to this rived at the office his nurse recognized his behavior from day he has no recollection of performing the operation. two years earlier. She called his son, a medical student in The obstetrics-gynecology resident who scrubbed on psychiatry rotation at a nearby hospital, and asked him to the case noticed that something was wrong, as the sur- come to the office. "Your father's having one of his geon repeatedly announced each step of the operation. 'spells' again," she said. When the son arrived, the patient For example, he said, "Now I am taking the cardinal liga- was perplexed and asked, "What are you doing here?" ment," over and over again while doing that procedure. "I came down because your nurse called and said you This behavior was unusual, even for this man who was weren't feeling well," replied the son. well known to teach during surgery. "I feel fine," responded the patient emphatically. His office nurse also began to suspect that something Then, with an expression on his face ofjust noticing his was wrong. Every hour that morning he called her up and son, he asked, "What are you doing here?" asked when his first patient was scheduled. She patiently After this sequence was repeated several times, the told him that his first appointment was a new patient patient changed topics and asked, "Where's Mother?" scheduled at noon. Because his office hours always "She's in Israel; she'll be coming back tomorrow," started at noon, these calls seemed unnecessary and answered the son. bizarre. At 1 PM he strolled into his office an hour late, un- With an expression of shock, the physician replied, aware that anything was wrong. His nurse noticed that he "Israel? How long has she been there?" looked "detached." He saw all the patients on his roster The son informed him, "She left three weeks ago." that afternoon, but spent little time with them and ap- Exasperated, the patient declared, "Israel. She's been *Professor and Vice Chair, Department of Medicine, University of California, gone three weeks? Oh, my, something is very wrong." San Francisco (UCSF), School of Medicine. tRobert Wood Johnson Chief Medical Resident, Department of Medicine, Then, after a slight pause and again with a fresh expres- UCSF School of Medicine. sion, he asked, "Where's Mother?"

Reprint requests to James A. Tulsky, MD, Health Services Research Division, VA Medical Center, Duke University Medical Center, 501 Fulton St, Durham, NC 27705. 466 AMNESIA IN MEDICAL PRACTICE

oped the ventricular localization theory that identified ABBREVIATIONS USED IN TEXT as a specific function of the located in the CT = computed tomography fourth ventricle. This theory was illustrated in a famous MRI = magnetic resonance imaging woodcut that appeared in his encyclopedia of the sci- NMDA = N-methyl-D-aspartate ences, the Marginata Philosophica (Figure 1). Rene Descartes (1596-1650), following up on this work, placed This last exchange was repeated at least ten times. As memory in the pineal gland. In 1664 Thomas Willis hard as he tried, the son could not break the cycle. Over (1621-1675) published the Cerebri Anatome, the most the next hour and a half, however, the patient's mentation complete and accurate description of the nervous system began to clear, and he was able to remember what was to that date. In addition to describing the cranial arteries told to him. He recognized that his memory was not nor- and nerves and coining the word "," he recog- mal and repeated again and again, "God, I can't believe nized that the cerebrum was the organ of thought and that what happened." memory was located in the cortical gyri. Like most scien- tists of the time, Willis depended more on imagination Discussion This patient suffered from an episode of transient global amnesia. As would be expected from this bizarre, poorly understood, and benign disease, the patient is do- ing extremely well eight years later, having never experi- enced another episode. I have chosen to discuss transient global amnesia and the related disorders for three reasons. First, this is a surprisingly common problem that often presents to primary care physicians and yet about which little is known. Second, study of the amnesic syndromes has helped unlock the door to understanding the anatomy and pathophysiology of memory, a subject of enormous interest. And, finally, this patient was my father. Transient global amnesia is one of a group of amnesic syndromes that includes posttraumatic amnesia, drug-in- duced amnesia, Korsakoff's syndrome, and others. Al- though clinically separate and distinguishable, these vari- ous disorders share similar structural pathways. Our understanding of these diseases is a result of work in three fields: neuroanatomy, neuropsychology, and neurophysi- ology. After providing a background of the work in each of these fields, I shall discuss the individual clinical syn- dromes. Two thousand years of history passed before scientists learned that memory is formed and stored in the brain. The exploration of memory is rarely mentioned in classi- cal studies of medical history, and until this century, it Figure 1.-This woodcut by Gregor Reisch illustrates the ventric- was the purview of only a handful of neuroanatomists. ular localization theory of psychological functions. Messages from Hippocrates (circa 460-377 BC), the first great physi- the organs of hearing, sight, taste, and smell were thought to cian, never explicitly discussed memory. He did, how- unite in the sensus communis in the forepart of the front ventricle and to produce fantasy and imagination. Thought and judgment ever, understand that was a function of the brain resided in the middle ventricle. Memory is located in the poste- and that damage to one side of that organ produced paral- rior fourth ventricle (Memoritiva). ysis and convulsions on the other side of the body. Plato (427-347 BC) mentioned memory and thought it was lo- than empiricism. Nevertheless, many of his descriptions cated in the mind. Aristotle (384-322 BC) placed it in the were surprisingly accurate. heart. Galen (131-201 AD), the accepted medical author- The power of modern neuroanatomic investigation of ity for centuries, never mentioned amnesia. Given that he memory has been the ability to correlate functional attended to injured gladiators and must have been witness deficits with anatomic lesions. Two famous cases pro- to episodes of posttraumatic amnesia, this oversight is pe- vided the basis for most of the knowledge until the intro- culiar.' duction of modern x-ray imaging techniques. The first of After a long period during which few important dis- these was "HM," a 27-year-old man who in 1953 un- coveries were made, Gregor Reisch (1467-1525) devel- derwent bilateral resection of the medial temporal lobe THE WESTERN JOURNAL OF MEDICINE * OCTOBER 1993 159 * 4 467

developed and confrm the earlier findings. A study of pa- tients with permanent amnesia found substantial hip- pocampal abnormalities. A second study found patients with Korsakoff's disease to have damaged mamillary bodies and normal temporal lobes whereas patients with the characteristics of bitemporal amnesia had the opposite findings.34 Studies of monkeys have also helped to uncover the functional anatomy of the memory system.5 By using MRI imaging and stereotactic neurosurgery, monkey preparations have been created to evaluate the loss of each component of the medial temporal lobe memory system. These studies show that the , peri- rhinal cortex, and parahippocampal cortex are critically integrated and necessary for the creation of declarative memory. Contrary to previous thought, the amygdala is Figure 2.-The schematic represents the medial surface of one not part of this system and, instead, has a separate func- hemisphere, showing the structures most important to memory tion in the control of a number of other behaviors. transmission. These include the hippocampus, fornix, hippocam- pal gyrus (HG), and amygdala (A) in the temporal lobe, and the Neuropsychology of Memory dorsomedial nucleus of the thalamus (DM) and mamillary bod- ies (MB) in the diencephalon. Neuropsychology is a much younger science than neuroanatomy. Investigations in this field have led to the region in an attempt to relieve severe and intractable characterization of the different processes used to store epilepsy (Figure 2). In this operation both the amygdala and retrieve (Table 1). Neuropsychologists and hippocampus were removed. Although previous uni- have defined two major categories of memory, declara- lateral temporal lobe excisions had been successful in this tive and procedural. Memories in the first category in- disease and had not caused adverse side effects, a pro- clude facts about the world and past personal events that found amnesic state developed without any change in the must be consciously retrieved to be remembered. Proce- patient's other intellectual abilities.2 This syndrome is dural memory, on the other hand, is what we use when known as bitemporal amnesia and is seen in transient learning and retaining a skill or procedure like riding a bi- global amnesia, postencephalitic amnesia, and after elec- cycle. Declarative memory can be further divided into se- troconvulsive therapy. mantic memory, the of "eternal" facts, principles, The second case was of "NA," who became amnesic associations, and rules about the world (for example, that in 1960 after a penetrating brain injury from a miniature the United States is a democracy), and , fencing foil into the region of the left dorsomedial tha- that is, information about events occurring in a specific lamic nucleus. His syndrome has been called dien- place and time (US independence was declared in 1776). cephalic amnesia, of which Korsakoffs disease is an ex- As memory data are processed in the brain, they can ample. Extensive study of both of these patients has led to be viewed as passing through several different storage much of our understanding of amnesia. "buffers" of differing capacity and duration.' The first of Magnetic resonance imaging (MRI) techniques that these is primary memory, also sometimes called immedi- visualize the hippocampus in detail have recently been ate or short-term memory. It lasts half a minute and has a

TABLE 1.-T7he Structur and Process ofMemory categorie ofMeor Description Categiories Declaratie.The meory subse involve in learing,facts about the world and pastpersonal events that must be consciously retrieved tobe remembered Semantic...... Pertains to etemal'facts principles, associations, and rules about the world Episodic...... Pertains to events occurring in a s$pecific time and place Procedural.Th...... le memory subset involved in:learning and retaining askUl or procedure,such as riding abicycle Sbvtrutre Primary.Immediatei:d:nemory (often visl asts -about 30 scd unaffe in amnesia Secondary.Lathe:but till temra m obur astin nutes to monts dfce in mnesic syndromes Remote ...... Long-termimemory which includes most knwWge -about the world and pesnaeI elne Process Registration ...... Acquisiti onf information; corrlae with primary memory Storage ...... ty tore..a infortion overtime in an intat r. Retrieval... Abily to reteve sto inforaon the fira ste in memory recall 468 AMNESIA IN MEDICAL PRACTICE capacity of about seven items (just enough for a phone deficient in postencoding processes involved in the con- number). If one is distracted during this 30-second period solidation of memory. In the diencephalic type of antero- of , the information may be lost. grade amnesia (as in patient NA), the defect is in the Secondary memory, also known as recent or short-term initial of information, with a normal ability to memory, is the second buffer. It can last from minutes to retain information that can be acquired. These patients months and exhibits a much larger storage capacity than have tremendous difficulty learning, but once they ac- primary memory. The classic amnesic syndromes all in- quire information they retain it. An interesting current re- volve defects in secondary memory. Finally, there is re- search question is whether normal reflects only mote, or long-term, memory. Information is stored from a change in retrieval or is associated with a loss of infor- months to a lifetime in this unlimited space. This area of mation from the brain. There is considerable evidence memory includes a vast array of personal experiences and supporting both concepts, but no final conclusion has knowledge about the world. been reached. If these terms describe what might be called a neu- ropsychological "anatomy" of memory, then there is also Neurophysiology and Neurochemistry a neuropsychological "physiology" that describes the of Memory process of memory. Registration, the first step, is the en- Neuroanatomy and neuropsychology describe the coding or acquisition of information and is the "physio- structure and organization of memory, but it will be the logic" process that correlates with the primary memory molecular neurosciences that eventually explain it. Most buffer. It requires intact and a conscious effort. memory-related neurologic processes are conducted by Registration is tested by asking a person to repeat a short one of three classes of neurotransmitter: cholinergic, statement immediately after it is given. adrenergic, and neuropeptide. We know that learning and Storage, also described as retention or consolidation, memory are partially mediated by cholinergic transmis- is the ability to retain information over time in an intact sion. The cholinergic route is particularly well docu- form. This process correlates with the secondary memory mented in age-related memory loss. Anticholinergic buffer. Retrieval, also called decoding, is the ability to re- agents may cause learning and memory deficits that trieve stored information and is the final step in memory mimic those seen in Alzheimer's disease. Furthermore, recall. Like registration, retrieval requires volitional cell loss in the cholinergic-rich fibers of the nucleus processes. Patients' ability to "store" may be difficult to basalis of Meynert as well as reductions in choline acetyl- separate from their ability to retrieve. Tests of storage by- transferase activity in the septohippocampal pathway are pass the retrieval process by the use of recognition tasks found in of patients with Alzheimer's disease.8 in which the information is first given alone and then af- Yet, none of these changes are seen in patients with the ter a set period of time is given again alone or alongside amnesic syndrome. other items. We also know that disrupting the catecholaminergic What is known about neuropsychology and neuro- systems disrupts memory storage, whereas agonists pro- anatomy has been integrated into a "road map" for the duce dose-dependent facilitation. Administering adrener- various components of memory. Primary memory is gic stimulants does not improve memory in elderly per- thought to be located in the perisylvian cortex or the retic- sons, and the catecholamine systems are probably not ular activating system. Secondary memory, as discussed associated with age-related memory loss. Adrenergic de- earlier, is divided between the medial temporal lobes and pletion is probably involved in the memory loss of Kor- diencephalon, whereas remote memory (the bulk of our sakoff's syndrome, and, as mentioned later, repletion may permanent memories) is stored in the cerebral cortex. Fi- help. nally, (as distinct from declarative The hypothalamic and pituitary neuropeptides may memory) is thought to reside in the .7 also be involved in learning, and clinically it has been With this background, it is possible to explore amne- shown that elderly patients given vasopressin do better on sia, the loss of memories. is the in- tests of attention, concentration, and memory than those ability to remember events that occurred in the premorbid given placebo. This improvement may be due to in- period. This may include information located in either creased motivation rather than enhanced memory. secondary or remote memory. This memory loss is typi- The most interesting hypothesis of memory creation is cally temporally graded, which means that there is a that memories are consolidated in the brain by a unique greater loss of more recent events and a better memory process called long-term potentiation.9 Impulses are car- for more distant events. In contrast, ried across neural synapses by calcium ions that flow is the inability to learn new material, a defect of sec- through membrane channels regulated by postsynaptic N- ondary memory. Primary memory and registration are un- methyl-D-aspartate (NMDA) and non-NMDA receptors. affected. Anterograde amnesia is the most pronounced The non-NMDA receptors are open to calcium influx af- and classic finding in the amnesic syndrome. In its bitem- ter normal, constant amplitude stimulation and mediate poral form (such as in patient HM), the problem is char- the usual transient depolarizations. In contrast, NMDA acterized by an abnormally rapid rate of forgetting. Pa- receptors exhibit a magnesium-mediated, voltage-depen- tients with this problem can learn briefly, but quickly dent blockade that is only overcome by high-frequency forget whatever it is they were taught. They are probably tetanic stimulation. Once opened, the NMDA-receptor THE WESTERN JOURNAL OF MEDICINE * OCTOBER 1993 159 * 4 469

ion channels remain open for a long period, and the den- amnesia is similar to the experience in transient global dritic ultrastructure actually changes in response. There- amnesia, as explained later. Because of retrograde amne- after, even after low-level stimulation, the magnitude of sia, the events that led up to a head injury cannot usually the postsynaptic response is increased, which accounts be recalled. Highly overleamed personal and demograph- for "learning." Whether amnesia is due to neuron failure, ic information is generally not lost, however. The retro- chemical failure, or an interruption of this circuit is not grade amnesia is temporally graded, and it is rare for the clear. period of retrograde amnesia to exceed the period of an- terograde amnesia. In addition, older patients take longer Amnesic Syndromes to recover from posttraumatic amnesia. There is a direct correlation between the severity of Clinically, amnesia is a loss of memory in the pres- head trauma and the duration of posttraumatic amnesia. ence of a clear sensorium. Generally only secondary In one study, none of the 239 patients who were con- memory is affected, and primary and remote memory should remain intact. The patient's other intellectual scious when admitted to the hospital had amnesia for more than a day, and in 80% posttraumatic amnesia lasted processes should also be normal. The amnesic disorders, less than an hour.'0 A large Glasgow collaborative head which include a variety of acute and chronic illnesses, all share this presentation. injury study demonstrated the same finding in more than 1,000 patients." Coma of less than a day led to Because the defect is in declarative and not procedural amnesia of more than a month in less than 20% of memory, an interesting feature common to most amnesic survivors, whereas after one to two weeks of coma, more than 62% patients is an ability to acquire new skills but an inability had amnesia for more than a month. In addition, a rela- to recall having previously engaged in the task. For exam- tionship exists between the duration of posttraumatic am- ple, an amnesic patient may be taught to solve the Tower of Hanoi puzzle, which involves moving five rings of dif- nesia and the subsequent cognitive outcome. Those with longer periods of amnesia have more permanent cogni- ferent sizes between three pegs without ever placing a tive deficits.12 larger ring on top of a smaller one. After learning the task, these patients will repeatedly solve the puzzle perfectly Closed-head injuries cause damage in three ways. Coup contre coup injury inflicts damage at the site of im- but deny ever having seen it before. Table 2 summarizes pact and directly opposite. The frontal and temporal lobes the key features of the major amnesic syndromes seen in clinical practice. are injured by brain movement against the sharp sphenoid ridge and the rough middle fossa floor. Finally, vortex- type injuries occur in which rotary forces their Acute Global spread shock waves down the brain stem.'3 Acceleration-decel- Posttraumatic amnesia. Perhaps the most common eration closed-head injuries are most likely to result in form of acute global amnesia is that which occurs after memory loss. Contusions are typically found on the un- closed-head injuries. After recovery from traumatic un- dersurface of the temporal lobe and probably interfere consciousness, the last recognizable function to return is with limbic structures. Shearing forces cause diffuse ongoing memory. damage to neural tissue, affecting particularly the white Posttraumatic amnesia is characterized by both an- matter. terograde and retrograde memory loss. The anterograde Transient global amnesia. Transient global amnesia

TABLE 2.-The Major Amnesk Syndromes Syndrme Prentation Etiology Prgnosis Posttraumatic amnesia. Acute, after closed-head injLuy; de- Shearng forces of injury cause Varable; in patients without pro- gree correlates with severity of in- damage to lmbic neural tssue longed unconsciousness, usually jury; both anterograde and retro- lasts less than an hour, after coma amnesia of grade less than 24 hours, usuallyI lasts less tan a month Transient global amnesia...... Acute, often a precipitating event Unknown; probably due to bilat- Excellent; neady always resolves such as sex or cold water expo- eral temporal lobe from within 24 hours; few recurrent sure; amnesia primarily antero- arterial spasm, atherosclerosis, or episodes and no notable long- grade with temporally graded ret- both te-rm sequelae rograde; repetitive queries are characteristic feature Drug-nduced amnesia ...... Acute onset up to 24 hours after Usually mediated by drugs that Excellent resolves spontaneously ingestion ofdrug (usually benzodi- depress limbic neural activity; azepine); otherwise similar t( tran- bitemporal pattemof amnesia sient global type Korsakoffs syndrome...... Chronic; sometimes preceded by Thiamine deficiency in the pres- Poor; fewer than 15% of,patients Wemicke's encephalopathy; usu- ence of alcoholism; characterized ever improve; thiamine supple- ally disoriented to aqe and place anatomicall by destruction of ments may help in early diagnosed but not name; is mamillarybodiesandpunctatle- cases; adrenergic a9onists and charactersic; may have affective sions oF 3rd and 4th ventrcles; serotonergic antagoists available and psychotic features frontal lobe ma be involved as exeietalthrp 470 AMNESIA IN MEDICAL PRACTICE was first introduced as a unique disorder in 1958, and in sistent with seizure in patients with this disorder, except 1964 Fisher and Adams published a major monograph on in those with known seizure disorders. Although tempo- the topic.'4 Over the years more than 500 cases have been ral lobe epilepsy may likely present in a form similar to reported. transient global amnesia, it is not the explanation in most This disease is more common than generally thought. patients. A Mayo Clinic study estimated the incidence as 5.2 per Ischemia as a cause of this form of amnesia is a much 100,000 people among the general population in the more appealing hypothesis. The precipitating events of Rochester, Minnesota, area.'5 In people aged 50 years and cold water dip or sexual climax can be explained as older the incidence was 23.5 per 100,000. A second episodes of excess sympathetic activity or hyperventila- prospective one-year cohort study from Finland found an tion causing reduced cerebral blood flow to a stenotic annual incidence of 10 per 100,000 in the general popu- vessel in an area affecting secondary memory. lation and 32 per 100,000 in patients older than 50.16 In In support of this explanation, we learn that as many this group there was a 3:1 female-to-male predominance. as 70% of patients in some studies of the disorder have The average age is 58, and the disease is uncommon in thrombotic risk factors.20 In a retrospective study of 42 younger patients. Although the recurrence rate is 10% to patients with this disorder who underwent head computed 20%, patients rarely have more than three episodes. tomographic (CT) scans, 4 had lesions consistent with an Transient global amnesia is characterized by a severe, acute stroke-2 in the medial part of the temporal lobe, 1 isolated anterograde amnesia of acute onset, without in the left thalamus, and 1 in the left lentiform nucleus.2' other neurologic deficits. A variable period of retrograde This is a higher prevalence than would be expected in the amnesia occurs that initially encompasses a period of general population. Furthermore, in a case-control study days, months, or years before the attack but gradually of 18 patients with transient global amnesia, a history of shrinks after the attack, leaving permanent amnesia only transient ischemic attacks or completed stroke was the for the events during the episode itself. Despite this tem- most significant association with amnesia.22 A corner- porally graded retrograde amnesia, remote memory ap- stone of evidence is missing, however. In virtually all pears to be preserved. The patients find the presence of large series there is no increased risk for a cerebrovascu- amnesia to be extremely upsetting, and their behavior lar accident after transient global amnesia."'2023 " If the during the episode is usually marked by repetitive disorder was, indeed, a transient ischemic attack, excess queries, as in the case of my father. morbidity would be expected in these patients on follow- Attacks of transient global amnesia last 20 minutes to up, whereas none is found. several hours and nearly always resolve within 24 hours. This leaves as the most satisfactory explana- Nevertheless, subclinical memory deficits may persist for tion for the occurrence of transient global amnesia. The days to months. In a study of 41 patients followed up at mechanism of transient ischemia is still invoked, but on six months and compared with a group of controls there the basis of spasm rather than stenosis. In a large case- was a small but notable deficit present in control study of 114 cases of transient amnesia compared those who had this disorder, suggesting mild permanent with both normal persons and controls with transient is- left-sided hippocampal-diencephalic dysfunction.'7 chemia, Hodges and Wallace found no increased risk of Many of the affected patients mention a putative incit- amnesia in patients with cardiovascular risk factors. Mi- ing event. Common themes include a cold shower or dip graine, however, was more common in patients with tran- in the sea, sexual intercourse, an excited emotional state, sient amnesia than in the control subjects.4 In fact, all se- and pain. In one study that actually looked at this prop- ries include a high rate of migraineurs, and many patients erty, 26 of 85 spells were precipitated by an event of this report a headache in combination with the amnesia.25 type.'8 Cerebral blood flow studies further support this hypothe- Three major explanations have been proposed for the sis by showing an impaired vasomotor response charac- cause of transient global amnesia, all supported, at best, teristic of migraine.26 There are even reports of identical by circumstantial evidence. The weakest of these views twins who suffer from both migraine and transient global the disorder as a seizure. A second popular explanation amnesia. 27 Perhaps the most convincing evidence is the attributes it to cerebral ischemia, calling it a transient is- overwhelmingly benign prognosis of patients with tran- chemic attack of the medial temporal lobes. Finally, a sient amnesia. These patients are not at increased risk for new and intriguing proposal is that transient global amne- subsequent stroke or transient ischemia and have no sia is a form of migralne. added mortality compared with unaffected controls. Al- Epilepsy as a cause of this disorder is initially appeal- though classic migraine headache is associated with an ing for several reasons. The episodes are bizarre, bear a increased risk of stroke, common migraine is not.28 Even resemblance to partial complex seizures, and involve the if transient global amnesia is a form of migraine, it is not temporal lobes. In addition, a few patients have been re- a classic migraine and should not be expected to share the ported to have epilepsy after an episode of transient same prognosis. global amnesia, and one young female patient with re- This is not to suggest that migraine is the sole cause of peated episodes of amnesia improved after treatment with the disorder. Atherosclerosis may play a role if amnesia is carbamazepine was started.'9 Most studies, however, have a result of arterial spasm in a region of relative stenosis. failed to find electroencephalographic abnormalities con- Because the incidence of atherosclerosis increases with THE WESTERN JOURNAL OF MEDICINE * OCTOBER 1993 1159 * 4 471

age, this mechanism could account for the increased risk ness, or as the classic syndrome of acute encephalopathy of the disorder among elderly people. followed by a chronic amnesic state. I shall discuss only The prognosis for patients with transient amnesia is the chronic illness. excellent. These patients should be allowed to lead nor- The disease is fairly common among persons with al- mal lives, and there is no reason to restrict their driving or coholism, and as many as 10% of patients with alco- other activities.2' The diagnosis can usually be made with holism and debilitating mental disease may have Kor- a thorough history and physical examination, and expen- sakoff's.m The mean age of onset is 55, and although the sive tests, such as CT or MRI scans, electroencephalo- disease afflicts the sexes equally, women are probably grams, and angiograms are rarely needed. Patients with more vulnerable but have less exposure to the causal new neurologic findings or histories that are not consis- agent. Patients with Korsakoff s syndrome are alert and tent with the amnesic syndrome form the only exception responsive with a normal intellectual capacity but demon- to this rule and deserve further workup. In Hodges and strate a profound amnesia. In addition to the expected loss Warlow's initial series of 153 patients with transient am- of secondary memory, they have an extensive impairment nesia, only 114 fulfilled the criteria for transient global of remote memory. In the past, this was thought to be due amnesia. Those patients who did not fulfill the criteria to an anterograde learning deficit that begins 10 to 20 had a substantially worse prognosis, usually due to cere- years earlier and leads to a progressive deficit in the en- bral ischemia.30 coding of new memories. A good deal of evidence now Drug-induced amnesia. Benzodiazepines are the drugs supports two defects in these patients: one in retrograde that most commonly cause the amnesic syndrome.3' Al- memory and a second in anterograde memory.35 though triazolam (Halcion) is best known for this adverse Patients are generally not oriented to age and place, effect, midazolam hydrochloride, diazepam, and loraz- but they do remember their name. They also tend to con- epam have all been reported to produce an identical syn- fabulate, a phenomenon sometimes seen with frontal le- drome. Patients typically present after taking a transoce- sions and dementia but not in transient global amnesia. anic flight during which they drank some alcohol and Impaired attention and mood disorders may also be a took a benzodiazepine to help them sleep on the plane. problem, accounting for the term "Korsakoff s psy- They wake up in a foreign city with the worst jet lag in chosis." In the acute stage, they may act euphoric, but ap- their lives and no idea where they are and how they got athy dominates the chronic phase. Hallucinations and there. The drug produces a severe but short-lived antero- delusions occur in as many as 20% of patients. Although grade amnesia.32 neurologic signs are more characteristic of Wernicke's Several other drugs can also cause the syndrome, in- encephalopathy, nystagmus, peripheral neuropathy, and cluding chloroquine, clioquinol, and alcohol. A recent re- ataxia may persist through the chronic stage. port describes that scopolamine hydrobromide, which Korsakoff s disease is not the same as alcoholic de- causes a transient state of anterograde amnesia and sub- mentia. In the latter disease there is an insidious occur- missive behavior, is administered in Colombia, South rence of personality changes, abnormality of mood, and America, for criminal purposes.33 deterioration of all intellectual functions. There is no se- These drugs probably cause problems in the encoding lective impairment of either intelligence or memory, and of memories by depressing the limbic neural activity. We thus the two diseases can be differentiated by neuropsy- know that the use of benzodiazepines decreases repetitive chological testing. neural firing (which is how they stop seizures), and for The prognosis of Korsakoff's syndrome is poor. Wer- this to cause a defect in memory is consistent with the nicke's encephalopathy may improve over the first two long-term potentiation explanation mentioned earlier. In months, but established Korsakoff's syndrome is nearly addition, the action ofbenzodiazepines may mimic that of always irreversible. In the most optimistic series, about -y-aminobutyric acid, which inhibits an excitatory loop in 15% of patients improve over time. the hippocampus. The disease is characterized by small, punctate, sym- metrical brain lesions along the walls and floor of the Chronic Global Amnesias third and fourth ventricles and in the cerebellum and cere- Korsakoff's syndrome. Korsakoffs syndrome, first de- bral cortex. In most cases, the mamillary bodies are obvi- scribed in 1889, is the most important and best under- ously involved. The frontal lobes are also usually in- stood of the chronic global amnesias. Because it is often volved, but some of this damage may be due to direct referred to as the Wernicke-Korsakoff syndrome, it is alcoholic neurotoxicity.A6 worth clearing up the confusion created by this eponym. Although thiamine deficiency is known to cause Kor- Wernicke's encephalopathy is the acute syndrome of thi- sakoff's syndrome, the exact mechanism of injury and its amine deficiency characterized by mental status changes, selectivity are unclear. A genetic defect in the metabolism ophthalmoplegia, and ataxia. Korsakoff s syndrome is a of thiamine may be carried by some persons-perhaps chronic alcoholic amnesic disorder, also due to thiamine preferentially expressed in women-that under normal deficiency, marked by a short- and long-term memory circumstances does not result in any functional deficit. impairment in the absence of clouding of consciousness. Only long-term drinkers are affected when they become The disease can present either as Wernicke's without thiamine deficient because of the added reductive stress Korsakoff's, as Korsakoff's with no previous acute ill- incurred with alcohol consumption. 472 AMNESIA IN MEDICAL PRACTICE

The treatment of choice is to administer thiamine as whelming. Although patients forget their personal iden- early as possible in the disease. By the time Korsakoff's tity, it is unusual for them to assume a new one. They may is diagnosed it is usually too late for thiamine supplemen- remain like this for an indeterminate period until, typi- tation to make any difference; nevertheless, it is common cally, their memory returns spontaneously after someone practice to try a three-day course.3 Clonidine hydrochlo- provides a key to the past or until they reach a point ride, a catecholamine agonist, and methysergide maleate, where they feel psychologically safe. Compared with pa- a serotonin antagonist, have been given in small trials tients with the organic amnesic syndromes, these patients with limited success, but their use is still experimental.37 have total "retrograde amnesia" but intact ongoing mem- Other illnesses. Other diseases may rarely result in a ory. If interviewed after the administration of amobarbi- chronic amnesic syndrome. Herpes encephalitis, caused tal (Amytal) or under hypnosis, old memories can often by a virus with a predilection for the limbic system, be elicited. results in a pure amnesic syndrome similar to that ex- Fugue states have been described as a "tendency to perienced by patient HM.38 Other viral encephalitides, in- avoid the awakening of emotional pain through mem- cluding Epstein-Barr virus encephalitis, have also been ory."42 Fisher studied a number of soldiers in World War II reported to cause this deficit.39 who were found wandering unprotected through the Electroconvulsive therapy is an iatrogenic cause of battlefields, having simply arisen mindlessly from their bitemporal amnesia. Although the memory loss was far posts after forgetting who and where they were.43 Through more profound in the early days of this treatment when hypnosis he found that just before losing memory, they bipolar electrodes with high voltages were used, transient had felt powerless and out of control. The fugue state was and sometimes long-term amnesia is still one of its major a psychological escape from an unbearable situation. As side effects.40 a Freudian therapist, he interpreted the amnesia as a Patients with cardiorespiratory insults resulting in method of deceiving the superego by concealing the ego cerebral hypoxia are also commonly amnesic. As with identity, thus preventing depression, despair, and suicidal trauma, memory is usually the last major cognitive func- thoughts." Although this is generally a psychological tion to return after a cerebral hypoxic injury.41 The ante- phenomenon, there is some sort of fugue state in as many rior thalamus and the hippocampus are the areas most as 78% of patients with , usually consistently damaged after such injury, and the choliner- occurring in the postictal period. Therefore, temporal lobe gic system is particularly vulnerable to hypoxia. Acetyl- epilepsy needs to be considered in the differential diagno- choline synthesis may be impaired under even relatively sis of fugue states. mild hypoxic conditions. Multiple personality is the most extreme form of dis- An "amnesic stroke" may occur from bilateral thala- sociative disorder. Patients assume a number of different mic infarction or posterior cerebral artery occlusion re- personalities, whereas amnesia is often experienced by sulting in hippocampal damage, yet isolated amnesia due the parent personality. It is usually a result of severe and to a cerebrovascular accident is rare. Other extremely un- repetitive childhood trauma.45 usual but reported causes of the amnesic syndrome in- clude recurrent hypoglycemia, brain tumor, poly- Diagnosing Amnesia cythemia, and even myxomatous degeneration of the The amnesic disorders are diagnosed by a good his- mitral valve. tory and physical examination. Because a patient's mem- Finally, amnesia is often a component of progressive ory deficit may be far worse than is apparent on cursory neurologic diseases. Although usually accompanied by review, a complete mental status examination is requisite. other notable cognitive findings, amnesia may be the For the memory tests to have validity, a patient must be dominant presentation in such illnesses as multiple scle- able to pay attention. It is particularly important to corre- rosis, Parkinson's disease, and Huntington's chorea. Of late the questions asked with specific memory processes. course, it is also often the presenting feature of Primary memory is tested by the digit span or the "A" Alzheimer's and Pick's diseases.6 test. In the digit span test, the patient is asked to immedi- ately repeat back a sequence of six or seven numbers. In the "A" test, the examiner recites a list of letters and asks Most of the sensational episodes of amnesia portrayed the patient to tap on the table every time the letter "A" is in literature and film are actually cases of psychogenic heard. Secondary memory is tested by asking the patient amnesia. Also known as dissociative states, these to recall three unrelated words or objects after a two- to episodes are not amnesic syndromes in the classic sense five-minute break. Finally, asking patients about general but deserve discussion because of their frequent confu- topics, such as a list of the most recent presidents, or sion with the organic illnesses. about their own personal history tests remote memory. Of The most common presentation of psychogenic amne- course, far more advanced psychological tests are avail- sia is the fugue state, a subclass of dissociative illness also able, but the few tests just mentioned, in the context of a known as poriomania, dromomania, and periodic wander- well-described history, should lead to a diagnosis in most ing. In this condition patients suddenly become totally cases. amnesic of their past, an occurrence usually preceded by In conclusion, when evaluating amnesia in a patient, an intense emotional experience that they find over- it is most important to first determine whether the mem- THE WESTERN JOURNAL OF MEDICINE * OCTOBER 1993 * 159 * 4 473

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