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Neurocase The Neural Basis of Cognition ISSN: 1355-4794 (Print) 1465-3656 (Online) Journal homepage: <a href=http://www.tandfonline.com/loi/nncs20 Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure? Gerald H. Burgess & Bhanu Chadalavada To cite this article: Gerald H. Burgess & Bhanu Chadalavada (2015): Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?, Neurocase, DOI: 10.1080/13554794.2015.1046885 To link to this article: http://dx.doi.org/10.1080/13554794.2015.1046885 Published online: 15 May 2015. Submit your article to this journal Article views: 7501 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=nncs20 Download by: [University of Bristol] Date: 20 October 2015, At: 07:50 " id="pdf-obj-0-2" src="pdf-obj-0-2.jpg">

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The Neural Basis of Cognition

Neurocase The Neural Basis of Cognition ISSN: 1355-4794 (Print) 1465-3656 (Online) Journal homepage: <a href=http://www.tandfonline.com/loi/nncs20 Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure? Gerald H. Burgess & Bhanu Chadalavada To cite this article: Gerald H. Burgess & Bhanu Chadalavada (2015): Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?, Neurocase, DOI: 10.1080/13554794.2015.1046885 To link to this article: http://dx.doi.org/10.1080/13554794.2015.1046885 Published online: 15 May 2015. Submit your article to this journal Article views: 7501 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=nncs20 Download by: [University of Bristol] Date: 20 October 2015, At: 07:50 " id="pdf-obj-0-8" src="pdf-obj-0-8.jpg">

ISSN: 1355-4794 (Print) 1465-3656 (Online) Journal homepage: http://www.tandfonline.com/loi/nncs20

Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?

Gerald H. Burgess & Bhanu Chadalavada

To cite this article: Gerald H. Burgess & Bhanu Chadalavada (2015): Profound anterograde amnesia following routine anesthetic and dental procedure: a new classification of amnesia characterized by intermediate-to-late-stage consolidation failure?, Neurocase, DOI:

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Downloaded by [University of Bristol] at 07:50 20 October 2015 Neurocase , 2015 http://dx.doi.org/10.1080/13554794.2015.1046885 Profound anterograde

Profound anterograde amnesia following routine anesthetic and dental procedure: a new classication of amnesia characterized by intermediate-to-late-stage consolidation failure?

Gerald H. Burgess a * and Bhanu Chadalavada b

a Department of Clinical Psychology, University of Leicester, Leicester, UK; b Consultant Psychiatrist, Northamptonshire Healthcare Foundation NHS Trust, Northampton, UK

(Received 12 December 2014; accepted 27 April 2015)

Anterograde amnesia caused by bilateral hippocampal or diencephalon damage manifests in characteristic symptoms of preserved intellect and implicit learning, and short span of awareness with complete and rapid forgetting of episodic material. A new case, WO, 38-year-old male with anterograde amnesia, in the absence of structural brain changes or psychological explanation is presented, along with four comparison cases from the extant literature that share commonalities between them including preserved intellect, span of awareness greater than working memory, and complete forgetting within hours or days following successful learning, including notably for both explicit and implicit material. WOs amnesia onset coincided with anesthetic injection and root canal procedure, with extended vasovagal-like incident. The commonalities between the ve cases presented may suggest a shared biological mechanism involving the breakdown of intermediate-to- late-stage consolidation that does not depend on the structural integrity of the hippocampi. Speculation on the mechanism of consolidation breakdown and diagnostic implications are discussed.

Keywords: anterograde amnesia; memory; neuropsychological assessment; consolidation; accelerated long-term forgetting

Milner s (Scoville & Milner, 1957) detailed assessments of Henry Molaison ushered in the modern understanding of the basis of human memory functioning. Her ndings, which documented the characteristic symptoms of medial temporal lobe (MTL) amnesia, have been replicated time and again in numerous subsequent case studies. A review of 147 cases of restricted bilateral hippocampal (or fornix) lesions found in common a selected profound anterograde amnesia and span of awareness for unfolding events that did not far exceed that of working memory (i.e., seconds to minutes), in the context of preserved intellect, everyday executive ability, and working memory (Spiers, Maguire, & Burgess, 2001). Notably, implicit learning is commonly intact in these cases, evident in the capacity to learn and then retain new motor procedures or skills, and via demon- stration of priming effects in ofce-based testing. Amongst these 147 cases were also inconsistencies (Spiers et al., 2001). For example, there was marked variability in the presence and extent of retrograde amne- sia, a phenomenon of forgetting ones past, thought to be caused by a ceased and thus permanently incomplete con- solidation process, or due to blocked access or retrieval of stored information. When retrograde amnesia occurs in the context of neurological damage, it manifests as temporally graded, meaning more distant, well-consolidated mem- ories are generally remembered and those nearer to the point of neurological onset are not. Vast individual vari- ably amongst the cases in duration of retrograde amnesia

*Corresponding author. Email: gb222@le.ac.uk

© 2015 Taylor & Francis

from moments before neurological onset, to encompassing ones entire lifetime, were reported. Memory is formed via a bottleneck(Markowitsch, 1996) complex that incorporates multiple inter-connected structures within and between the MTL, fornix, and the diencephalon. Damage to any of these areas bilaterally causes the manifest symptoms of organic amnesia, though damage to diencephalon structures tend to be additionally characterized by marked and extended autobiographical retrograde amnesia, severe temporal order confusion, and confabulation (Gold & Squire, 2006; Kopelman, 2002). The amygdaloid complex plays an auxiliary yet vital role in new memory formation due to its extensive neural net- works and role in taggingthe emotional valence and personal or biological signicance of information (Christianson, 1992; McGaugh, 2004). MTL and dience- phalon amnesias are categorized as organic amnesia due to their distinctive and relatively consistent features, and traceable path to damaged brain structures known to be involved in the formation of new memories. Much less clear and much less clearly dened are amnesias of the so-called psychogenic or functional type (De Renzi, Lucchelli, Muggia, & Spinnler, 1997), which by denition occur in the absence of structural brain changes, the former usually associated with psychiatric co-morbidity or feigning, and the latter dened by uncer- tainty of physiological or psychological, and in any case unknown, cause. Dissociative amnesia,on the other

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G.H. Burgess and B. Chadalavada

hand, is a classiable diagnosis with set criteria (Spiegel et al., 2011), established in part due to the existence of a critical mass of known cases with shared characteristics, and transparent linkage to established psychological the- ories (e.g., psychological defense mechanisms). Dissociative amnesia is associated with severe acute psy- chological stress or trauma, which manifests as sections of ones past and/or identity being made inaccessible to the conscious awareness of the individual, whilst new episodic learning ability tends to remain relatively intact. Anterograde amnesia in the absence of structural brain damage is rare, or at least rarely reported. There are four known cases, documented separately (De Renzi & Lucchelli, 1993; Kessler et al., 1997; Markowitsch, Kessler, Kalbe, & Herholz, 1999; Smith et al., 2010), which as yet have not been compared and contrasted to each other and that is what we endeavor to do in this article. Additionally, we present a fth, original case report, WO with an unexplained profound anterograde amnesia that has persisted indenitely, and which directly followed a medical emergency in a dentists ofce invol- ving anesthetic injection and root canal procedure in March 2005. Our aim is to compare all ve cases, and investigate whether preliminary conclusions and consistent features may be derived about these cases as a group, we hope for the sake of initiating a process toward establish- ing a more precise and specic diagnostic category, under- standing of the mechanism of consolidation failure, and importantly treatment options.

Case report

WO is a left-handed, male, UK National who was 38-years-old at the time of the dental procedure that pre- ceded the onset of his amnesia, married with two children, and ranked in the military, stationed abroad. Developmentally, he was of normal birth, met milestones appropriately, and was an average student. Previously t and healthy, he joined the army at age 17, is a Gulf War I veteran, and married at age 22 his wife to whom he is still married. Signicant medical history includes a coccyx injury in 1989 with minor but persistent complications, and he presented to his general practitioner (GP) in February 2005 with increased back pain. He had a history of hyper- tension, but which was reportedly normal at the time of the dental appointment. Once in his early thirties following alcohol consumption, WO became unrousable for an hour during a hypnotism stage show, and he did not fully regain a normal level of conscious awareness until the next day. WO had no previous psychiatric history or mood dis- turbance, and was in good standing in the military and in his role as a husband and father. There is no history of mental illness in his family. His grandfather had Lewy bodiesdementia and died of complications several days

before the incident-in-question, to which WO and his family ew back to the UK for his funeral, then back abroad. WOs grandmother had angina, and his mother developed type II diabetes, and later suffered a stroke.

Incident description and aftermath

WO attended a routine dental appointment for root canal treatment at 13:40 hours. He was injected with the anes- thetic, Citanest with Octapressin 3% just prior to the beginning of treatment. He wore tinted dental glasses, obscuring a view to his level of responsiveness. The procedure was completed at 14:30 hours, and at this time it became apparent that WO was pale and faint, and could not get himself up when re-positioned from the supine to the upright position. Records and observations indicated that he was vacantand with slow speech.A vasovagal incident was suspected, and WO was provided with dex- trose tablets and high-ow oxygen. By 17:00 hours his condition had not improved, and he was taken by ambu- lance to emergency, in which he remained an inpatient for 3 days. Whilst an inpatient, and for the succeeding month, WO exhibited only a 10-min span of awareness for events, after which he had no memory. This improved to an approximately 90-min span of awareness, where it has remained to date. There are no observable or reported physical/mobility impairments. He reportedly experiences constant tinnitus.

Initial assessment and diagnosis

While still abroad, WO was referred to psychiatry from neurology because no clear neurological basis for his symptoms could be found. Initially WOs symptoms were thought to be an atypical reaction to the anesthetic, with possible subsequent cerebral damage. This was inves- tigated as felt appropriate by EEG and brain scans (CT, MRI, and later SPECT), which were normal, and by neuropsychological testing, which was abnormal. The emphasis on diagnosis shifted from organic to psycho- genic, and initially classied as a dissociative amnesia.

Orientation and mental status

Several months post-onset, it became apparent that WOs condition had not improved, and he and his family returned to his childhood home in the UK, which his mother had vacated. WO knew the house, local amenities, and geography, which aided in his orientation and self- management of the condition. Though over the years WO has implicitly adjusted to his circumstances to some extent, in general each morning he is surprised to wake up in his mother s house. He wakes up believing that he should still be in the military, stationed abroad. Every day he thinks it is the day of the dental appointment.

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Through prompting by his wife, WO checks his com- puter each morning on which they have listed (and keep updated) key facts he should be aware of. Some events that have occurred since the onset of his condition in March 2005 continue to elicit genuine surprise or aston- ishment each time he sees or hears about them, such as the marriage of some family friends or that a family pet has since passed away. WO manages his daily life and gen- erally remains oriented throughout the day via the use of continuous access to an electronic diary and prompts. Technically apt, he learned to use satellite navigation and a new digital camera prociently, and he originally pro- blem solves other tasks each time, such as how to turn on the power to his familys new television. He drives himself to appointments through the use of satellite navigation, and/or previous familiarity with the region in which he lives. Preserved ability to parent and deal effectively with emergencies has been demonstrated. His wife reported subtle differences in his ability to cope with stress or multiple demands on his attention, and he reportedly becomes more easily frustrated and intolerant and takes less interest in everyday family affairs, though his person- ality otherwise remains largely intact. WO has remained completely oriented to his own identity, and that of his family, though he expects everyone to still be the age they were in March 2005. He has written down his childrens current schools and achievements, and wifes new job. When ofce-based assessment sessions lasted more than 90 min, WO became completely disor- ientated to time and place, if kept from referencing his electronic calendar, appointment letter, or a clock. Though we have seen WO on multiple occasions, he demonstrates no recognition of ever having seen us before, and we must start afresh with introductions each time we meet. He is attentive socially, though requires his wife to answer ques- tions regarding events since March 2005 that he has not otherwise written down and/or reviewed within the last hour or two. If asked, he may say, I know I have a memory problem,or I think it is March 2005, but it is not,based on the daily reviews of his notes. Typical of known cases of amnesia, he has not lost knowledge of the purpose and use of clocks and calendars which help to keep him orientated, and he has maintained relevant, per- sonal information and about the use of objects in the environment.

Current general intellectual and cognitive skills

WO sat neuropsychological testing on four occasions between June 2005 and May 2012. His digit span (i.e., working memory) was assessed at each session (Wechsler, 1997a). WO initially scored in the low average range (16th percentile) in 2005, but subsequently improved though never surpassed the 50th percentile, and generally he remained a standard deviation or more below an adult

reading test-estimated premorbid IQ between the 75th and 84th percentiles. The visuo-spatial equivalent, spatial span suggested preserved performance at the 84th percen- tile (Wechsler, 1997b). WO scored in the upper percentiles (i.e., 63rd and above) on all executive functioning tests he was administered, several with timed components. WOs current IQ/verbal comprehension (i.e., word knowledge, facts, and verbal reasoning) tested at the 63rd percentile (Wechsler, 1997a). His perceptual organi- zation (i.e., visual reasoning and spatial construction) tested at the 84th percentile. Conclusions drawn from these results suggested that WO was of above average intelligence, and somewhat stronger visuo-spatially than verbally/numerically, and it would appear that his cogni- tive skills (i.e., working memory and visuo-motor cleri- calprocessing speed) had diminished somewhat from pre-amnesia-onset levels at the 37th percentile.

Explicit learning and memory

Memory testing results are outlined in Table 1. Reected in these scores are WOs everyday reported symptoms, namely that he could learn new material, but if that mate- rial was not recalled or rehearsed within a 90-min time- frame, it was lost completely. WOs initial learning capacity appeared to have improved from the rst months following amnesia onset to a year or more after onset, and he selectively learnt certain types of material more effec- tively, for example reproducing a complex geometric g- ure after having copied it, or recalling the details of a story. He was least effective at learning a random list of 15 unrelated words (5th percentile overall), and was some- what less effective on face recognition in the context of other evidently exceptional visual memory abilities. He demonstrated more effective list learning when words could be chunkedinto semantic categories, in other words he effectively utilized encoding strategies inherently offered in the tests design. Extending the timeframe of WOs retention of acquired/learnt information was possible by asking him to recall or recognize (i.e., call back into conscious aware- ness) what he had learnt before the expiration of 90 min had elapsed since the learning trial(s). Through use of this procedure, he was able to recall precisely the same items/ material at 110 min as he had at 30 min. Evidence sug- gested that he either acquired/learnt information, or he did not. In other words, following the standard 30-min delay, he only tended to recognize that which he could also only previously and independently freely recall. Cueing was of little, if any, benet in improving his scores. Furthermore, his score on immediate recall trials tended to be precisely replicated (even in phraseology or approach) to that of his delayed recall, if elicited from him before 90 min had elapsed. Decay, even what may be considered normal decay, of the memory trace did not occur before 90 min

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G.H. Burgess and B. Chadalavada

Table 1. Results of memory testing (20052012).

June 2005 (1 Day of Testing) 3 months post-onset* MEMORY & LEARNING WMS III (Wechsler, 1997b) Story Memory

Low average

Story 30-min Delay

Low average

Visual Reproduction

Low average

Visual Reproduction 30-min Delay

Low average

RAVLT (Rey, 1964) Immediate

Impaired

Delayed

Impaired

October 2006 (2 Days of Testing) 19 months post-onset

MEMORY & LEARNING WMS-III Story Memory Immediate Recall 1st Story

76% recalled

Immediate Recall 2nd Story (rst reading)

24% recalled

Immediate Recall 2nd Story (second reading)

36% recalled

Immediate (Story) Memory (overall scaled score)

37th percentile

Story Recall at 95-min Delay

Nil

Story Recognition at 95-min Delay

Chance

KBNA (Leach, 2000) List Learning Immediate Trial List Learning 30-min Delay List Learning plus additional 80-min Delay (110 min) List Recognition Delayed Complex Figure Immediate Complex Figure 30-min Delay Complex Figure plus additional 80-min Delay (110 min) Picture Recognition at 95-min Delay

37th percentile 63rd percentile Same as above 37th percentile 91st percentile 98th percentile Same as above Nil

AMIPB (Coughlan & Hollows, 1985) List Learning Immediate

5th percentile

Interference List Trial

<5th percentile

List Learning Post-interference

<5th percentile

Design Learning Immediate

63rd percentile

Interference Design Trial

90th percentile

Design Learning Post-interference

16th percentile

January 2008 (2 Days of Testing) 34 months post-onset

MEMORY & LEARNING WMS-III Story Memory Immediate

Total Errors (Day 1) Day 2

75th percentile

Story Memory 30-min Delay

84th percentile

Story Recognition 30-min Delay

75th percentile

Faces Immediate

25th percentile

Faces 30-min Delay

50th percentile

CVLT (Delis, Kramer, Kaplan, & Ober, 1987) Immediate 95-min Delay 95-min Cued Delay 95-min List Recognition

50th percentile Nil A few items guessed Just above chance

IMPLICIT LEARNING Reverse-image Mirror Maze (Day 1, seconds) Day 2, seconds Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Trial 6 Trial 7

(49 s) 49 s (35 s) 43 s (30 s) 33 s (27 s) 30 s (24 s) 24 s (23 s) 23 s (23 s) 23 s (2) 1

May 2012 (1 Day of Testing) 86 months post-onset

RETROGRADE AMNESIA Headline News & Social Events (recognition knowledge of)

 

(continued )

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Table 1. (Continued).

20012002

4/7

2003

1/9

2004

2/7

January to March 2005 (amnesia onset March 2005)

0/2

Rest of 2005

0/4

2006

0/5

2007

0/6

Note: *The 2005 scores were derived from WOs rst neuropsychologists report, which were reported only as classication labels, not percentiles; for the sake of clarity, low averagerepresents the 9th to the 24th percentiles, and impairedrepresents <5th percentile.

had expired he retained precisely the same amount. WO was extremely susceptible to proactive and retroactive interference. When administered interference trials on word lists or design learning, or read two different stories back-to-back, his performance was drastically impacted, either by rapidly forgetting a large portion of the content from the rst trial, or becoming much less effective in learning the second.

Implicit learning and memory

Implicit learning was not evident in WOs test-based per- formance through perceptual priming or via demonstration of savings on reverse-image mirror maze completion, when tested on exactly the same material after a 3-day delay. Perceptual priming was assessed using silhouetted and distorted animal or object forms. On the rst day, WO was instructed to guess what 30 distorted forms were and achieved a score of 25/30. Of those he guessed incorrectly, he was provided the correct answer and asked if he could or could try to perceive it as that particular animal or object? The results of this strategy were mixed in that he reluctantly agreed that only two-of-the-ve could be the named animal or object. On the second administration 2 days later, he scored 24/30 missing the exact same items with exactly the same incorrect guesses, plus one he had previously guessed correctly. WO was also presented two objects which were rst presented in very distorted form, then pictorially rotated through stages eventually revealing a very clear two- dimensional prole image of the object. WO was instructed to guess what the object was as soon as he was able, with successive rotations of the object. Day 1 was considered an opportunity to prime his response for Day 2, and it was hypothesized that he would correctly guess the objects with fewer rotations on Day 2. This did not occur; he guessed the objects after exactly the same number of rotations as Day 1, and again he made the same incorrect guesses on precisely the same frames as Day 1. Also on Days 1 and 2, WO was provided a paper-and- pencil maze that he was instructed to complete as quickly as he was able without making contact with the pencil to the maze boundaries, and that this had to be completed

through sight of only a reverse-mirror image. He was administered the maze multiple times, in order to learn the task and reach a plateau of speed in completing the task. This is a task that is considered to require new motor or procedural learning, and those with bilateral hippocam- pal damage are able to improve and then retain the new motor skill over subsequent days (Milner, Corkin, & Teuber, 1968). It was expected that WO would demon- strate the same pattern of retention, but he did not. On Day 1 he demonstrated normal learning, increasing speed and made fewer errors across six trials. WOs performance on Day 2 was for all intents and purposes a replica of his performance on Day 1. On Day 2 he demonstrated no savings in the time it took to complete the trials, nor did he make signicantly fewer errors, but instead he demon- strated a very similar course or pattern of learning, begin- ning on trial one as if a novice performance, and then progressing similarly to that of Day 1. Table 1 delineates his times and errors across successive trials.

Retrograde amnesia

WO reported that he recalled personal events up to the day of amnesia onset in March 2005, including receiving the anesthetic and commencement of drilling for the root canal. This would suggest an absolute minimal episodic- autobiographical retrograde amnesia. In 2012 we assessed his memory for 40 news events, interspersed major head- lines between September 2001 and September 2007 (see Table 1). He could explain in great detail world events that led up to the First Gulf War and the ground assault that began in mid-March 2003. He did not recall or recognize subsequent key events of that war. WOs memory for news events was patchy between 2001 and 2004, and seemingly complete amnesia thereafter. Interestingly, however, he did recall that a Tsunami occurred in southeast Asia (December 2004), indicating that, we did a fund-raiser for that(in early 2005), thus linking this event to a personal (autobiographical) episode, presumably the cata- lyst of its permanence in his memory. Conclusions drawn from this suggest that events personally experienced, of personal signicance (i.e., episodic-autobiographical memories), were more likely to be remembered than

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G.H. Burgess and B. Chadalavada

impersonal news events (i.e., semantic/impersonal episo- dic memories).

have attempted to map onto and discuss in regard to the presenting features of WO and the four comparison cases.

Episodic learning since March 2005

Without known precedent to us, amongst people with anterograde amnesia, WO has made one new memory since amnesia onset. He also extended recognition mem- ory beyond his usual 90 min (more than 24 hr in fact) on one occasion for a newborn baby in a photo. This coin- cided with his being on an experimental 12-week trial of a cholinesterase inhibitor. This recognition did not transfer into permanent memory storage, however, and it remains unclear precisely when that trace faded permanently. The other, permanent memory successfully stored occurred in regard to the death of his father in 2005, which occurred after the amnesia onset. WO does not recall the episode of his father s death (though he was at his bedside all day), but does have an awareness or the knowledge that his father is deceased.

Language

Initially, in the rst few days following amnesia onset, WO reportedly presented with slowed, slurred speech, and with comprehension difculties. Though this has improved over the years, WO still may exhibit semantic paraphasias (e.g., calling the wardrobe, shed) and cir- cumlocutions (e.g., little yellow bitsfor corn) in his spontaneous speech. Informal screening of confrontation naming and his ability to comprehend and follow multi- staged commands detected no abnormalities from 2006 forward, though that year (in March) WO experienced an acute expressive aphasic incident that persisted for 2 weeks, characterized by extreme word-nding difculties and labored speech. No medical reason for this incident was detected.

Discussion

The particular sets of symptoms presented in this article are extremely difcult to categorize neurologically or psy- chically in either of the two widely used classication systems, DSM-5 (American Psychiatric Association, 2013) and ICD-10 (World Health Organization, 1993). Several lines of speculation have so far been considered in an attempt to understand the mechanism of consolida- tion failure, which will now be reviewed. We have had at- hand multiple assessments over years with WO, and four cases from the extant literature that share remarkable simi- larities and some differences between them (see Table 2 and Appendix 1 for comparisons). Additionally we had empirical research and theories of memory consolidation that appear may have some relevance, and of which we

General comparison of WO with four similar cases of anterograde amnesia

Initially, what is striking about WO and the four compar- ison cases (De Renzi & Lucchelli, 1993; Kessler et al., 1997; Markowitsch et al., 1999; Smith et al., 2010), in the absence of structural damage, is their specic resem- blances to particular cardinal features of bilateral organic amnesia, namely profound anterograde amnesia, with intact intellect and everyday executive ability and personal identity. Retrograde amnesia is variably represented and characteristically temporally graded amongst these cases, demonstrating the classic Ribot effect, as is the case with organic amnesias (Spiers et al., 2001). Dissimilar to amne- sias involving direct damage to diencephalon structures, there is an absence of temporal confusion and confabula- tion All ve of these individuals were reported as of at least average intelligence, and it was not suspected that drugs or alcohol, trauma, or feigning illness/malingering was the cause of their symptoms, though psychological peculiarities were attributed in two cases (i.e., cases known as AA, FL). Four-of-the-ve comparison cases (exception AA) were of sudden onset, preceded by a medical emer- gency/event. It was not common that a loss of conscious- ness, other than brief(FL) was caused by the preceding injurious event; however, the four cases of sudden onset did demonstrate a subsequent period of altered conscious- ness (e.g., stupor, disorientation, incoherent speech) last- ing between hours to days after the event. The primary feature that draws these ve cases together for comparison is the existence of anterograde amnesia in the absence of a known and/or detectable neurological event preceding it, and in the context of at least insufcient MRI structural brain imaging evidence that would appear to justify and/or explain the extent and profound nature of the amnesia. PET/SPECT scan evi- dence was equivocal, and in any case (PI, TA) did not demonstrate hypometabolism in any region known to be particularly associated with the consolidation of memory. Each of these cases shares a span of awareness for events that exceeds that of working memory, which suggests that the engram or memory trace evaporates at some later stage than the immediate, as would be typical in organic amne- sia. The range of span of awareness was reportedly between a minimum of 5 min and a maximum of 13 days, though the authors indicated that these two extremes may be accounted for by extremely poor effort (Kessler et al., 1997) and no opportunity to assess over subsequent days following testing (De Renzi & Lucchelli, 1993), respectively. Similar to cases of organic amnesia, retrograde amne- sia demonstrated the classic Ribot effect and manifested as

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Notes: * Denotes De Renzi and Lucchelli were not able to assess on successive days, therefore the duration before amnesia onset is unknown precisely, though extrapolating from the text, it appeared that PIs span of awareness was greater than 24 hr; NAD denotes no abnormalities detected; N/A denotes not applicable.

Burgess & Chadalavada (current article)

Anesthetic/root canal/ possible period of

2 months complete, 4 years patchy

WO

hypotension

Unknown

Minimal

38 years

Variable

Variable

Sudden

Sleep for 4 hr + results 90 min in onset of complete

Worse

6.8% less hippocampal NAD volume compared to controls bilaterally

NAD

Male

Yes

No

No

Seems likely, extrapolating from the case report

Possibly perceptual priming, but not motor skills

(within 1 SD of control norm)

Smith et al., 2010

Neck injury/car

Decades nearly

FL

Not reported

complete

accident

amnesia

Minimal

51 years

Sudden

Female

Worse

Worse

Worse

No

No

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8 + months not assessed prior to onset, though reported as normal

Worse fading trace with time

No (memory traces from test content fade with time)

Markowitsch et al., 1999

30 years Female Neck injury/car accident

Left Pons (brain stem)

TA

Equivalent

Minimal

Sudden

Brief

Worse

NAD

Span of awareness for events Between 4 hr and 510 min (authors attribute to extreme 2 hr

No

No

independence and university demands attributed

Thoracic/cervical None known, stress related to

Much worse impoverished

Not completely assessed

Gradual (over 1 month) N/A

AA

Kessler et al., 1997

No, or not known

poor effort)

1 year patchy

29 years

Better

Better

NAD

Posterio-superior NAD temporal cortices

Male

Yes

Table 2. Comparison of anterograde amnesia cases.

No

Not reported

De Renzi & Lucchelli,

13 days*

cyanotic

Equivalent

Equivalent

Working memory relative to Equivalent current IQ

trauma/

PI

Complete

Retrograde amnesia for news Complete events

  • 1993 24 years

Sudden

NAD

Male

Extended span of awareness/ Yes retention with rehearsal

No

No

PET/SPECT evidence of brain region hypometabolism

Immediate memory recall relative to current IQ

Author and year reported

Retrograde amnesia for personally experienced events

Implicit memory/learning evident in ofce-based tests

30-min delayed recall relative to current IQ

Co-morbid personality disturbance

Onset Loss of consciousness

Age at onset Sex Preceding event

Initials

MRI

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8

G.H. Burgess and B. Chadalavada

variable along time and content axes, though an apparent selective preference for the preservation of episodic auto- biographical memories (in three cases up to the point of amnesia onset) over episodic impersonal (e.g., headline news stories) memories was evident. Dissimilar to organic amnesia, the preservation of implicit learning was not a foregone conclusion, with only one case possibly evincing perceptual priming (FL), and no case evincing retention of motor/procedural learning over successive days. This would appear to suggest that all forms of learning were vulnerable to loss at a later stage than the active learning stage, whether episodic/semantic or procedural. Neuropsychologically, other trends amongst the compari- son cases included a relatively better visual learning system (compared to verbal) when learning involved spatio-constructional tasks, such as a complex geometric gure copy and recall. Face recognition, on the other hand, tended to demonstrate relatively poorer learning, and in two cases impoverished (PI, AA). Considering for a moment the medical events that preceded amnesia onset, it was difcult to ignore the fact that three-of-the-ve comparison cases involved spinal column trauma, and four cases were sudden onset follow- ing a medical emergency of some kind, giving the impres- sion that some physiological stress or trigger initiated the amnesia, and AA was reported to be in a chronic state of psychological stress with more gradual onset. WOs med- ical event was not obviously related to spinal or central nervous system trauma, though he presented to his GP a few weeks before the amnesia onset with increased back pain from a previous coccyx injury. His amnesia was causally or coincidently precipitated by an anesthetic injection in the mouth and root canal procedure, coincid- ing with a possible extended period of vasovagal or hypo- tensive incident, which unbeknownst to the dental team treating him, could have been 40 min. Case PI reportedly experienced a period of anoxia and/or hypotension.

An unusual manifestation of psychogenic amnesia?

In an attempt to explain WOs symptoms, early evaluators attributed his presentation to a psychogenic amnesia. In considering this, it is noteworthy that in the case of AA, described by Kessler and colleagues (1997), the gradual onset of persistent anterograde amnesia was attributed to the psychological torment and avoidance associated with vocational stress and adult responsibilities. As was men- tioned earlier, WOs grandfather died a few days before the amnesia onset, and WO and his family made a brief trip back to the UK for the funeral. This event and its associated stress was initially attributed as the cause of WOs amnesia and subsequently he was diagnosed with dissociative amnesia. It has become apparent, however, that though this explanation may be true for some with such amnesia

symptoms, WO does not share similar personality features as AA, quite the opposite actually, and though WO was close to his grandfather, it was difcult to consider this event having caused WO sufcient distress to manifest in so profound an illness, nor does this brand of amnesia match existing diagnostic criteria of psychogenic or func- tional amnesias that, for example, characteristically involves a period of acute stress and a relatively greater proportion of retrograde (in particular autobiographical) rather than anterograde amnesia (Piolino et al., 2005; Spiegel et al., 2011).

Widening the denition of accelerated long-term forgetting?

WO and the others share similarities with reported cases of accelerated long-term forgetting (ALF), a phenomena associated with temporal lobe epilepsy, characterized in part by normal volume hippocampi and normal perfor- mance on 30-min delayed recall in standardized neurop- sychological memory testing, but then followed by atypically accelerated and extensive forgetting over sev- eral days or weeks, compared to healthy controls (Blake, Wroe, Breen, & McCarthy, 2000; Elliot, Isaac, & Mulhert, 2014; Muhlert, Milton, Butler, Kapur, & Zeman, 2010). Epilepsy is not indicated in WO or the comparison cases, and none have been witnessed having any type of seizure (including absence) or unusual transient perceptions or behaviors, and all demonstrated normal EEGs. Furthermore, ALF occurs at a slower rate (i.e., days-to- weeks compared to minutes-to-hours), demonstrates a u- shaped retrograde amnesia rather than the classic Ribot temporal gradient, and crucially implicit or procedural learning remains intact in ALF (Elliot et al., 2014; Muhlert et al., 2010), all features that would appear to describe a different type of amnesia, or at least later-stage and independent mechanism of consolidation failure than the current cases under discussion. It is compelling to consider ALF further, however, since ALF shares the remarkable similarity to the cases presented herein of signicant forgetting well past the phase of short-term or working memory, and because studies have attempted to link ALF with structural hippo- campal damage, and have not found an association. Butler, Bhaduri and colleagues (2008), using MRI evidence, found that hippocampal volume was associated with learn- ing capacity and retention at 30 min, but not to ALF, suggesting that ALF may be caused by a more diffuse physiological process rather than due to the structural integrity of the bilateral hippocampi per se. Indeed, evi- dence in support of this notion came from Magnetic Resonance Spectroscopy (MRS), that in the context of normal volume hippocampi, metabolic abnormalities were discovered in the right hippocampus in people demonstrating ALF, specically a decrease in the N-

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acetylasperate ratio compared to healthy controls, suggest- ing a sort of metabolic dysfunction may relate to the ALF phenomena (Tramoni et al., 2011).

A previously latent congenital or acquired metabolic disorder?

Following on from Tramoni and colleaguesndings, an intriguing speculation was whether the mechanism that caused the forgetting was the prevention or inhibition of metabolic processes involved in memory formation. Most intriguing was the function of new messenger ribonucleic acid (mRNA) protein synthesis, which coincidently gets initiated roughly during the intermediate-to-late stage of memory consolidation (i.e., 10 min to 24 hr after learning), congruent with the time period of forgetting amongst the cases, and is the de novo mechanism that is responsible for the eventual permanence of memories, involving the re- structuring of synapses (Bekinschtein et al., 2007; Carew & Sutton, 2001; McGaugh, 2000; Medina, Bekinschtein, Cammarota, & Izquierdo, 2008; Ng & Gibbs, 1988). If this speculation were to hold merit, the structural integrity of the hippocampi or other brain regions would be less relevant than an individuals capacity to metabolically process and synthesize proteins responsible for micro- scopic structural changes in the synapses, and the longer span of awareness would be backed-up by a plausible, temporally congruent hypothesis, worthy of further inves- tigation. What is further intriguing and tting, is that in animal and human studies both explicit/episodic and implicit/procedural memory works along a similar timeline to consolidate, and each ultimately appears to require mRNA protein synthesis for permanent memory storage (Brashers-Krug, Shadmehr, & Bizzi, 1996; Igaz, Vianna, Medina, & Izquierdo, 2002; Luft, Buitrago, Ringer, Dichgans, & Schulz, 2004).

New learning in the context of anterograde amnesia

The case of WO revealed, to our knowledge, a unique capacity for learning in the context of profound amnesia, namely that he made two memories that extended his usual 90-min span of awareness. It may be noteworthy that one of these memories occurred in the context of a one-off, 12- week trial of a cholinesterase inhibitor, that perhaps a chemical intervention extended his retention for 24-plus hours, before again the trace was permanently lost. The other incident of, in this case permanent, new learning was the awareness WO gained about his father dying or being deceased, which occurred after the onset of WOs amnesia. The amygdaloid complex is a powerful auxiliary to learn- ing, tagging the personal or biological signicance of an event or information, and it is proximal and makes multiple connections to brain structures whose primary function involves learning/memory (Cahill, Babinsky,

Markowitsch, & McGaugh, 1995; Markowitsch & Staniloiu, 2011; Turnbull & Evans, 2006). WO was very emotionally bonded to his father, and his death carried a great deal of personal signicance. Neuropsychological testing evidenced that WOs retention of information could be refreshed if recalled back into conscious aware- ness before 90 min had expired, a means of extending awareness and retention also seen in ALF cases (Jansari, Davis, McGibbon, Firminger, & Kapur, 2010). It seems plausible that WO could have brought the engram of his father s death into conscious awareness on multiple occa- sions during the day his father died, keeping it refreshed, and presumably could have carried on in this manner throughout tful REM and non-REM periods of sleep, creating the necessary elements that stamped a permanent awareness or feeling into long-term storage.

Conclusion

Based on the cases presented herein, it may be surmised that the anatomical integrity of the MTL, diencephalon, or basal ganglia/striatum structures are not all that is neces- sary in the consolidation of explicit and implicit memories. We set out in this article to describe a new case of ante- rograde amnesia alongside four similar cases that share astonishing similarities between them, and yet do not t within any existing neurological or psychiatric disorder or diagnostic category. None of these cases exhibited evident structural brain damage, but yet likely at least by the rst nights sleep, complete and profound forgetting occurs, in the context of intact learning, intellect, and identity. This speed of forgetting is slower than witnessed in cases of organic (MTL or diencephalon) amnesia (i.e., seconds to minutes), but faster than the phenomena of ALF observed in some cases of temporal lobe epilepsy (i.e., days to weeks). Furthermore, while procedural learning remains intact in organic and ALF cases, in the comparison cases presented herein, procedural learning is not sustained, following successful learning. We have suggested that a plausible explanation due to two key coincidences is a breakdown of mRNA protein synthesis, which coincides with the intermediate-to-late stage of memory consolida- tion and appears responsible for the permanence of both explicit and implicit/procedural memories. Future research should include further investigating this stage and mechan- ism of consolidation in humans perhaps through the use of fMRI or MRS, reasons for metabolic failure whether genetic or acquired, and possibly chemical treatments, of which a cholinesterase inhibitor potentially demonstrated promise, enhancing recognition memory in WO. Overall, this brand of amnesia needs another diagnostic or classi- cation category than any currently existing, as between the cases presented in this article, a small but critical mass of distinctive qualities compose them, and the mechanism

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10

G.H. Burgess and B. Chadalavada

appears different to other types of amnesia, as subse- quently would any choices of treatment.

Disclosure statement

No potential conict of interest was reported by the authors.

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Appendix 1: Rated criteria (from most shared to least shared) for symptoms of anterograde amnesia amongst the ve comparison cases

A Profound anterograde amnesia. No evidence of structural brain changes/damage from CT/MRI and normal neurological examination. Preserved intellect/executive ability. Preserved personality/identity. Span of awareness for events that exceeds working memory. Absence of identiable psychiatric trauma or psychiatric diagnosis preceding onset. Not believed to be due to conscious feigning/malingering. Not due to alcohol or drugs. Prior to onset leading productive (i.e., work/school/family) life. Symptoms persist indenitely (in absence of identied treatment).

B Concurrent but non-permanent motor/procedural learning. Better visual memory for complex/visuo-spatial material than verbal material and face recognition memory. Retrograde amnesia occurs within a temporal, not selective, gradient and personally experienced events (i.e., episodic- autobiographical) are better preserved than impersonal (e.g., news headlines).

  • C Perceptual priming/classical conditioning demonstrated? Physical injury precedes/initiates onset? In particular back/neck injury? Vasovagal/anoxic/cyanotic episode precedes onset? Sudden or gradual onset? Fading memory trace directly subsequent to active learning phase or preserved trace up until denite point? Memory trace refreshed and subsequently extended via recall back into conscious awareness? Hypometabolism in specic brain region, evident by PET/SPECT? Consolidation failure at what point (5 min to 13 days, or with 4+ hr sleep)? Working memory and information processing speed reduced relative to IQ?

  • D Transient recognition memory extended with cholinesterase inhibitor?

E Co-morbid personality/motivational disturbance. Possible incentive for symptoms (i.e., avoidance of individuation/immaturity). New learning in highly emotive and unique circumstances. Anesthetic injectionand/orroot canal procedure preceded onset. Belief system about the nature and limitations of ones own amnesia inuenced performance (i.e., perceptual priming or recognition memory after 24 hr when nights sleep purportedly causes complete amnesia).

A: All ve cases demonstrated this characteristic. B: All who were or could be assessed for this characteristic demonstrated it (rest is missing data). C: Controversial (clear, convincing evidence amongst cases that contradict each other). D: Seemingly convincing evidence, though assessed/reported in only one individual (i.e., could be true of others, but was not assessed). E: Unique features in one individual and not represented in other individuals.