Short Description or Definition

Amnestic disorders are defined by a decline in explicit memory in the absence of other significant cognitive impairments and represent a deterioration from previous levels of function. The hallmark feature of classic amnestic disorders is anterograde amnesia (impairment in the ability to form new explicit memories), although retrograde amnesia (inability to remember previously learned information) can be seen, usually in a temporal gradient with recent memories affected more than earlier ones. This entry focuses on persistent, nonprogressive etiologies of amnestic disorders, excluding etiologies such as transient global amnesia, neurodegenerative conditions (e.g., Alzheimer’s disease), and psychogenic amnesias.

Categorization

Amnestic disorders can result from a variety of causes, including hypoxic/anoxic events, infections, nutritional deficiencies, and lesions such as those occurring following stroke or surgical ablation, and are associated with damage to several brain regions. Two subtypes of amnestic disorders have received the most attention: bitemporal amnesia and diencephalic amnesia (e.g., Korsakoff’s syndrome and patients with discrete thalamic or mammillary body lesions). A third subtype, basal forebrain amnesia, is viewed as clinically distinctive (Bauer et al. 2003).

Epidemiology

Amnestic disorders can be observed in several classes of patients, including following viral infections (e.g., herpes encephalitis), anoxic/hypoxic events (e.g., after heart attack or near-drowning, carbon monoxide exposure), nutritional impairments (e.g., Korsakoff’s syndrome), bilateral temporal lobectomies, traumatic brain injury, and cerebrovascular events; epidemiological data are available by specific etiology, although pure global amnestic syndromes themselves are relatively rare. For example, herpes simplex encephalitis carries a 70% mortality rate without treatment. The cognitive impairments in survivors are ranging, and in one study of long-term survivors, 19 of 22 participants experienced some form of memory impairment, although only five subjects had memory difficulties that were categorized as severe (Utley et al. 1997). In a review of studies of cerebral anoxia, Caine and Watson (2000) concluded that while 54% of case studies describe memory impairments, only 19% report memory deficits in isolation.

Natural History, Prognostic Factors, and Outcomes

The amnestic disorder is exemplified by the case study of H.M., a patient who underwent a radical, experimental surgery in which the medial temporal lobes were removed bilaterally in an attempt to treat intractable epilepsy. His resection included the hippocampal formation and adjacent structures including most of the amygdala and parahippocampal gyrus, including the entorhinal cortex. Following surgery, H.M. developed severe anterograde amnesia which manifested as impaired episodic memory. In addition, he developed partial retrograde amnesia for events within 19 months before his surgery. However, earlier memories were unaffected, and his working memory and procedural memory (skill learning) also remained intact (Corkin 2002; Scoville and Milner 1957).

Course: Onset is often acute due to the nature of the pathological processes that cause amnestic disorders (e.g., cerebrovascular events, anoxic/hypoxic events, surgical ablation, and infections such as herpes encephalitis). Although some degree of improvement may occur in some patients, for example during the immediate period of natural recovery which occurs following cerebrovascular infarcts or traumatic injuries, deficits typically are persistent. Barring any additional injury, worsening of memory over time would not be anticipated.

General neuropsychological profile: Patients exhibit deficits in explicit memory marked by significant anterograde amnesia. They may also exhibit retrograde amnesia, although this is typically less severe and exhibits a temporal gradient with older memories less likely to be disturbed. Attention, working memory, procedural memory, implicit learning, and general cognition remain largely intact.

Amnestic disorders resulting from bitemporal or diencephalic insults are the most frequently studied and similar in their neuropsychological profiles. Although early studies suggested that individuals with bitemporal amnesias have a more rapid forgetting rate, McKee and Squire (1992) found equivalent forgetting curves for pictures when severity of amnesia was controlled. Both subtypes of amnesia display a degree of retrograde amnesia (Kopelman et al. 1999). Bauer et al. (2003) argue that despite these similarities, some deficits are unique to patients with diencephalic amnestic disorders; although some studies suggest patients with Korsakoff’s syndrome display a unique deficit in memory for temporal order (e.g., Squire 1982; Kopelman et al. 1999), others fail to support this finding (Downes et al. 2002).

Basal forebrain amnesia typically results from vascular lesions or aneurysm surgery in the region of the anterior communicating artery. After basal forebrain damage, patients may demonstrate extensive anterograde amnesia (Bottger et al. 1998; Tidswell et al. 1995). Confabulation is common and may relate to the extent of orbitofrontal involvement (Hashimoto et al. 2000), but it often subsides following the acute phase, while the amnestic state remains. There is evidence that patients with basal forebrain amnesia benefit from the presentation of cues to enhance recall (Osimani et al. 2006).

Evaluation

As amnestic disorders are defined by deficits in new learning, memory is the cognitive domain that should be emphasized within a comprehensive neuropsychological evaluation that also includes assessment of other areas of cognitive function such as orientation, attention, language, executive functions, visuospatial skills, and psychological functioning. Patients fitting the classic amnestic disorder profile will exhibit deficits in memory with generally intact cognition within other domains.

It is important to establish the specific nature of patients’ memory impairments. Immediate memory span (typically assessed through tests such as Digit and Spatial Span from the Wechsler Memory Scales) should be within the normal range. Anterograde learning may be assessed with measures such as list learning, story learning, or figure memory. While patients will be able to retain items and repeat them back as long as they can keep them in memory, learning curves are typically flat, and an intervening distractor task will typically cause items to be lost completely. It is important to examine free recall vs. cued/recognition formats, as patients with frontally medicated amnestic disorders may show some benefit (typically no benefit seen for patients with bitemporal or diencephalic etiologies). Some degree of laterality to memory profiles may be expected depending on the nature of injury (e.g., left hemisphere damage leading to verbal memory impairments, right hemisphere damage impacting visual memory).

In addition, retrograde amnesia and memory for remote events can be examined in a qualitative manner by inquiring about autobiographical events or memories that one can assume to be present in most people from a given society (e.g., pictures of famous individuals, questions regarding salient historical events). The aspects of memory that remain intact in classic amnestic disorder patients (such as semantic memory and motor skill learning) could also be assessed.

The main differential diagnoses to consider include delirium and neurodegenerative dementias (e.g., Alzheimer’s disease). Delirium is defined by a disturbance in attention and consciousness, both of which are intact in amnestic disorders. Although neurodegenerative dementias present similarly to amnestic disorders in that patients often present with memory impairments, cognitive decline (rather than stability) occurs and impairments in other cognitive domains such as language or executive functions are present.

Treatment

Treatment of amnestic disorders is nonspecific and focused primarily on compensation for memory impairments. Cognitive rehabilitation and memory training programs often emphasize the teaching of mnemonic strategies or the use of external memory aids such as note-taking or audiotaping in order to enhance patients’ functioning in daily life, although patients would consciously need to recall learning these strategies and to utilize them. Implicit training procedures, such as those involving errorless learning strategies, can be helpful, as are environmental supports (e.g., electronic reminders) and assistance from family, friends, and/or caregivers.

The use of pharmacologic agents to treat amnestic disorders is not well studied, and large randomized controlled trials are lacking. In an open-label pilot study, Benke et al. (2005) administered donepezil, a cholinesterase inhibitor, to patients with a chronic amnestic syndrome from a ruptured and repaired aneurysm of the anterior communicating, anterior cerebral, or pericallosal artery. Some measures of performance on a list-learning task improved significantly during the 12-week medication administration period, suggesting future double-blind controlled studies would be useful to more thoroughly examine the potential utility of cholinergic medications. Studies have also examined the use of cholinesterase inhibitors following traumatic brain injury; a recent review (Bengtsson and Godbolt 2016) found only three studies meeting somewhat relaxed inclusion criteria (no studies located using their initial inclusion criteria). One study found no effect of treatment, and two studies showed limited effects. Given that included studies had several methodological limitations, further studies are needed to examine whether acetylcholinesterase inhibitors may be beneficial in this population.

In addition, due to their memory impairment, patients are likely to experience impairments in their social and vocational activities and may also require supervision and/or support in their living environment and a guardian or conservator to assist with legal and medical concerns in more severe cases.

Cross-References