Lactology Foundation

AMNESIA

Memory is the ability to store and subsequently retrieve past experience, and it is fundamental to many cognitive functions. Amnesia can be defined as a loss of previous memories and an inability to form new ones. Altered alertness, attention, language and motivation may all confound the clinical assessment of memory function, and they must be absent for the term 'amnesia' to have clinical usefulness. Memory is conventionally divided into registration (which includes perception in all modalities); encoding and storage; and retrieval. Learning includes encoding and the initial storage of information.

CLASSIFICATION AND NOMENCLATURE
Memory is not a unitary function and can be divided up in many different ways. One classification is presented in the table. It is conventional to divide memory into short-term (also called primary, immediate or working) memory and long-term (also called secondary) memory. Long-term memory may be further subdivided into recent (from initial learning to hours) and remote (extending back to childhood). Short-term memory is tested at the bedside by digit span testing, although poor attention can confound this test. A normal person's digit span is seven or eight digits, which are forgotten over about 30 seconds unless rehearsed. Long-term memory has been traditionally regarded as a consolidated form of short-term information, but this concept does not explain patients with impaired digit span but normal
learning and long-term memory. Ribot's law states that there is an inverse relationship between memory strength and recency (i.e. older memories are better preserved), and is a useful guiding principle often seen clinically. Semantic memory refers to an individual's store of previously acquired facts, concepts, words and beliefs, and is conceptually rather similar to long-term memory. Procedural memory is outside conscious awareness, and it allows the patient to remember how to perform tasks, for example driving or cycling. It may be relatively resistant to disease processes that profoundly affect the recent memory system, such as Korsakoff's syndrome or Alzheimer's disease.

Memory nomenclature above.

FUNCTIONAL ANATOMY OF MEMORY
Functional imaging of cerebral blood flow suggests that the prefrontal cortex is important for tasks involving working memory. Recent memory function involves a pathway that includes the hippocampus and the adjacent entorhinal cortex, which are rich
connected to multimodal neocortical association areas.
The hippocampus is thought to form new associations between ordinarily unrelated events, and damage therefore impairs learning. Midline structures, such as the medial and anterior thalamic nuclei and mamillary bodies, are also critical for recent memory. Functional imaging studies show that the hippocampus is activated during encoding; moreover, material that evokes the
most parahippocampal gyral activation is most likely to be remembered. There are anatomical links between the hippocampal formation and the midline structures, but the interaction between these structures is not well understood. The bilateral representation of the midline structures critical for memory means that bilateral cerebral damage is usually necessary to produce a severe amnesic syndrome.

Functional links between the working memory system (involving the prefrontal cortex) and recent memory system (involving the hippocampus, parahippocampal gyri and midline structures) must be important in creating long-term memories, which are likely to be stored in the neocortex.
The cholinergic neurotransmitter system plays a key role in recent memory, as shown by the damage to forebrain cholinergic projections in Alzheimer's disease. Furthermore, cholinergic antagonist drugs, for example scopolamine, markedly impair recent memory and learning.
The synaptic basis for the encoding and storage of memories is an area of active research. The process of long-term potentiation (the modification of a synapse's strength by the neural traffic across it) has been the most widely cited mechanism by which neural networks 'learn'. Memory disorders are common. When making a diagnosis in a clinical setting, it is useful to divide them according to whether the onset is rapid or gradually progressive, and whether they are of short duration or persistent. These types of memory loss are now
considered.

RECENT MEMORY LOSS OF RAPID ONSET AND
SHORT DURATION
Transient global amnesia
This is the prototype syndrome of recent memory loss with preserved attention. It occurs in middle-aged and elderly patients who develop sudden amnesia and bewilderment lasting several hours. There is amnesia for the recent past, as well as anterograde amnesia. They typically ask questions about their circumstances over and over again: 'Where am I?', 'How did I get here?', 'What time is it?' There is no impairment of consciousness, and the ability to do even complex tasks (procedural memory) is preserved. Patients remain capable of high-level intellectual performance throughout. Normal memory function will return within minutes to hours, and the patient has no subsequent recall for the period of amnesia and a brief spell before the attack. Most patients suffer only a single attack, but there is an annual risk of recurrence of about 5 percent.
The cause of this syndrome is uncertain, but antecedent events are commonly identified, including emotion or stress, cold water exposure, sexual intercourse and mild head trauma. It has been suggested that transient global amnesia (TGA) is due to an unusual form of complex partial seizure activity or cerebral ischaemia. Recent data from diffusion-weighted magnetic resonance imaging have shown restricted diffusion in the left mesial temporal lobe in seven out of ten patients during an attack, suggesting that TGA may have similarities with the cortical spreading depression thought to underlie migrainous aura propagation. A history of migraine is often found in patients with TGA.
In clinical practice, the important conditions to be considered in the differential diagnosis of TGA are complex partial seizures, and posterior circulation ischaemia (which will usually cause additional brainstem symptoms and signs). Transient ischemic attacks (TIAs) involving isolated ischemia of the thalamus or hippocampi may produce selectively impaired recent memory and a TGA-like syndrome.
Once the diagnosis of TGA is secure, the patient can be reassured that the condition is remarkably benign, with no increased risk of ischemic stroke.

Ictal amnesia
Amnesia for the duration of the seizure is usual in tonic-clonic seizures, complex partial and absence seizures, due to disrupted electrical activity in components of the brain memory systems. There may be brief retrograde amnesia prior to attacks as well as a period of post-ictal amnesia. Memory loss may occasionally be the only symptom of an epileptic seizure involving temporal lobe structures, although observers usually describe speech or motor
disturbance, or automatic behaviours. The brief episodes of memory disturbance seen in childhood 'petit mal' absence may cause problems with learning and behaviour. Rarely, complex partial seizures in adults may result in prolonged non-convulsive status epilepticus, which may last for days or weeks and for which the patient is subsequently amnesic.

PERSISTENT RECENT MEMORY LOSS
Korsakoff's syndrome
Korsakoff's syndrome, first described between 1887 and 1891, is a dramatic example of the amnesic syndrome. It is related to thiamine deficiency and commonly associated with long-term alcohol abuse, although it can also result from other causes of thiamine deficiency such as persistent vomiting (including hyperemesis gravidarum), intestinal obstruction, malabsorption, puerperal sepsis and metastatic carcinoma. It usually follows or accompanies Wernicke's encephalopathy, which is characterized by confusion, ophthalmoplegia and ataxia. The definition of a pure Korsakoff's syndrome requires that the patient is awake and attentive, responsive, and capable of understanding language, making appropriate deductions and solving problems. Newly presented information is correctly registered, but cannot be retained for more than a few minutes (anterograde amnesia or learning failure). There may be an associated variable dysfunction of recall of older memories – days, weeks or even years – i.e. retrograde amnesia. Confabulation, or falsification of memory, is commonly (but not invariably) seen. If recovery occurs, the period of retrograde amnesia shrinks but leaves a gap in memory for the period of anterograde amnesia following the onset of the illness. Neuropathological studies have shown a degeneration of neurons and loss of myelin in the mamillary bodies, the anteroventral and pulvinar nuclei of the thalamus, and the fornix.

Head injury
A severe head injury, sufficient to impair consciousness, invariably results in amnesia for the period of unconsciousness. It is also apt to cause retrograde amnesia, which extends for seconds, minutes or sometimes hours prior to the injury, and post-traumatic amnesia (PTA), which extends for days, weeks or, rarely, months after the injury. PTA is associated with reduced orientation and difficulty learning, and therefore has a major impact on rehabilitation. The duration of the retrograde amnesia will tend to shrink with time, whereas the anterograde amnesia is more persistent. The duration of PTA is of considerable value in assessing the severity of injury and prognosis: the longer the PTA, the more severe the head injury and the poorer the prognosis.
As a guide, of patients with PTA of less than an hour, 95 percent can be expected to return to work within 2 months; if the amnesia lasts over 24 hours, only 80 percent will return to work at 6 months. The most severely injured may remain permanently disabled.
Patients who have recovered consciousness may appear capable of conversing and carrying out normal activities, yet are unable to recall these activities later when recovery is complete because they are still in a state of PTA. This can impair their rehabilitation, and must be taken into account. Following recovery from PTA, patients may be forgetful and may complain of problems with memory for 2 or 3 years. A residual defect remaining this long is likely to be permanent.

Assessment of memory loss after head injury is difficult, and is sometimes influenced by litigation.
Formal psychometric assessment of memory function should always be undertaken, although this may be difficult or impossible in the context of profound PTA.
Head injuries that do not cause loss of consciousness are unlikely to result in severe amnesia. Penetrating wounds of the head, unless they specifically injure the medial temporal lobes, are also unlikely to cause problems with memory. Permanent memory defects may follow single severe acute head injuries or repeated minor traumas, as in the case of boxers (dementia pugilistica). The pathology of memory loss after closed head injury varies. Trauma can result in cerebral edema followed by infarction of the
hippocampus and cingulate gyri. Memory loss may be due to diffuse microscopic injuries causing diffuse axonal injury.

Vascular disease
Bilateral limbic structure infarction (including the hippocampi and medial thalamic nuclei) may cause persistent amnesia. There are often associated neurological signs to indicate posterior cerebral artery territory infarction, including visual disturbances, cortical blindness, aphasia or alexia. Unilateral infarction in the same areas may rarely cause problems with memory. Isolated frontal infarcts have also been reported to cause memory impairment. Patients who suffer rupture of an anterior communicating artery
aneurysm, or undergo surgical treatment for such a lesion, may suffer ischaemia (due to vasospasm), and consequent infarction in the distribution of the small penetrating branches of the anterior communicating artery. This results in damage to the posterior inferior medial frontal areas, and to the anterior portion of
the fornix and corpus callosum. These patients may present with acute amnesia, which may recover in those in whom the ischaemia is temporary and related to vasospasm.
An acute hypoxic cerebral insult, such as that resulting from cardiac or respiratory arrest, or after carbon monoxide poisoning, may produce an irreversible amnesic syndrome because of involvement of the medial temporal lobes and thalamus.

Encephalitis and other inflammatory conditions
Herpes simplex encephalitis is a striking cause of an acute persistent amnesic syndrome. Patients with this severe illness typically present with seizures, behavioral changes, encephalopathy, dysphasia and hemiparesis; because of the predilection of the virus to cause haemorrhagic infarction in the temporal lobes, there may be a specific amnesic syndrome.
If memory deficits persist for 1 month or more, the prognosis for recovery is likely to be poor. In addition to herpes simplex infection, any pathological process involving the functional networks underlying memory systems, particularly limbic structures, can cause amnesia. Subtle cognitive decline frequently
occurs in multiple sclerosis and, in rare cases, there may be specific and severe memory impairment.
Neurosarcoidosis, cerebral lupus and neurological Behçet's disease may also cause memory impairment.
In patients with small-cell lung carcinoma, there is an associated form of 'limbic encephalitis' in which memory defects occur as a non-metastatic, distant manifestation of the cancer. Specific antibodies to neuronal components (most commonly anti-
Hu antibodies) may be identified in serum or cerebrospinal fluid. More rarely, this syndrome can be associated with other tumors, including carcinoma of the testis or breast.
Cerebral tumor
Amnesic syndromes are rare as the presentation of cerebral tumors. They do nevertheless occur with masses arising in the diencephalus–mammary body region in the midline. Causes include corpus callosum tumors (e.g. astrocytoma) arising in the region of the fornix. The fornix may be damaged after removal of a
colloid cyst of the third ventricle, causing postoperative
amnesia.

Memory loss associated with dementias
Insidious recent memory loss is the most common presenting symptom in Alzheimer's disease, and it becomes increasingly severe as the condition progresses. Other neurodegenerative conditions, including the frontotemporal dementias, may also involve memory function, although recent memory is typically preserved for longer in these illnesses than in Alzheimer's disease. Dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration may all involve progressive recent memory impairment, but these should have other neurological features to suggest the correct diagnosis. Vascular dementia is another common cause of progressive (classically 'stepwise') memory impairment, and infarctions in the thalamus
or hippocampi, or in the white matter pathways connecting these regions to the neocortex, are the probable cause. In all of these conditions, the progression of memory loss is usually associated with intellectual, perceptual, linguistic, praxic, attentional, personality and mood disturbances, indicating the diffuse evolving nature of the underlying pathology

OTHER TYPES OF MEMORY LOSS
Drugs
Many drugs impair memory as part of a central nervous depressant effect, but others have a more specific amnesic effect. The latter include cannabis, organic solvents, heavy metals such as lead and mercury, anticonvulsant drugs, anticholinergic drugs
and benzodiazepines. Older anticonvulsant drugs, particularly phenytoin and the barbiturates, have marked effects on memory in normal volunteers and in patients with epilepsy. The new anticonvulsant topiramate may also cause mental slowness and
verbal learning disturbance. Other new anticonvulsant drugs, including gabapentin and lamotrigine, appear to have fewer cognitive side effects than older medications.
'Psychogenic amnesia'
Complaints of memory impairment are common in depression and anxiety, but formal assessment with psychometry will usually reveal that reduced attention motivation or low mood is the cause for the symptom. More florid psychogenic amnesic states do
occur, but differ from organic amnesia in the pattern of the memory defect and in the time course of onset and recovery. Loss of personal identity is common in psychogenic amnesia, but extremely rare in organic amnesia. The common setting of the 'psychogenic fugue', in which the patient is discovered wandering,
often a long distance from home, is associated with loss of personal identity and amnesia. There may be a triggering event such as financial or marital problems. Recovery of normal learning and alertness is often sudden, but loss of personal identity and
profound retrograde amnesia may persist, unlike the usual temporal memory gradient and gradual recovery seen in organic amnesias. Inability to recognize their spouse or partner is also typical. The retrospective forgetting of circumscribed periods from the past is often found after distressing events, as in wartime, but may include periods of alleged criminal activity in malingerers. Feigned amnesia may be detected by the 'two-choice' recognition test of memory, in which malingerers will score significantly worse than they would by chance.