Differential Diagnosis in Neurology

15.8. Memory and Amnesia

Isolated memory disorders or amnesia frequently occur following bilateral involvement of limbic structures. In a core amnesic syndrome, patients suffer a global anterograde and retrograde memory deficit with occasional confabulation. Other cognitive functions including attention and motivation are intact.

Anterograde amnesia is the inability to learn new material. Retrograde amnesia is the inability to remember events prior to injury. Rabat's law is frequently seen which states that the older memories are most resistant to amnesia. Retrograde amnesia with a temporal gradient, loss of most recent memory is different from amnesia for remote events. Confabulation is the use of fabricated verbal responses concerning questions about recent events. This appears to be a compensatory mechanism to conceal a severe short term memory deficit. Patients with the amnestic syndrome may retain learning tasks that depend on the acquisition of motor skills.

Amnesias with Bilateral Limbic Involvement (The Amnestic Syndrome)

Korsakoff's Syndrome

The syndrome is most often from thiamine deficiency (alcohol, pernicious vomiting, renal dialysis) and may be progressive or follow a global confusional state. It may be accompanied by ataxia, ophthalmoplegia, nystagmus and peripheral neuropathy. After the acute confusional state clears, the patient may be left with variable difficulty in acquiring new information, confabulation, and a temporal gradient of retrograde amnesia.

Three Major Features of Korsakoff's Syndrome

• Euphoria, anosognosia, confabulation
• Disorientation, difficulty in maintaining goal directed activity
• Pure memory impairment

The temporal evaluation of Korsakoff's syndrome may feature each of the three components. Anatomically, there are bilateral lesions of the mammillary bodies, the anterior column of the fornix, hypothalamic nuclei, the dorsal medial nuclei of the thalamus, medial pulvinar and lateral dorsal thalamic nuclei. Dorsal medial nuclei of the thalamus may be important for confabulation as well as memory.

Hypothalamic Tumors

Amnestic syndromes have been reported in cases of hypothalamic tumors particularly in those surrounding the floor and walls of the third ventricle.

Thalamic Lesions

Bilateral dorsomedial thalamotomies cause transient loss of temporal organization and chronology of the patient's experience. Thalamic infarcts affecting the paramedian and dorsomedial nuclei are associated with severe antegrade and retrograde memory loss. Unilateral left thalamic lesions in the dorsomedial or anterior thalamic nuclei have been associated with anterograde amnesia particularly for language.

Basal Forebrain Lesions

Lesions affecting the septum, hypothalamic and caudal orbitofrontal regions from tumor or anterior communicating aneurismal rupture cause severe amnesia. These pathologies may damage the septal nuclei and the nucleus basalis of Meynert which would destroy the cholinergic innervation of the limbic and frontal cortex.

Bilateral Fornix Lesions

Patients with tumors or bilateral section of the fornix may develop an amnestic syndrome.

Cingulate Lesions

Bilateral cingulotomies are associated with transitory memory disorders with confabulation similar to Korsakoff's Syndrome. These patients may also suffer difficulty in ordering memories in a proper temporal sequence. Amnestic syndromes after callosal commissurotomy or posterior corpus callosum tumors may be due to posterior cingulate gyrus damage.

Selective Amnesias from Unilateral Temporal Lesions

The recognition of recurring nonsense figures, faces and maze learning may be deficient after right temporal lobe lesions. The recall of verbal material is disturbed after left temporal lobectomy. These impairments are independent of the modality in which they are presented. The right temporal lobe can recognize nonverbalizable tactile patterns better than the left after commissurotomy.

Amnesias of Unknown Anatomical Cause

Head Trauma

• Long fiber bundles including the fornix are damaged by shearing forces
• The temporal poles and the orbitofrontal cortex are often severely damaged.
• There is a correlation between the amount of damage in these areas with the severity of ante grade and retrograde amnesia

Electroconvulsive therapy

• Comparable to head injury
• Unilateral ECT-material specific amnestic syndromes.

Epilepsy

Fugues and amnesias occur in patients with complex seizures. Hippocampal involvement occurs in the amnesia of chronic epilepsy.

Drugs

• Benzodiazepines cause a state similar to transient global amnesia.
• Amytal induces "blackouts".
• Scopolamine memory loss similar to amnestic syndromes.

Huntington's Disease

Memory loss can occur early in HD.

Depression

Depression is associated with a partial and relatively mild memory disorder probably in the encoding stage of short term memory.

Transient Global Amnesia

Men are more frequently affected than women; it is primarily anterograde amnesia that lasts for 3 to 24 hours. Anterograde amnesia is acute; the patients are aware and anxious as well as perplexed. Temporal disorientation is severe; spatial disorientation is variable. Retrograde amnesia affects the 1st few hours preceding the onset of the disorder. Some biographical data is forgotten. General knowledge is intact and there are no accompanying intellectual or neurologic deficits. Recovery is rapid. Differential diagnosis includes posterior cerebral artery ischemia, migraine headache, seizures. Transient global amnesia may appear during periods of high stress.

Benign Senescent Forgetfulness

The greatest difficulty is for names and details although minor events are easily recalled. Cueing improves performance. The deficit may be at the retrieval stage.

Psychogenic Amnesias

These are also known as functional retrograde amnesia ("forgetting the disagreeable"). It occurs after strong emotion or psychological trauma. Loss of personal identity, patients forget their names and their past, but memory for recent events is normal. Anxiety is not great although it is often accompanied by a fugue, which ceases after a few days or weeks.

Anatomical Basis of Memory

Memory can be divided into three major phases:

• Inscription:
  • This takes place during the first 30 seconds, is an electrical process that occurs primarily in the medial hippocarpal structures. It appears to be related to reverberating circuits and acetylcholine is the primary neurotransmitter.
• Consolidation:
  • The structures that are most important for this phase of memory are:
    • The medial hippocampus
    • The mammillary bodies and the mamillothalamic tract
    • The dorsomedial nucleus of the thalamus
  • Messenger RNA is synthesized during this phase of memory
  • It is vulnerable to intrusion
• Protein synthesis:
  • Memory appears to be related to protein synthesis that occurs in specific parts of the brain
  • Long term potential of individual cells utilizing NMDA receptors appears to be important
• Retrieval:
  • The dorsolateral frontal cortex is important for activating and retrieving memory that has been consolidated
  • Cueing appears to occur here
• Forgetting may be related to unfolding of the tertiary structures of synthesized proteins.

Confusional States

An acute confusional state is a change in mental status, the most important feature of which is failure of attention. Most often there are no neurological signs other than a coarse tremor, myoclonus, or asterixis. Vigilance is defective in intensity and selectively. Attention either wanders aimlessly or is suddenly focused with inappropriate intensity or an irrelevant stimulus becomes the source of distractibility. Thought and skilled movement are diminished by interference, impersistence and perseveration. The stream of thought is interrupted by frequent intrusions of competing thoughts and sensations.

• The three cardinal features of confusional state are:
  • Disturbance of vigilance and heightened distractibility
  • Inability to maintain a coherent stream of thought
  • Inability to carry out a sequence of goal-directed movements.

Causes and Mechanisms of Confusional States 

• Toxic-metabolic encephalopathy
• Multifocal brain lesions
• Head trauma
• Epileptic seizures
• Space-occupying lesions
• Focal brain lesion

Toxins and drugs that interfere with cholinergic transmission are particularly apt to produce confusional states. Drugs with anticholinergic effects (antihistamines, neuroleptics, antidepressants) also cause confusional states.

Multifocal Brain Disease

• ALZ (abiotrophies)
• Meningitis
• Encephalitis
• Anoxia
• DIC
• Fat emboli
• Head trauma
• Ictal/postictal state
• SDH

Focal Brain Lesions

Unilateral lesions in the parahippocampal fusiform and lingual gyrus on either side of the brain. Infarcts of the posterior parietal and inferior prefrontal regions of the right hemisphere. The left caudate nucleus and the intraparietal gyrus on the right side have been associated with acute confusional states.

Detection, Vulnerability, and Clinical Course of Confusional States

An acute confusional state may be the presenting clinical sign of an underlying systemic disease. The elderly and those with pre-existing brain disease (dementia) are more vulnerable to mild metabolic stress. Patients that demonstrate extreme vulnerability and indolent recovery may have an underlying dementing illness such as diffuse Lewy Body Disease.

Unilateral Neglect as a Disorder of Directed Attention

Unilateral neglect is a fundamental disturbance in directed sensory attention. Some patients are abnormally distracted by sensory events within the intact hemispace. One mechanism that may underlie extinction is the abnormal magnetism of the stimulus toward the intact side. There may be task related shifts in the inner representation of space.

Motor Aspects of Unilateral Neglect

The motor aspects of attention, orienting, scanning and searching within extrapersonal space are deficient in patients with unilateral neglect. Patients with left unilateral neglect have difficulties with the manual exploration of the environment. This implies that at certain stages of motor integration, the motor programs are organized not according to muscle groups that are being activated, but according to the hemispace within which the movement is to occur.

Motivational Aspects of Unilateral Neglect

Neglect can occur with lesions of the posterior parietal cortex, lateral prefrontal cortex, cingulate gyrus, striatum and thalamus. It may be seen with lesions of the right inferior parietal lobule. Lesions of the superior parietal may be more closely associated with neglect behavior. Patients with parietal damage have multimodal extinction to double simultaneous stimulation; they neglect the internal sensory representation of left extra-personal space and they have difficulty with leftward shifts of attention.

The Limbic Connection in Neglect

Medial frontal infarcts involving the cingulate region of the right hemisphere cause unilateral neglect of left hemispace.

The Reticular Component in Neglect

Brain stem raphe, NLC, pontomesencephalic cholinergic nuclei of the PF project to PG (and almost all parts of the cortex). This input may regulate the overall attentional tone in area PG. A vector function such as directed attention operates on a background of underlying matrix of attentional tone. The frontal eye fields mediate the internal planning and spatial organization of eye movements. The inferior parietal lobule projects to the superior colliculus and the frontal eye fields. In humans, bifrontal lesions that include the frontal eye fields disturb the ability to systemically scan complex visual scenes in the absence of a gaze paresis. Unilateral lesions that include the frontal eye fields can cause contralateral neglect. Head and eye deviation may be a manifestation of neglect rather than weakness.

Subcortical Neglect

Unilateral neglect has been seen after lesion of the thalamus. Possibly the DM and medial putamen are most important. The medial pulvinar projects to the posterior parietal lobe and the DM projects to the frontal eye fields. Unilateral striatal damage is a cause of neglect in humans.

Neglect of the Body Surface and Motor Neglect

Right hemisphere lesions also demonstrate motor neglect or negligence (motrice) reluctance to use the contralateral limbs in the absence of weakness. Specific commands to use the limb may overcome this hypokinesis. This type of deficit has also been noted with lesions of the striatum, thalamus, and frontoparietal cortex. This type of motor neglect is confined to the contralateral extremity and may be seen from lesions in either hemisphere (a "loathness to move"). These patients may have no neglect for extrapersonal space.

• Right hemispheric specialization for attention is demonstrated by:
  • Simple reaction times to ipsilateral visual stimuli are faster with the left hand
  • Patients with right hemisphere lesions have bilateral deficits in reaction time more frequently than those with left hemisphere lesions
  • In split brain patients, vigilance performance is better when the task is being performed by the right hemisphere
  • Right hemisphere damaged patients show smaller galvanic skin responses in reaction to stimulation than left hemisphere damaged patients
  • Event-related patients and EEG desynchronization occur in the left hemisphere after stimulation of only the right hand whereas this occurs in the right hemisphere after stimulation of either hand
  • F¹⁸-2DG activation is increased in the right hemisphere to a greater degree than the left when a relevant visual stimulus is placed centrally

Unilateral neglect for the right side of space may develop rarely after left hemisphere lesions but it suggests bilateral damage.

Attentional deficits are the major component of the hyperkinetic state of childhood, infantile autism and schizophrenia. This deficit may represent the breakdown of a possible filtering mechanism that normally differentiates relevant from irrelevant stimuli.