What is the differential diagnosis for amnesia?

Differential Diagnosis for Amnesia

When evaluating amnesia, systematically categorize by temporal pattern (acute vs. progressive), type (anterograde vs. retrograde), and associated features to distinguish between neurodegenerative, vascular, epileptic, traumatic, toxic-metabolic, autoimmune, and psychogenic etiologies.

Progressive Amnestic Syndromes (Chronic/Insidious Onset)

Alzheimer's Disease (Most Common)

• Alzheimer's disease accounts for 50-70% of all dementia cases and is the most common cause of progressive amnestic disorder 1
• Characterized by insidious onset with gradual progression of difficulty learning and remembering new information (anterograde amnesia) 2
• Memory impairment is the initial and most prominent feature, often accompanied by executive dysfunction, depression, or anxiety 2
• Diagnosis requires impairment in at least one other cognitive domain beyond memory 2
• Consider CSF biomarkers (decreased Aβ42, elevated tau/p-tau) or amyloid PET when diagnosis is uncertain 2, 1

Other Neurodegenerative Causes

• Hippocampal sclerosis, argyrophilic grain disease, primary age-related tauopathy (PART), and TDP-43 proteinopathy/LATE can present with progressive amnesia 2
• Dementia with Lewy bodies presents with fluctuating cognition, visual hallucinations, parkinsonism, and REM sleep behavior disorder alongside memory impairment 2
• Frontotemporal lobar degeneration (FTLD) rarely causes isolated amnesia but may present with behavioral/executive dysfunction and memory complaints 2

Vascular Cognitive Impairment

• Pure vascular cognitive impairment and disease (VCID) can cause progressive amnesia, particularly with strategic infarcts affecting memory circuits 2
• History of stroke temporally related to cognitive decline, multiple infarcts, or severe white matter disease suggests vascular etiology 2

Mixed Pathologies

• In patients over 85 years, multiple etiologies are highly likely, particularly Alzheimer's pathology combined with cerebrovascular disease 1
• AD frequently coexists with VCID, Lewy body disease, or both (AD + VCID + LBD) 2

Acute/Subacute Amnestic Syndromes

Transient Global Amnesia (TGA)

• TGA is the most common cause of acute-onset amnesia, characterized by sudden profound anterograde and retrograde amnesia lasting up to 24 hours (average 6-8 hours) 3, 4
• Incidence is 3-8 per 100,000 population/year, predominantly affecting ages 50-70 4
• Diagnosis is clinical; MRI may show punctate DWI/T2 lesions in hippocampus (especially CA1 region) when performed 24-72 hours after onset 4
• TGA in patients under 50 years is rare and mandates rapid search for alternative causes 4
• Prognosis is favorable with no chronic sequelae 4

Transient Epileptic Amnesia (TEA)

• Caused by focal seizure activity affecting memory circuits 5
• Distinguished from TGA by recurrent brief episodes, often upon awakening 3
• EEG may help differentiate TEA from TGA, especially in recurrent amnestic attacks 4

Stroke/Vascular Events

• Stroke at strategic memory-related sites (thalamus, hippocampus, fornix, mammillary bodies) can present as sudden amnesia 5, 3
• If DWI changes occur outside the hippocampus, vascular etiology should be considered with prompt sonographic and cardiac evaluation 4

Traumatic Brain Injury

• Post-traumatic amnesia follows head trauma with variable duration and severity 5, 3
• Both anterograde and retrograde components possible 5

Autoimmune Encephalitis

• Limbic encephalitis (anti-NMDA receptor, anti-LGI1, anti-CASPR2, others) can cause acute to subacute amnesia 5
• Often accompanied by seizures, psychiatric symptoms, or movement disorders 5

Toxic-Metabolic Causes

• Alcohol-induced amnesia (blackouts) is the most prominent drug-related cause with variable duration and non-specific effects 5, 6
• Wernicke-Korsakoff syndrome from thiamine deficiency causes severe anterograde amnesia 5
• Benzodiazepines, anticholinergics, and other medications can impair memory 5, 3
• Hypoglycemia, hypoxia, carbon monoxide poisoning affect memory circuits 5

Psychogenic/Dissociative Amnesia

• Functional focal retrograde amnesia characterized by impaired recollection of past events with preserved anterograde memory 7
• May follow psychic trauma, fugue states, or stressful events 5, 7
• Retrograde amnesia can be so severe as to erase personal identity 7
• No structural lesions on neuroimaging; represents functional memory inhibition 7
• Typically reversible within days, leaving gap for the onset period 7

Electroconvulsive Therapy (ECT)

• Can cause variable degrees of retrograde amnesia 6

Diagnostic Approach Algorithm

Step 1: Temporal Pattern Assessment

• Sudden onset (minutes to hours): Consider TGA, TEA, stroke, trauma, toxic exposure, or psychogenic causes 5, 3, 4
• Insidious onset with gradual progression: Consider Alzheimer's disease or other neurodegenerative disorders 2

Step 2: Memory Type Characterization

• Predominantly anterograde amnesia: Alzheimer's disease, TGA, Wernicke-Korsakoff, hippocampal lesions 2, 4
• Predominantly retrograde amnesia: Psychogenic/dissociative amnesia, functional FRA, some traumatic cases 7
• Mixed pattern: Most organic causes have both components 5

Step 3: Associated Features

• Fluctuations, hallucinations, parkinsonism: Dementia with Lewy bodies 2
• Behavioral/personality changes: Frontotemporal dementia 2
• Seizure activity: Transient epileptic amnesia 5, 4
• Vascular risk factors or stroke history: Vascular cognitive impairment 2
• Recent head trauma: Post-traumatic amnesia 5, 3

Step 4: Initial Diagnostic Testing

• MRI brain without contrast is preferred for all cases to detect vascular lesions, hippocampal atrophy, and structural abnormalities 8
• Include 3D T1 volumetric sequences with coronal reformations, FLAIR, DWI, and susceptibility-weighted imaging 8
• For acute amnesia, MRI performed 24-72 hours after onset has highest sensitivity for TGA 4
• CT is acceptable alternative when MRI unavailable but less sensitive 8

Step 5: Additional Testing Based on Clinical Context

• EEG if recurrent episodes or suspected seizure activity 4
• CSF analysis (Aβ42, tau, p-tau ratios) when Alzheimer's diagnosis uncertain in progressive cases 2, 1
• FDG-PET when diagnosis remains unclear after structural imaging and clinical evaluation 2, 8
• Amyloid PET for atypical presentations when biomarker support needed 2
• Thyroid function, B12 level, metabolic panel to exclude reversible causes 1

Critical Pitfalls to Avoid

• Do not assume single etiology in patients over 85 years; multiple pathologies are the rule rather than exception 1
• Do not diagnose TGA in patients under 50 without exhaustive exclusion of other causes 4
• Do not overlook autoimmune encephalitis in subacute presentations with psychiatric features or seizures 5
• Do not dismiss psychogenic amnesia when neuroimaging is normal and retrograde amnesia is disproportionate to anterograde deficits 7
• Do not order amyloid PET without specialist consultation as interpretation requires expertise and positive results don't confirm AD as sole cause 2, 8
• Only 1.5% of mild-moderate dementia cases are completely reversible (hypothyroidism, B12 deficiency), so maintain realistic expectations 1