Differential Diagnosis of Acute Neural Cognitive Decline
The differential diagnosis of acute cognitive decline must systematically exclude metabolic encephalopathies, infectious causes (particularly viral encephalitis), cerebrovascular events, autoimmune conditions, and toxic/medication effects before attributing symptoms to primary neurological disease. 1
Initial Clinical Assessment Framework
The presence of fever with altered mental status, new seizures, or focal neurological signs should immediately raise suspicion for CNS infection, particularly viral encephalitis, requiring urgent investigation 1. However, metabolic, toxic, and autoimmune causes must be considered early, especially when certain features are present 1:
Red Flags Suggesting Non-Infectious Encephalopathy
- History of similar episodes 1
- Symmetrical neurological findings 1
- Myoclonus or asterixis (strongly suggests metabolic encephalopathy) 1
- Absence of fever 1
- Acidosis or unexplained negative base excess 1
Major Diagnostic Categories
1. Metabolic and Toxic Encephalopathies
Hepatic encephalopathy presents with cognitive impairment and asterixis in cirrhotic patients, requiring exclusion through blood tests (ammonia, liver function) and assessment for precipitating factors 1. The differential for asterixis specifically includes 1:
- Uraemia, hypercapnia, hypoglycaemia
- Hydroelectrolytic disorders (hypokalaemia, hypomagnesaemia)
- Drugs: antiepileptics, levodopa, opiates, anticholinergics, benzodiazepines, lithium, clozapine
Essential metabolic workup includes blood glucose, electrolytes (sodium, potassium, calcium, magnesium), renal function (urea, creatinine), liver function tests, thyroid function, vitamin B12, and inflammatory markers 1.
2. Infectious Causes
Viral encephalitis classically presents with fever (91% of HSV cases), altered behavior, personality changes, speech disturbances (59%), and seizures (33%) 1. Subacute presentations (weeks to months) suggest autoimmune or paraneoplastic etiologies rather than typical viral infections 1.
Bacterial meningitis with lymphocytic pleocytosis can mimic viral encephalitis, particularly 2:
- Listeria monocytogenes (accounts for 20-40% in immunocompromised, elderly, diabetics)
- Tuberculous meningitis
- Partially treated bacterial meningitis
CSF interpretation is critical 2:
- Normal glucose with lymphocytic pleocytosis suggests viral infection
- Low CSF:plasma glucose ratio (<0.5) suggests tuberculosis, fungal infection, or partially treated bacterial meningitis
- CSF lactate <2 mmol/L effectively rules out bacterial disease
3. Cerebrovascular Disease
Poststroke cognitive impairment (PSCI) occurs in up to 60% of stroke survivors, with 38% having mild cognitive impairment and 7-41% having dementia 1. Even transient ischemic attacks without frank infarction can cause delayed brain atrophy and cognitive decline 3.
Key differentiating features 1:
- Acute stepwise decline in cognition temporally related to stroke event
- Focal neurological deficits corresponding to vascular territory
- MRI evidence of acute infarction or hemorrhage
- Risk factors: hypertension, diabetes, atrial fibrillation, prior stroke
Delirium must be distinguished from PSCI by alterations in arousal and fluctuating course 1.
4. Autoimmune and Paraneoplastic Encephalitis
Antibody-mediated encephalitis should be suspected with 1, 2:
- Subacute presentation (weeks to months)
- Orofacial dyskinesia, choreoathetosis, faciobrachial dystonia
- Intractable seizures (often without fever)
- Hyponatremia
- Psychiatric symptoms, seizures, or movement disorders
Specific conditions include 2, 4:
- Anti-NMDA receptor encephalitis
- Limbic encephalitis (paraneoplastic and non-paraneoplastic)
- Hashimoto encephalopathy (corticosteroid-responsive with thyroid autoimmunity)
- Neuropsychiatric SLE (50-70% have mild-to-moderate CSF abnormalities with lymphocytic predominance)
5. Alcohol-Related Cognitive Disorders
Wernicke-Korsakoff syndrome must be differentiated from hepatic encephalopathy in cirrhotic patients with alcohol use 1, 5. Key features include 5:
- Anterograde episodic memory impairment
- Visuoconstructive impairments
- Progressive evolution without fluctuations
- Critical: glucose administration before thiamine can precipitate or worsen the syndrome
Other alcohol-related causes include post-traumatic dementia, alcohol-related dementia, and vitamin deficiencies (B12, folate) 1.
6. Neurodegenerative Diseases
Alzheimer's disease and other dementias typically present with 1:
- Temporospatial disorientation
- Anterograde episodic memory impairment with storage deficits
- Visuoconstructive impairments
- Word-finding problems
- Progressive course without fluctuations
This contrasts with covert hepatic encephalopathy, which shows isolated cognitive impairment with slower thinking, impaired attention, and frontal-subcortical syndrome (memory retrieval without storage impairment) 1.
7. Additional Considerations
In cirrhotic patients specifically 1:
- Cerebral microangiopathy (vascular leukoencephalopathy)
- Sleep apnea syndrome
- Chronic infectious and autoimmune meningoencephalitis
- Psychiatric disorders (anxiety, major depression, psychotic disorders)
In stroke patients 1:
- Poststroke depression (affects one-third in first year)
- Medication effects (sedating and anticholinergic drugs)
- Sleep disorders including obstructive sleep apnea
- Hearing and vision impairments
Essential Diagnostic Workup
Blood tests 1:
- Complete metabolic panel (electrolytes, glucose, calcium, magnesium, liver and renal function)
- Complete blood count with differential
- Thyroid-stimulating hormone
- Vitamin B12, folate
- Inflammatory markers (ESR, CRP)
- Ammonia (if hepatic encephalopathy suspected)
Brain imaging 1:
- MRI is preferred over CT for detecting subtle abnormalities
- Look for: acute infarction, hemorrhage, white matter hyperintensities, brain atrophy, mesial temporal lobe signal changes (limbic encephalitis), mass lesions
CSF examination when indicated 1, 2:
- Cell count and differential
- Glucose and protein
- Lactate
- HSV PCR (if encephalitis suspected)
- Autoimmune encephalitis antibody panel if clinical features suggest
EEG may help distinguish metabolic encephalopathy from seizure activity or specific patterns in encephalitis 1.
Critical Pitfalls to Avoid
Never administer glucose before thiamine in patients with suspected Wernicke-Korsakoff syndrome, as this can precipitate or worsen the condition 5.
Do not delay empiric antibiotics if bacterial meningitis cannot be definitively excluded; treatment should begin within one hour when suspected 2. For patients >50 years or immunocompromised, add ampicillin to cover Listeria (resistant to cephalosporins) 2.
Recognize that hyperammonemia can occur without encephalopathy, so ammonia levels alone do not confirm hepatic encephalopathy 1.
In patients with metabolic syndrome and NAFLD, vascular dementia may coexist with or mimic hepatic encephalopathy 1.