What laboratory tests are recommended for a patient presenting with encephalopathy?

Laboratory Workup for Encephalopathy

All patients presenting with encephalopathy require a comprehensive metabolic panel, complete blood count, blood cultures, urinalysis with culture, liver function tests, and blood glucose as first-tier essential tests, with additional targeted testing based on clinical context and suspected etiology. 1

Essential First-Tier Laboratory Tests (Obtain in All Patients)

Core Metabolic and Hematologic Studies

• Complete metabolic panel including sodium, potassium, chloride, bicarbonate, blood urea nitrogen, and creatinine to identify electrolyte disturbances and renal dysfunction 1
• Blood glucose measurement to detect hypoglycemia or hyperglycemia 1
• Serum calcium and magnesium levels, as disturbances commonly contribute to altered mental status 1
• Complete blood count with differential to assess for infection or hematologic abnormalities 1
• Liver function tests including transaminases, bilirubin, albumin, and INR to evaluate for hepatic encephalopathy 1

Infection Screening

• Blood cultures (at least two sets) to identify bacteremia 2
• Urinalysis with culture to detect urinary tract infection 2
• Chest imaging (chest X-ray or CT) to identify pneumonia 2

Additional Baseline Studies

• Thyroid-stimulating hormone (TSH) to exclude hypo- or hyperthyroidism 1
• Blood alcohol level and toxicology screen to identify toxic causes 1

Cerebrospinal Fluid Analysis (When Indicated)

Lumbar puncture should be performed when infectious or autoimmune encephalitis cannot be excluded clinically, after neuroimaging excludes mass effect. 2, 3

Standard CSF Studies

• Opening pressure measurement 2
• Cell count with differential (WBC, RBC) 2
• Protein and glucose (with simultaneous serum glucose) 2
• Gram stain and bacterial culture 2

Infectious Workup

• HSV-1/2 PCR (consider HSV CSF IgG and IgM if PCR not immediately available) 2
• VZV PCR (consider VZV CSF IgG and IgM as sensitivity may be low) 2
• Enterovirus PCR 2
• Cryptococcal antigen and/or India Ink staining 2
• VDRL for neurosyphilis 2

Autoimmune Studies

• Oligoclonal bands and IgG index 2

Collect at least 20 cc of CSF if possible and freeze 5-10 cc for additional testing. 2

Serum Studies for Specific Etiologies

Infectious Causes

• HIV serology (consider RNA testing) 2
• Treponemal testing (RPR and specific treponemal test) 2
• Hold acute serum and collect convalescent serum 10-14 days later for paired antibody testing 2

Autoimmune Encephalitis (Based on Clinical Features)

• Anti-NMDAR antibody (serum and CSF) if psychotic features or movement disorder present 2
• Autoimmune limbic encephalitis panel if prominent limbic symptoms 2
• Anti-VGKC antibody (serum) if hyponatremia present 2

Nutritional Deficiencies

• Vitamin B12 and folate levels, especially in patients with alcohol use disorder or malnutrition 1
• Thiamine deficiency assessment should be considered, though treatment should not be delayed for test results in at-risk patients 1

Context-Specific Testing

Immunocompromised Patients

• CMV PCR, HHV6/7 PCR, HIV PCR (CSF) 2
• Toxoplasma gondii serology and/or PCR 2
• Mycobacterium tuberculosis testing 2
• Fungal testing 2

Seasonal and Exposure-Based Testing

• Arbovirus and tick-borne disease testing in summer/fall presentations 2
• Bartonella antibody (serum) with cat exposure, particularly if seizures and paucicellular CSF 2
• Rabies testing with animal bite or bat exposure 2
• Naegleria fowleri (CSF wet mount and PCR) with freshwater swimming or nasal irrigation history 2

Symptom-Specific Testing

• Mycoplasma pneumoniae serology and throat PCR with respiratory symptoms (if positive, perform CSF PCR) 2
• Rickettsia serology with elevated transaminases 2

Hepatic Encephalopathy-Specific Considerations

Ammonia Testing

Ammonia level should be measured if hepatic encephalopathy is suspected, but proper technique is critical: 1

• Collect in EDTA-containing tube 1
• Avoid venous stasis (no tourniquet) 4, 1
• Place immediately on ice 4, 1
• Transport to laboratory within 60-90 minutes at 4°C 4, 1

Critical caveat: Do not rely solely on ammonia levels for diagnosis or exclusion of hepatic encephalopathy—clinical context is paramount. 4, 1 A normal ammonia level should prompt reconsideration of the diagnosis. 1

Precipitant Identification

When hepatic encephalopathy is suspected, systematically evaluate for precipitants: 4

• Diagnostic paracentesis in patients with ascites to exclude spontaneous bacterial peritonitis (this is frequently omitted—77% of eligible patients in one study did not receive this test) 5
• Stool culture if diarrhea present 2
• Review medications for sedatives, diuretics, or other precipitants 4

Neurophysiology and Imaging

Electroencephalography

EEG should be obtained to identify non-convulsive seizures and grade severity of encephalopathy. 2, 1 EEG may show diffuse slowing characteristic of metabolic encephalopathy and can detect epileptiform discharges in the absence of clinical seizure activity. 6, 7

Neuroimaging

Brain MRI is the preferred imaging modality and should be obtained in the initial evaluation to exclude structural lesions, subdural hematoma, stroke, or other focal pathology. 1 CT is acceptable if MRI unavailable but is less sensitive. 8

Neuroimaging is mandatory in: 4, 3

• First episode of encephalopathy
• Focal neurological findings
• Patients with liver disease or alcohol abuse
• Diagnostic uncertainty or failure to improve with treatment
• Anticoagulated patients (to exclude subdural hematoma)

Critical Pitfalls to Avoid

Do not attribute encephalopathy to a single cause without excluding concurrent precipitants. 4 Infection (UTI, pneumonia), gastrointestinal bleeding, constipation, electrolyte disturbances, and medications frequently coexist. 4

Do not delay brain imaging while pursuing metabolic workup—22% of patients with suspected metabolic encephalopathy have alternative structural diagnoses. 3

Do not skip diagnostic paracentesis in cirrhotic patients with ascites—spontaneous bacterial peritonitis is a critical precipitant that is frequently missed. 5

Do not confuse alcohol withdrawal with hepatic encephalopathy in cirrhotic alcoholics—they require different treatments and can coexist. 4

Do not order ammonia levels in isolation or use them to guide treatment decisions—clinical diagnosis based on West Haven Criteria after excluding other causes is the standard approach. 4, 1

Adherence to Guidelines

A retrospective study found only 22% of hospitalized patients with hepatic encephalopathy received complete diagnostic workup within 24 hours, with blood cultures missing in 30%, urinalysis in 21%, and chest radiograph in 20%. 5 Paradoxically, serum ammonia (not endorsed by guidelines for routine workup) was ordered in 95% of patients. 5 This underscores the need for systematic adherence to evidence-based diagnostic algorithms.