Causes and Diagnosis of Encephalopathy
Encephalopathy is global cerebral dysfunction caused by metabolic, toxic, infectious, or immune-mediated processes—not primary structural brain disease—and diagnosis requires identifying altered mental status plus systematically excluding reversible causes through targeted laboratory testing, neuroimaging, and cerebrospinal fluid analysis. 1
Key Distinction: Encephalopathy vs. Encephalitis
Encephalopathy and encephalitis are often confused but represent different pathophysiologic processes. 1 Encephalopathy refers to altered mental status with or without brain inflammation, triggered by metabolic, toxic, or systemic conditions. 1 In contrast, encephalitis involves actual brain parenchymal inflammation from direct infection, post-infectious immune responses, or autoimmune processes. 1 Critically, encephalitis can present without CSF pleocytosis or neuroimaging abnormalities, so normal studies do not exclude it. 1, 2
Major Causes of Encephalopathy
Metabolic Causes
- Hyponatremia is the most common metabolic cause in elderly patients 2
- Electrolyte disturbances: hypokalaemia, hypomagnesaemia, hypocalcemia 2
- Hepatic encephalopathy from liver dysfunction with neurotoxin accumulation 2
- Uremic encephalopathy from renal failure 2
- Hypercapnia (CO₂ retention) from respiratory disorders 2
- Endocrine disorders: hypothyroidism, hyperthyroidism 2
- Inherited metabolic disorders such as urea cycle defects 2
Toxic Causes
- Medications: antiepileptic drugs, levodopa, opiates, anticholinergics, benzodiazepines, lithium, clozapine 2
- Alcohol-related: acute intoxication, withdrawal, Wernicke-Korsakoff syndrome (thiamine deficiency), alcohol-related dementia 2
- Chemotherapy-induced: ifosfamide, high-dose cytarabine, methotrexate 1
Infectious Causes (When Encephalitis is Present)
- Herpes simplex virus (HSV-1, HSV-2) is the most common viral cause in industrialized nations 2
- Varicella zoster virus (VZV) during primary infection or reactivation 2
- Enteroviruses, cytomegalovirus (CMV), human herpes viruses 6 and 7 2
- Bacterial: Bartonella henselae, Mycobacterium tuberculosis, Treponema pallidum 2
- Fungal: Cryptococcus neoformans, Coccidioides species 2
- Parasitic: Toxoplasma gondii, cerebral malaria 2
Immune-Mediated/Autoimmune Causes
- Anti-NMDA receptor encephalitis (antibody-mediated) 1, 2
- Acute disseminated encephalomyelitis (ADEM) - post-infectious or post-vaccination 2
- Limbic encephalitis (may be paraneoplastic, e.g., ovarian teratomas) 2
Septic Encephalopathy
- Occurs in 50-70% of septic patients, most frequently in elderly with extracranial sepsis 1
- Diagnosis of exclusion when encephalopathy cannot be attributed to other organ dysfunction 1
- Uncommon in pediatrics but can occur with urinary tract infections, shigella, typhoid fever 1
Clinical Presentation
Core Features Requiring Immediate Evaluation
Altered mental status is the mandatory criterion for diagnosis. 1 This includes: 1, 3
- Consciousness changes: impaired attention → confusion → delirium with psychotic features → drowsiness → coma
- Cognitive dysfunction: disorientation (76% of cases), speech disturbances (59%), behavioral changes (41%) 1, 3
- Affective changes: apathy, anxiety, agitation 1
Motor and Neurological Signs
- Asterixis (flapping tremor) is a hallmark early-to-mid-stage sign, elicited by hyperextending wrists; appears at Grades I-II and disappears as patients progress to stupor/coma 3
- Parkinsonian features: reduced facial expression, rigidity, bradykinesia, monotonous speech 3
- Focal signs: paresis, speech disorders, cranial nerve dysfunction may accompany global encephalopathy 1, 3
- Seizures occur in approximately one-third of patients 1, 3
Temporal Patterns Guide Differential Diagnosis
- Acute onset (hours-to-days) with fever, altered behavior, new seizures, or focal signs → suspect encephalitis or CNS infection 1, 3
- Subacute course (weeks-to-months) with orofacial dyskinesia, choreoathetosis, faciobrachial dystonia, intractable seizures, or hyponatremia → suspect antibody-mediated encephalitis 1, 3
Associated Systemic Features
- Fever is present in 91% of infectious encephalitis cases on admission 3
- Headache, nausea, vomiting are classic accompanying symptoms 3
Diagnostic Approach
Initial Clinical Assessment
Look for features suggesting non-encephalitic metabolic/toxic processes: 1
- Past history of similar episodes
- Symmetrical neurological findings
- Myoclonus or asterixis
- Lack of fever
- Acidosis or unexplained negative base excess
A normal Glasgow Coma Scale does not exclude encephalopathy, as it misses subtle behavioral alterations. 1, 3
Laboratory Investigations
Comprehensive metabolic panel to identify reversible causes: 1
- Serum glucose, sodium, calcium, magnesium, potassium
- Liver function tests (hepatic encephalopathy)
- Renal function tests (uremic encephalopathy)
- Arterial blood gas (hypercapnia)
- Thyroid function tests
- Ammonia level (if hepatic encephalopathy suspected)
- Toxicology screen and medication levels
Neuroimaging
CT or MRI is mandatory when: 1
- Focal neurological signs are present
- Seizures occur
- Cerebral infection is suspected
- Encephalopathy remains unexplained after initial workup
MRI findings in specific conditions: 1
- Posterior reversible encephalopathy syndrome (PRES): T2-weighted hyperintensities in bilateral parietal-occipital lobes, predominantly white matter
- Risk factors for PRES: hypertension, renal impairment, autoimmune diseases, high-dose chemotherapy, stem-cell transplantation, immunosuppression
Lumbar Puncture and CSF Analysis
Perform LP when: 1
- Any doubt of meningitis exists
- Infectious encephalitis is suspected
- Autoimmune encephalitis is considered
CSF studies should include: 1
- Opening pressure
- CSF and serum glucose
- CSF protein
- Cell count and differential
- Gram stain and bacterial culture
- Viral PCR (HSV-1, HSV-2, VZV, enteroviruses)
- Consider paired oligoclonal bands for autoimmune causes
Critical caveat: Normal CSF does not exclude encephalitis. 1, 2
Electroencephalography (EEG)
EEG is required when: 1
- Seizures are witnessed or suspected
- Non-convulsive status epilepticus (NCSE) is possible
- Encephalopathy remains unexplained
NCSE occurs in 8% of comatose patients with unexplained encephalopathy and can only be diagnosed with EEG. 1 Progressive slowing of EEG background activity and decreased reactivity to external stimuli provide diagnostic and prognostic information. 4
Critical Diagnostic Pitfalls
Do not assume metabolic encephalopathy will resolve quickly—22% of patients with suspected metabolic encephalopathy have alternative structural diagnoses requiring different management. 5
Asterixis is not pathognomonic for hepatic encephalopathy; it occurs in uremic, hypercapnic, and drug-induced metabolic encephalopathies with only 45% specificity. 3
Subtle HSV encephalitis presentations include low-grade fever, speech disturbances, and behavioral changes mistaken for psychiatric illness, drugs, or alcohol effects. 1
Immunocompromised patients may present with subtle or atypical features, prolonged history, and absence of fever. 2
Do not delay imaging while pursuing metabolic workup—subdural hematoma and other structural lesions can mimic metabolic causes. 5
If CSF HSV PCR was not sent on first LP, repeat CSF PCR on second LP. Consider HSV CSF IgG at 10-14 days. 1