What is the differential diagnosis for altered sensorium?

Differential Diagnosis of Altered Sensorium

The differential diagnosis of altered sensorium encompasses five major categories that must be systematically evaluated: structural neurological causes (30-35% of cases), toxic/pharmacologic causes (20-25%), metabolic derangements (15-20%), infectious etiologies (9-18%), and autoimmune/inflammatory conditions, with neurological causes being most common but requiring exclusion of rapidly reversible metabolic and toxic causes first. 1, 2, 3

Immediate Clinical Assessment Framework

The initial approach must prioritize life-threatening reversible causes before pursuing definitive diagnosis:

• Check fingerstick glucose immediately at bedside, as hypoglycemia causes permanent neurological damage if untreated and is rapidly reversible 2, 4
• Administer thiamine 500mg IV before glucose in any malnourished, alcoholic, or at-risk patient to prevent precipitating Wernicke encephalopathy 2, 4
• Secure airway if Glasgow Coma Scale ≤8 or patient cannot protect airway 2, 4
• Quantify mental status objectively using Glasgow Coma Scale or FOUR score rather than subjective descriptors 2, 4

Critical Historical Red Flags

Certain features strongly suggest specific etiologic categories and guide diagnostic workup:

Features Suggesting Non-Infectious Encephalopathy

• History of similar episodes points toward metabolic or toxic causes rather than acute infection 5, 1
• Symmetrical neurological findings suggest metabolic derangement over structural lesions 5, 1
• Myoclonus or asterixis strongly indicates metabolic encephalopathy (hepatic, uremic, hypercapnic, or drug-induced) 1
• Absence of fever makes infectious causes less likely but does not exclude them 5, 1
• Acidosis or alkalosis suggests metabolic derangement 5, 1

Features Suggesting CNS Infection

• Fever with altered behavior, personality changes, or new seizures should immediately raise suspicion for viral encephalitis requiring urgent investigation 5, 1
• Focal neurological signs with fever mandate consideration of encephalitis or brain abscess 5, 1
• Severe headache, nausea, and vomiting with fever are classical features of infectious encephalitis 5

Major Diagnostic Categories

1. Structural Neurological Causes (30-35% of cases)

Structural lesions represent the most common category and require urgent neuroimaging when suspected. 2, 3

• Cerebrovascular disease including ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage accounts for the largest proportion of structural causes 1, 3
• Intracranial hemorrhage (subdural, epidural, or intraparenchymal) particularly in patients on anticoagulation or with recent trauma 5, 1
• Brain tumors (primary or metastatic) causing mass effect or obstructive hydrocephalus 1
• Traumatic brain injury including concussion and diffuse axonal injury 1
• Obtain non-contrast head CT immediately if focal neurological deficits, head trauma, anticoagulation use, or age >60 with unexplained altered mental status 2, 4
• Consider MRI brain if CT negative but high suspicion for encephalitis, posterior circulation stroke, or inflammatory conditions 2, 4

2. Toxic and Pharmacologic Causes (20-25% of cases)

Medication and substance effects account for one-quarter of altered sensorium cases, making complete medication reconciliation essential. 2, 6

• Polypharmacy particularly in elderly patients with anticholinergics, benzodiazepines, opioids, or sedative-hypnotics 6
• Alcohol intoxication or withdrawal including delirium tremens 1, 6
• Opioid toxicity presenting with pinpoint pupils and respiratory depression, responsive to naloxone 4
• Illicit drug use including cocaine, amphetamines, synthetic cannabinoids, and hallucinogens 6
• Carbon monoxide poisoning in patients with headache, nausea, and potential exposure history 6
• Obtain complete medication list including over-the-counter medications, recent antibiotic use, alcohol intake, and illicit drugs 2, 4
• Perform toxicology screen and acetaminophen level when substance use suspected or history unclear 2, 4

3. Metabolic Encephalopathies (15-20% of cases)

Metabolic derangements are highly prevalent and often rapidly reversible with appropriate treatment. 2, 6

Hepatic Encephalopathy

• Presents with cognitive impairment and asterixis in cirrhotic patients 5, 1
• Requires exclusion through ammonia level and liver function tests, though hyperammonemia can occur without encephalopathy 5, 1
• Precipitating factors include gastrointestinal bleeding, infection, constipation, dehydration, and medications 5
• 22% of patients with liver disease and suspected hepatic encephalopathy have alternative extrahepatic causes including infections, stroke, and subdural hematoma 5

Other Metabolic Causes

• Hypoglycemia requires immediate glucose administration after thiamine 1, 4
• Hyponatremia and hypernatremia causing osmotic shifts 5, 1
• Hypercalcemia can present as encephalopathy, particularly in malignancy including multiple myeloma 7
• Uremic encephalopathy with asterixis in renal failure 1
• Hypercapnia (CO2 narcosis) in chronic respiratory failure, accounting for 17.3% of cases in one series 3
• Thyroid dysfunction (myxedema coma or thyrotoxicosis) 5, 1
• Hypoxic-ischemic brain injury following cardiac arrest or severe hypoxemia 3

Essential Metabolic Workup

• Order complete metabolic panel, complete blood count, liver function tests, thyroid-stimulating hormone, vitamin B12, and inflammatory markers simultaneously 5, 1, 2
• Check ammonia level if hepatic encephalopathy suspected 5, 1
• Obtain arterial blood gas if hypercapnia or hypoxemia suspected 3

4. Infectious Causes (9-18% of cases)

CNS infections require urgent recognition and empiric treatment while awaiting diagnostic confirmation. 5, 2, 6

Viral Encephalitis

• Herpes simplex encephalitis classically presents with fever (91% of cases), altered behavior, personality changes, speech disturbances, and seizures 5
• 85-91% of adults with HSV-1 encephalitis are febrile on admission, though absence of fever does not exclude diagnosis 5
• Start empiric acyclovir 10mg/kg IV every 8 hours immediately if encephalitis cannot be excluded 4

Bacterial Meningitis

• Bacterial meningitis with lymphocytic pleocytosis can mimic viral encephalitis, particularly Listeria monocytogenes, tuberculous meningitis, and partially treated bacterial meningitis 1
• Start empiric antibiotics immediately (vancomycin plus third-generation cephalosporin, adding ampicillin if age >50 or immunocompromised) if meningitis suspected, even before lumbar puncture if any delay 4

Other Infections

• Systemic sepsis causing encephalopathy without direct CNS infection 5
• Urinary tract infection and pneumonia particularly in elderly patients 5
• HIV-associated opportunistic infections including toxoplasmosis and cryptococcal meningitis 6

Diagnostic Approach

• Perform lumbar puncture when CNS infection suspected, but only after neuroimaging rules out mass effect 2, 4
• Send CSF for cell count with differential, protein, glucose, Gram stain, bacterial culture, and viral PCR panel 2, 4
• Normal CSF glucose with lymphocytic pleocytosis suggests viral infection 1
• Low CSF:plasma glucose ratio suggests tuberculosis, fungal infection, or partially treated bacterial meningitis 1

5. Autoimmune and Inflammatory Encephalitis

Antibody-mediated encephalitis should be suspected with subacute presentation and specific clinical features. 1

• Anti-NMDA receptor encephalitis presenting with psychiatric symptoms, seizures, movement disorders, and autonomic instability 1
• Limbic encephalitis with memory impairment, seizures, and psychiatric symptoms 1
• Hashimoto encephalopathy responsive to corticosteroids 1
• Neuropsychiatric systemic lupus erythematosus 1
• Key features include subacute presentation (weeks to months), orofacial dyskinesia, choreoathetosis, faciobrachial dystonia, intractable seizures, and hyponatremia 1

6. Neurodegenerative and Chronic Cognitive Disorders

Chronic neurodegenerative diseases may present with acute decompensation or be unmasked by concurrent illness. 5, 1

• Alzheimer's disease and other dementias typically present with temporospatial disorientation, anterograde episodic memory impairment, visuoconstructive impairments, and progressive course without fluctuations 1
• Mild cognitive impairment (MCI) shows overlap with covert hepatic encephalopathy, particularly in patients >60 years, but MCI preserves daily functioning and has been noticeable for at least 6 months 5
• Poststroke cognitive impairment occurs in up to 60% of stroke survivors, with 38% having mild cognitive impairment and 7-41% having dementia 1
• Wernicke-Korsakoff syndrome must be differentiated from hepatic encephalopathy in cirrhotic patients with alcohol use, with key features including anterograde episodic memory impairment and visuoconstructive impairments 1

Critical Diagnostic Pitfalls to Avoid

• Never administer glucose before thiamine in patients with suspected Wernicke-Korsakoff syndrome, as this can precipitate or worsen the condition 1, 2, 4
• Never attribute altered sensorium to psychiatric causes without completing full medical workup, as organic causes are far more common and missing them can be fatal 2, 4
• Do not delay empiric antibiotics and acyclovir if bacterial meningitis or encephalitis cannot be definitively excluded; treatment should begin immediately when suspected 5, 4
• Recognize that hyperammonemia can occur without encephalopathy, so ammonia levels alone do not confirm hepatic encephalopathy 5
• Consider multiple concurrent etiologies, especially in elderly patients who may have baseline dementia plus acute infection plus medication effect 2, 4
• Recognize that 22% of patients with liver disease and suspected hepatic encephalopathy have alternative extrahepatic causes requiring investigation 5
• Hypoactive delirium presents with cognitive and motor slowing rather than agitation, is more common in elderly patients, carries higher mortality, but is frequently missed 2

Systematic Diagnostic Algorithm

Follow this structured approach to efficiently identify the cause:

1. Immediate stabilization: Secure airway if GCS ≤8, check fingerstick glucose, administer thiamine before glucose if at risk, give naloxone if opioid toxicity suspected 2, 4

2. Vital signs and focused examination: Document fever, blood pressure abnormalities, perform Glasgow Coma Scale, and focused neurological examination for focal deficits 2, 4

3. Obtain critical history: Temporal profile, complete medication list (including over-the-counter, alcohol, illicit drugs), infectious symptoms, recent trauma, and comorbid conditions 2, 4

4. Initial laboratory workup: Point-of-care glucose, complete metabolic panel, complete blood count, liver function tests, urinalysis, toxicology screen, and acetaminophen level 2, 4

5. Neuroimaging decision: Obtain non-contrast head CT immediately if focal deficits, head trauma, anticoagulation, or age >60; consider MRI if CT negative but high suspicion for encephalitis or posterior circulation stroke 2, 4

6. Lumbar puncture: Perform when CNS infection suspected after neuroimaging rules out mass effect 2, 4

7. Empiric treatment: Start antibiotics and acyclovir if infection cannot be excluded, even before lumbar puncture if any delay 4