What is the differential diagnosis for confusion in a patient, considering age, medical history, and potential underlying conditions such as metabolic disorders, neurological conditions, or medication side effects, including dementia, delirium, depression, substance abuse, infections, and psychiatric disorders?

Differential Diagnosis of Confusion

The differential diagnosis of confusion must systematically distinguish between delirium, dementia, depression, and other acute medical conditions, with delirium being the most urgent diagnosis requiring immediate identification of reversible causes. 1

Priority Life-Threatening Causes (Rule Out First)

• Hypoglycemia and hyperglycemia require immediate point-of-care glucose testing as the most common reversible metabolic causes 2
• Hypoxia from respiratory failure or pulmonary embolism must be assessed immediately with oxygen saturation and arterial blood gas analysis 2, 3
• Acute myocardial infarction can present atypically with confusion alone, particularly in elderly women, requiring electrocardiogram 2
• Intracranial hemorrhage or stroke, especially in patients with hypertension or anticoagulation, necessitating neuroimaging when focal deficits present 1, 2
• Nonconvulsive seizures require EEG evaluation, not just imaging, as they may present without obvious motor manifestations 1, 2

Metabolic and Endocrine Disorders

• Hyponatremia and hypercalcemia are common electrolyte disturbances causing confusion 1
• Diabetic emergencies including ketoacidosis, hyperosmolar state, and lactic acidosis 1
• Thyroid dysfunction (both hypo- and hyperthyroidism) should be evaluated with thyroid function tests 4, 5
• Hepatic encephalopathy in patients with cirrhosis or portosystemic shunting, classified as Type C 1
• Uremic encephalopathy in end-stage renal disease, which may overlap with hepatic encephalopathy 1
• Hypoxia and hypercapnia from respiratory failure 2, 3
• Hypothermia can precipitate acute confusion 2

Infectious Causes

• Urinary tract infections are the most frequent precipitating infection in elderly patients 6, 4
• Pneumonia is the second most common infectious cause 6, 4
• Neuroinfections including meningitis and encephalitis require lumbar puncture when fever without clear source, meningeal signs, or immunocompromised status present 1, 6, 4
• Sepsis can produce encephalopathy independently and precipitate hepatic encephalopathy through pathophysiological interactions 1

Medication and Substance-Related Causes

• Polypharmacy is a major contributor to delirium in elderly patients 2
• Anticholinergic medications including antihistamines, tricyclic antidepressants, and bladder antispasmodics 2, 7
• Benzodiazepines, neuroleptics, and opioids are common precipitants 1, 2
• Alcohol intoxication, withdrawal, or Wernicke encephalopathy (characterized by eye movement paralysis, gaze-induced nystagmus, gait disturbances) 1
• Drug withdrawal syndromes including alcohol and sedative-hypnotics 1, 2

Neurological Conditions

• Subdural hematoma from unrecognized trauma, especially in elderly patients on anticoagulation 1, 2
• Intracranial bleeding and stroke including lacunar infarcts that may not present with obvious focal deficits 1, 2
• Normal-pressure hydrocephalus presenting with gait disturbance, urinary incontinence, and cognitive decline 5
• Brain lesions including traumatic injury and neoplasms 1
• Nonconvulsive epilepsy requiring EEG for diagnosis 1

Psychiatric Disorders

• Major depression can present with pseudodementia in elderly patients, characterized by prominent subjective memory complaints 1, 7
• Psychotic disorders including schizophrenia and late-onset psychosis, where awareness and consciousness remain intact 1
• Delirium tremens from alcohol withdrawal with increased heart rate, diaphoresis, and harsh tremor 1

Dementia Syndromes

• Alzheimer's disease as the most common irreversible cause of dementia 5
• Vascular dementia from chronic hypertension causing white matter demyelination and lacunar infarctions 2
• Lewy body dementia with fluctuating course and visual hallucinations 1
• Rapidly progressive dementia developing within weeks to months, requiring urgent subspecialist evaluation 1
• Korsakoff syndrome from thiamine deficiency with anterograde amnesia and confabulation 1

Other Medical Conditions

• Severe medical stress including organ failure and systemic inflammation 1
• Obstructive sleep apnea causing chronic hypoxemia 1
• Vitamin deficiencies particularly B12 and thiamine as potentially reversible causes 5
• HIV infection causing central nervous system damage 5

Critical Diagnostic Approach

Use the Confusion Assessment Method (CAM) to objectively diagnose delirium, which requires: (1) acute onset with fluctuating course, (2) inattention, and either (3) disorganized thinking or (4) altered level of consciousness 1, 6, 4

Distinguish delirium from dementia by time course: delirium develops over hours to days with fluctuating symptoms, while dementia progresses over months to years with stable daily function until advanced stages 1, 7, 5

Obtain collateral history from knowledgeable informant to establish baseline cognitive function and characterize acute changes, as this is foundational to accurate diagnosis 6, 4

Essential Immediate Workup

• Fingerstick glucose to rule out hypoglycemia/hyperglycemia 2, 6
• Vital signs with oxygen saturation to assess for hypoxia 2, 6
• Core temperature to identify hypothermia or fever 2, 6
• Comprehensive metabolic panel focusing on sodium, glucose, renal function, calcium 2, 4
• Complete blood count to assess for infection or anemia 4
• Urinalysis and culture given high frequency of urinary tract infections 6, 4
• Electrocardiogram to assess for myocardial ischemia 2, 4
• Medication reconciliation with special attention to recent additions, anticholinergics, and polypharmacy 2, 6

Selective Advanced Testing

• Non-contrast head CT when focal neurological deficits, recent head trauma, significantly elevated blood pressure, or lower Glasgow Coma Scale present 1, 2
• Lumbar puncture when fever without clear source, meningeal signs, or immunocompromised status 6, 4
• Thyroid function tests in elderly patients with new psychiatric symptoms 2, 4
• Toxicology screen including alcohol level when substance use suspected 2, 4
• Arterial blood gas when hypoxia or pulmonary embolism suspected 3

Common Pitfalls to Avoid

Do not assume confusion is normal aging or attribute acute symptoms to pre-existing dementia without investigating reversible causes, as delirium commonly occurs superimposed on dementia 6, 4, 8

Do not miss hypoactive delirium, which is frequently mistaken for depression or fatigue and is the most common missed diagnosis 6, 4

Do not overlook medication reconciliation, as elderly patients often take multiple medications that interact or accumulate, with anticholinergic burden being particularly problematic 2, 6

Do not forget nonconvulsive seizures, which require EEG rather than imaging for diagnosis 1, 2

Do not use physical restraints as first-line management, as they worsen agitation and confusion 6