What are the causes of encephalopathy?

Causes of Encephalopathy

Encephalopathy refers to a clinical state of altered mental status, manifesting as confusion, disorientation, behavioral changes, or other cognitive impairments, with or without inflammation of brain tissue. 1

Infectious Causes

• Viral encephalitis: Caused by direct infection of the brain parenchyma by viruses including:

  • Herpes simplex virus (HSV-1 and HSV-2) - most commonly diagnosed cause in industrialized nations 1
  • Varicella zoster virus (VZV) - can occur during primary infection or reactivation 1
  • Enteroviruses 1
  • Cytomegalovirus (CMV) - especially in immunocompromised patients 1
  • Influenza virus - associated with specific encephalopathy syndromes 1, 2
  • Measles virus (subacute sclerosing panencephalitis) 1
  • Human herpes viruses 6 and 7 1
  • JC/BK virus (progressive multifocal leukoencephalopathy) 1

• Bacterial causes:

  • Bartonella henselae (cat scratch disease) 1
  • Mycobacterium tuberculosis 1
  • Treponema pallidum (syphilis) 1
  • Borrelia burgdorferi (Lyme neuroborreliosis) 1
  • Listeria monocytogenes - especially in immunocompromised patients 1

• Fungal causes:

  • Cryptococcus neoformans 1
  • Coccidioides species 1
  • Histoplasma species 1

• Parasitic causes:

  • Toxoplasma gondii - especially in immunocompromised patients 1
  • Malaria (cerebral malaria) 1

Post-Infectious/Immune-Mediated Causes

• Acute disseminated encephalomyelitis (ADEM): Post-infectious or post-vaccination autoimmune response 1, 3

  • Common triggers include measles, mumps, rubella, varicella zoster, EBV, CMV, HSV, hepatitis A, influenza, and enterovirus infections 3
  • Can follow vaccination against anthrax, Japanese encephalitis, yellow fever, measles, influenza, smallpox, and rabies 3

• Antibody-associated encephalitis:

  • Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis 1, 3
  • Anti-voltage-gated potassium channel complex antibody encephalitis 1
  • Limbic encephalitis (may be paraneoplastic, e.g., associated with ovarian teratomas) 1

Metabolic Causes

• Electrolyte disturbances:

  • Hyponatremia - most common cause of metabolic encephalopathy in elderly 1, 4
  • Hypokalaemia 1
  • Hypomagnesaemia 1
  • Hypocalcemia 1

• Glucose metabolism disorders:

  • Hypoglycemia 1, 4
  • Diabetic ketoacidosis 5, 6

• Hepatic encephalopathy: Due to liver dysfunction causing accumulation of neurotoxins 1

• Uremic encephalopathy: Due to renal failure 1, 5

• Respiratory disorders:

  • Hypercapnia (CO₂ retention) 1
  • Hypoxia 5, 6

• Inherited metabolic disorders:

  • Urea cycle defects 1
  • Mitochondrial disorders 5, 6

• Endocrine disorders:

  • Hypothyroidism or hyperthyroidism 1
  • Adrenal insufficiency 5

Toxic Causes

• Medications:

  • Antiepileptic drugs 1
  • Levodopa 1
  • Opiates 1
  • Anticholinergics 1
  • Benzodiazepines 1
  • Lithium 1
  • Clozapine 1
  • Non-steroidal anti-inflammatory drugs (diclofenac sodium, mephenamic acid) 2
  • Theophylline 2
  • Salicylates (risk factor for Reye syndrome) 2

• Alcohol-related:

  • Acute intoxication 1
  • Withdrawal 1
  • Wernicke-Korsakoff syndrome (thiamine deficiency) 1
  • Alcohol-related dementia 1

• Other toxins:

  • Industrial toxins 5
  • Heavy metals 5

Vascular Causes

• Cerebral microangiopathy (vascular leukoencephalopathy) 1
• Hypertensive encephalopathy 7
• Posterior reversible encephalopathy syndrome (PRES) 7

Systemic Causes

• Septic encephalopathy: Most common in pneumonia 4
• Systemic inflammatory response syndrome (SIRS) 5
• Multiple organ failure 2
• Disseminated intravascular coagulation 2

Special Syndromes

• Reye syndrome and Reye-like syndrome: Associated with salicylate use during viral infections 2
• Hemorrhagic shock and encephalopathy syndrome 2
• Acute necrotizing encephalopathy 2
• Acute encephalopathy with febrile convulsive status epilepticus 2
• Hemiconvulsion-hemiplegia syndrome 2

Clinical Approach to Diagnosis

• Categorize by pace of onset and evolution: sudden, acute, subacute, or chronic 7
• Consider multiple etiologies, as they are present in approximately 30% of encephalopathy cases 4
• Early diagnosis and treatment (within 6 hours of symptom onset) is associated with better outcomes 4

Diagnostic Pitfalls

• Encephalitis and encephalopathy are often used interchangeably but may represent distinct pathophysiologic processes 1
• Normal cerebrospinal fluid and neuroimaging do not rule out encephalitis 1
• Subtle changes in mental status may be missed using crude assessment tools like Glasgow Coma Scale 1
• In elderly patients, presenting symptoms and signs may be minimal or atypical 4
• Immunocompromised patients may present with subtle or atypical features, even with prolonged history and absence of fever 1