What are the causes of acute encephalopathy?

Causes of Acute Encephalopathy

Acute encephalopathy has many causes including systemic infection, metabolic derangement, inherited metabolic encephalopathies, toxins, hypoxia, trauma, vasculitis, and central nervous system infection. 1

Definition and Clinical Presentation

Encephalopathy is defined as a clinical syndrome of altered mental status manifesting as reduced consciousness or altered cognition, personality, or behavior. 1

Key clinical features that should raise suspicion of encephalopathy include:

• Current or recent febrile illness with altered behavior, personality, cognition, or consciousness 1
• New onset seizures 1
• New focal neurological signs 1
• Headache, nausea, and vomiting (especially in infectious causes) 1

Major Causes of Acute Encephalopathy

1. Infectious Causes

Direct CNS Infections:

• Viral encephalitis:

  • Herpes simplex virus (HSV) - most commonly diagnosed cause in industrialized nations 1
  • Varicella zoster virus (VZV) - especially in immunocompromised patients 1
  • Enteroviruses (can cause brainstem syndrome) 1
  • Influenza viruses (particularly associated with encephalopathy in children) 2
  • Measles virus (can cause acute encephalitis, inclusion body encephalitis, or SSPE) 1
  • Cytomegalovirus (CMV) - primarily in immunocompromised patients 1

• Bacterial infections:

  • Intracellular bacteria (e.g., Mycoplasma pneumoniae) 1
  • Mycobacterium tuberculosis (subacute presentation) 1
  • Treponema pallidum (syphilis) 1
  • Borrelia burgdorferi (Lyme neuroborreliosis) 1
  • Listeria (can cause brainstem encephalitis) 1
  • Brucellosis 1

• Parasitic infections:

  • Toxoplasma gondii (especially in immunocompromised) 1
  • Trypanosoma brucei (African trypanosomiasis) 1

• Fungal infections:

  • Cryptococcus neoformans 1

Systemic Infections:

• Septic encephalopathy (found in 50-70% of septic patients) 1
• Systemic inflammatory response syndrome 1

2. Immune-Mediated Causes

• Para-infectious immune-mediated encephalitis:

  • Acute disseminated encephalomyelitis (ADEM) - often temporally related to prior infection or immunization 1

• Autoimmune encephalitis:

  • Anti-NMDA receptor encephalitis 1
  • Voltage-gated potassium channel complex antibody-associated encephalitis 1
  • Paraneoplastic encephalitis (e.g., limbic encephalitis associated with ovarian teratomas) 1

3. Metabolic Causes

• Endogenous metabolic disorders:

  • Hepatic encephalopathy 1
  • Uremic encephalopathy 3
  • Hypoglycemia 4
  • Hyperammonemia 1
  • Inherited metabolic disorders 3, 4
  • Electrolyte abnormalities (hyponatremia, hypercalcemia) 1, 5
  • Acid-base disturbances 1

• Exogenous toxins:

  • Medications (e.g., theophylline, NSAIDs like diclofenac sodium and mephenamic acid) 2
  • Alcohol intoxication or withdrawal 1, 6
  • Illicit drugs 6
  • Salicylates (risk factor for Reye syndrome) 2

4. Vascular Causes

• Stroke (ischemic or hemorrhagic) 1
• Vasculitis 1
• Hypertensive encephalopathy 5
• Hypoxic-ischemic injury 1

5. Other Causes

• Non-convulsive status epilepticus (found in up to 8% of comatose patients with no clinical evidence of seizure activity) 1
• Trauma 1
• Neoplastic/paraneoplastic disorders 1
• Heat stroke 4

Special Syndromes

• Acute necrotizing encephalopathy - characterized by systemic cytokine storm and vasogenic brain edema 2
• Reye syndrome and Reye-like syndrome - associated with salicylate use 2
• Hemorrhagic shock and encephalopathy syndrome 2
• Acute encephalopathy with febrile convulsive status epilepticus - characterized by localized edema of the cerebral cortex 2

Diagnostic Approach

When evaluating a patient with suspected encephalopathy, consider:

• Clinical presentation pattern:

  • Acute vs. subacute/chronic presentation (subacute presentation over weeks to months may suggest autoimmune, paraneoplastic, or metabolic etiologies) 1
  • Presence of fever (common in infectious causes but may be absent) 1
  • Symmetrical vs. asymmetrical neurological findings (symmetrical findings more suggestive of metabolic causes) 1

• Key investigations:

  • Blood tests: glucose, electrolytes, liver and renal function, inflammatory markers, ammonia, lactate 1
  • Cerebrospinal fluid analysis: opening pressure, protein, glucose, cell count, culture, PCR for viruses 1
  • Neuroimaging: CT or MRI to identify structural abnormalities or patterns suggestive of specific etiologies 1, 5
  • EEG: particularly important to rule out non-convulsive status epilepticus 1
  • Toxicology screening when appropriate 6

Pitfalls and Caveats

• Encephalitis and encephalopathy terms are often used interchangeably in literature but represent different pathophysiological processes 1
• Up to 22% of patients with liver disease suspected of having hepatic encephalopathy actually have extrahepatic causes for their acute encephalopathy 1
• Non-convulsive status epilepticus can mimic or result from acute encephalitis and requires EEG for diagnosis 1
• In children, febrile seizures must be distinguished from encephalopathy 4
• The clinical features of infectious and non-infectious causes of encephalopathy can be very similar, making definitive diagnosis challenging 1