What are the presenting features, pathophysiology, and management of limbic encephalitis?

Limbic Encephalitis: Presenting Features, Pathophysiology, and Management

Limbic encephalitis (LE) is characterized by inflammation of the limbic system, presenting with memory deficits, psychiatric symptoms, and seizures, requiring prompt diagnosis and immunotherapy for optimal outcomes. 1

Clinical Presentation

Core Symptoms

• Short-term memory impairment is the most common presenting symptom, occurring in up to 76% of patients 2, 1
• Psychiatric manifestations including behavioral changes, confusion, disorientation, and personality changes occur in 41-76% of cases 3, 4
• Seizures occur in approximately one-third of patients and can sometimes be the initial presenting feature 3
• Speech disturbances (dysphasia and aphasia) are seen in 59% of patients 3

Additional Features

• Fever may be present, though some patients present with low-grade pyrexia rather than high fever 3
• Autonomic dysfunction occurs in some cases 2
• Cerebellar features including ataxia may be present 2
• Intractable seizures, often without fever, are common in antibody-associated encephalitides 3

Pathophysiology

Classification

• LE can be broadly categorized into infectious and non-infectious causes 3
• Non-infectious causes include antibody-mediated encephalitis, which may be paraneoplastic (associated with cancer) or non-paraneoplastic 3, 1

Autoimmune Mechanisms

• Two main categories of antineuronal antibodies are associated with LE 1:

  1. Antibodies against intracellular (classic paraneoplastic) antigens: Hu, Ma2, CV2/CRMP5, and amphiphysin
  2. Antibodies against cell membrane antigens: voltage-gated potassium channels (VGKC), N-methyl-D-aspartate receptor (NMDAR), and others

• Disorders related to antibodies against intracellular antigens:

  • Frequently associated with cancer (lung, testis, and others)
  • Characterized by prominent brain infiltrates of cytotoxic T-cells
  • Limited response to treatment 1

• Disorders related to antibodies against cell membrane antigens:

  • Less frequently associated with cancer (thymoma, teratoma)
  • Appear to be antibody-mediated
  • Respond significantly better to immunotherapy 1

Associated Conditions

• Approximately 25% of LE cases are associated with malignancy 2
• Thyroid autoimmunity may be associated with non-paraneoplastic LE 5
• Some cases are associated with specific antibodies like anti-glutamic acid decarboxylase (GAD) 5

Diagnostic Approach

Clinical Evaluation

• A high index of suspicion is needed as early symptoms can be nonspecific (irritability, low mood, memory complaints) 6
• Patients require immediate neurological specialist assessment 7

Neuroimaging

• MRI is the imaging modality of choice, preferred over CT 7
• Typical findings include fluid-attenuated inversion recovery (FLAIR) or T2 bilateral temporal lobe hyperintensities, seen in approximately 50% of patients 2

Laboratory Testing

• Cerebrospinal fluid (CSF) analysis is critical for confirming diagnosis 7
• CSF may show inflammatory abnormalities including pleocytosis 3, 2
• In immunocompromised patients, CSF may be acellular despite CNS infection 8
• Testing for antineuronal antibodies should be performed when available 2, 1

Management

Acute Treatment

• Patients should be managed in appropriate settings including neurological wards, high dependency units, or intensive care units depending on severity 7
• Patients with falling level of consciousness require urgent assessment by Intensive Care Unit staff for:
  • Airway protection
  • Ventilatory support
  • Management of raised intracranial pressure
  • Optimization of cerebral perfusion pressure
  • Correction of electrolyte imbalances 7

Immunotherapy

• Early institution of immunotherapy is crucial for improved outcomes 2
• First-line treatments include:
  • High-dose corticosteroids 7
  • Intravenous immunoglobulin (IVIG) 6
  • Plasma exchange (particularly effective in some antibody-mediated cases) 5

Seizure Management

• Anti-seizure medications are indicated for seizure control 4
• Around half of patients may continue to have medically refractory seizures despite treatment 4

Long-term Follow-up

• Patients should not be discharged without either a definite or suspected diagnosis 7
• Arrangements for outpatient follow-up and plans for ongoing therapy and rehabilitation should be formulated at discharge 7
• All patients should have access to assessment for rehabilitation, as sequelae may not be immediately apparent at discharge 7

Prognosis

• With appropriate treatment, approximately 60% of patients show improvement 2
• Long-term complications may include:
  • Medically refractory seizures in about 50% of patients 4
  • New psychiatric diagnoses (mood disorders, anxiety disorders) in 44% of patients 4
  • Loss of employment in 43% of previously employed patients 4
  • Cognitive deficits requiring ongoing rehabilitation 6, 4

Clinical Pearls

• LE was once considered an extremely rare disorder, almost always related to cancer and refractory to treatment, but is now recognized as a relatively frequent disorder, often unrelated to cancer, with clinical-immunologic variants that respond to treatment 1
• Behavioral changes can be mistaken for primary psychiatric illness, leading to delays in diagnosis and appropriate treatment 3
• Neuropsychological consultation and team education can be helpful in managing these cases 6
• Antipsychotic medications may not be beneficial and patients may not begin to experience improvement until immunotherapy is initiated 6