Makindo Medical Notes

Related Subjects: |Anti-NMDA (NMDAR) receptor encephalitis |Herpes Simplex Encephalitis (HSV) |Acute Encephalitis |Limbic Encephalitis |Paraneoplastic Limbic Encephalitis (Dementia) |Hashimoto's (Steroid responsive) Encephalopathy |Acute Disseminated Encephalomyelitis

Introduction

Limbic encephalitis (LE) is an inflammatory condition primarily affecting the limbic system, which includes structures such as the hippocampus, amygdala, and cingulate gyrus. This condition often presents with a rapid onset of cognitive, behavioral, and neurological symptoms. LE can be classified into paraneoplastic, autoimmune, and infectious types, and is a rare but potentially treatable cause of delirium.

About

Limbic encephalitis is characterized by inflammation of the limbic system, leading to a variety of neuropsychiatric symptoms. Early recognition and treatment are crucial for improving outcomes.

Types

• Paraneoplastic Limbic Encephalitis:
  • Associated with underlying malignancies, such as small cell lung carcinoma, testicular tumors, breast cancer, or thymoma.
  • Often linked to autoantibodies against neuronal antigens (e.g., anti-Hu, anti-Ma2, anti-CRMP5, anti-amphiphysin).
• Autoimmune (Non-Paraneoplastic) Limbic Encephalitis:
  • Associated with antibodies targeting neuronal cell surface antigens.
  • Common antibodies include anti-NMDA receptor, anti-VGKC complex (LGI1 and CASPR2), anti-GAD (glutamic acid decarboxylase), and anti-AMPA receptor antibodies.
• Infectious Causes:
  • Viral encephalitis, particularly due to herpes simplex virus (HSV), can lead to inflammation of the limbic system.
  • Other infectious agents include HIV, autoimmune processes triggered by infections.

Clinical Presentation

• Cognitive Impairment: Memory loss, especially anterograde amnesia affecting recent events.
• Psychiatric Symptoms: Mood changes, anxiety, depression, hallucinations, psychosis.
• Seizures: Focal or generalized seizures, often temporal lobe in origin.
• Altered Level of Consciousness: Confusion, delirium.
• Movement Disorders: Myoclonus, ataxia, dyskinesias.
• Autonomic Dysfunction: Hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH), arrhythmias.
• Sleep Disturbances: REM sleep behavior disorders, insomnia (notably in VGKC/LGI1 antibody-associated encephalitis).

Differential Diagnosis

• Infectious Encephalitis: HSV encephalitis, other viral or bacterial CNS infections.
• Paraneoplastic Syndromes: Other neurological paraneoplastic manifestations.
• Dementias: Rapidly progressive dementias such as Creutzfeldt-Jakob disease.
• Autoimmune Encephalopathies: Hashimoto's encephalopathy, systemic lupus erythematosus (SLE) cerebritis.
• Toxic-Metabolic Encephalopathies: Wernicke's encephalopathy, hepatic encephalopathy, drug-induced states.
• Primary CNS Vasculitis: Inflammation of CNS blood vessels leading to neurological symptoms.
• Neoplastic Conditions: Primary CNS tumors, leptomeningeal carcinomatosis.
• Multiple Sclerosis: Demyelinating lesions may mimic limbic involvement.
• Neurosyphilis: Tertiary syphilis affecting the CNS.

Investigations

• Laboratory Tests:
  • Full Blood Count (FBC), Urea & Electrolytes (U&E), Liver Function Tests (LFTs), C-Reactive Protein (CRP).
  • Hyponatremia may be present due to SIADH, especially in VGKC/LGI1 antibody-associated encephalitis.
• Cerebrospinal Fluid (CSF) Analysis:
  • Typically shows mild lymphocytic pleocytosis and elevated protein.
  • Oligoclonal bands may be present.
  • Negative CSF 14-3-3 protein helps exclude Creutzfeldt-Jakob disease.
  • Antibody testing in CSF can detect specific autoantibodies (e.g., anti-NMDA receptor antibodies).
• Magnetic Resonance Imaging (MRI):
  • May reveal hyperintense signals on T2-weighted or FLAIR sequences in the medial temporal lobes and limbic structures.
  • Atrophy of temporal-limbic structures on T1-weighted images.
  • Contrast enhancement may be variable.
• Electroencephalography (EEG):
  • May show focal slow-wave activity or epileptiform discharges in the temporal lobes.
  • Non-specific findings but can support diagnosis.
• Antibody Testing:
  • Serum and CSF testing for neuronal antibodies (e.g., anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-GAD65, paraneoplastic antibodies like anti-Hu, anti-Ma2).
  • Voltage-gated potassium channel (VGKC) complex antibodies (note that specific antigens are LGI1 and CASPR2).
• Oncological Screening:
  • Computed Tomography (CT) scans of the chest, abdomen, and pelvis to detect underlying malignancies.
  • Positron Emission Tomography (PET) scans for whole-body imaging.
  • Testicular ultrasound in males, mammography in females as appropriate.
• Other Investigations:
  • Autoimmune and rheumatological screens to exclude other conditions.
  • Infectious disease workup if an infectious etiology is suspected.

Management

• Immunotherapy:
  • First-line treatments include high-dose corticosteroids (e.g., methylprednisolone), intravenous immunoglobulin (IVIG), and plasma exchange (plasmapheresis).
  • Second-line immunosuppressive agents such as rituximab (anti-CD20 monoclonal antibody) or cyclophosphamide may be used if there is no response to first-line therapy.
  • Early initiation of immunotherapy is associated with better outcomes.
• Management of Underlying Malignancy:
  • Surgical resection, chemotherapy, or radiotherapy of the associated tumor can lead to improvement in neurological symptoms.
  • Paraneoplastic limbic encephalitis often has limited response to immunotherapy alone.
• Antiviral Therapy:
  • If herpes simplex virus encephalitis is suspected, prompt initiation of intravenous acyclovir is critical.
• Symptomatic Treatment:
  • Antiepileptic drugs to control seizures.
  • Psychiatric medications for mood and behavioral symptoms.
  • Management of autonomic dysfunction and hyponatremia.
  • Rehabilitation services including physical, occupational, and speech therapy.
• Supportive Care:
  • Monitoring in a hospital setting for severe cases.
  • Multidisciplinary approach involving neurology, psychiatry, oncology, and rehabilitation specialists.

Prognosis

• Autoimmune Limbic Encephalitis: Patients may have a good response to immunotherapy, especially if treatment is initiated early.
• Paraneoplastic Limbic Encephalitis: Prognosis depends on the underlying malignancy and response to tumor treatment; neurological improvement may be limited.
• Infectious Causes: Early antiviral therapy improves outcomes in HSV encephalitis; delayed treatment can lead to significant morbidity and mortality.
• Some patients may have residual cognitive deficits, especially memory impairment.

References

• Lai M, et al. Clinical, neuropathological, and immunological characteristics of limbic encephalitis with VGKC-complex antibodies. J Neurol Neurosurg Psychiatry. 2010;81(7):714-718.
• Dalmau J, et al. Autoimmune encephalitis: clinical spectrum and diagnostic criteria. Lancet Neurol. 2011;10(1):63-74.
• Bien CG, et al. Immunopathogenesis of autoantibody-associated encephalitides. Trends Neurosci. 2012;35(3):79-89.
• Graus F, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
• Tüzün E, Dalmau J. Limbic encephalitis and variants: classification, diagnosis and treatment. Neurologist. 2007;13(5):261-271.