What are the key features and treatment approaches for paraneoplastic encephalitis?

Paraneoplastic Encephalitis: Key Features and Treatment

Paraneoplastic encephalitis presents with acute or subacute neurological symptoms (typically <3 months duration) in patients with known cancer or at high cancer risk, and requires aggressive early immunotherapy combined with tumor treatment for optimal outcomes. 1

Clinical Features

Temporal Presentation

• Acute to subacute onset over days to weeks, with symptoms developing in less than 3 months 1
• Neurological symptoms precede cancer diagnosis in 60% of cases, typically by 3.5 months 2
• Progressive course is characteristic, tending to plateau after cancer treatment 1
• Chronic presentations are atypical and should raise suspicion for alternative diagnoses 1

Core Neurological Manifestations

• Memory impairment and cognitive dysfunction are hallmark features, present in the majority of patients 3, 2
• Seizures occur in approximately one-third of patients, including new-onset refractory status epilepticus 1, 2
• Altered consciousness ranging from confusion to coma, with disorientation in 76% 1
• Behavioral and personality changes, including irritability, depression, and psychiatric symptoms 2
• Speech disturbances in 59% of cases 1

Polysyndromic Presentation

• Multifocal brain inflammation results in involvement of multiple neurological systems simultaneously 1
• Autonomic dysfunction with blood pressure fluctuations and cardiac arrhythmias 3
• Hypothalamic involvement in 70% of anti-Ta antibody cases 2
• Potential involvement of meninges, spinal cord, and peripheral nervous system 1

High-Risk Patient Populations

• Smokers, elderly patients, and those with rapid unintentional weight loss are at increased risk 1
• Patients with known cancer or receiving immune checkpoint inhibitors (which can cause accelerated paraneoplastic encephalitis) 1
• Preceding viral infection or viral-like prodrome is common 1

Associated Malignancies

Tumor Distribution

• Lung cancer (50%), predominantly small-cell lung cancer 2, 4
• Testicular tumors (20%), particularly in young men with anti-Ta antibodies 2
• Breast cancer (8%) 2
• Thymoma with potential for multiple antibody syndromes 5

Antibody-Tumor Associations

• Anti-Hu antibodies: 94% association with small-cell lung cancer, multifocal symptoms in 78%, poor neurological outcome 2
• Anti-Ta (Ma2) antibodies: 100% association with testicular tumors in young men, frequent hypothalamic involvement 2
• GABABR antibodies: Strong association with limited-stage small-cell lung cancer, better response to immunotherapy 4
• NMDA receptor antibodies: Can occur with thymoma and residual thymic tissue 5

Diagnostic Workup

Neuroimaging

• Brain MRI with contrast shows temporal lobe T2/FLAIR hyperintensities in 57% of cases 2
• Bilateral limbic encephalitis on MRI is sufficient for definite diagnosis in appropriate clinical context 1
• PET-CT reveals abnormal metabolic activity in temporal lobe/hippocampus in 69% and identifies lung neoplasms 4
• Scattered white matter hyperintensities and enhancing lesions may be present 5

CSF Analysis

• Lymphocytic pleocytosis with inflammatory changes but negative cytology 2
• CSF-specific oligoclonal bands or elevated IgG index 1
• Normal CSF does not exclude diagnosis—antibody testing should still be performed with high clinical suspicion 3

Antibody Testing

• Serum and CSF neuronal autoantibody panels are essential 3
• 60% of patients have identifiable antineuronal antibodies (anti-Hu, anti-Ta, GABABR, NMDA receptor) 2
• Collect blood samples before IVIG or plasma exchange to avoid false results 3
• Onconeural antibodies should be tested to confirm paraneoplastic etiology 1

EEG Findings

• Epileptic activity in temporal lobes 2
• Focal slowing or lateralized periodic discharges 3

Cancer Screening

• Chest CT or PET-CT for lung cancer screening 4
• Testicular ultrasound in young men 2
• Whole-body imaging as indicated by antibody profile 1

Treatment Approach

First-Line Immunotherapy

Initiate immediately without waiting for antibody results 1

• Intravenous methylprednisolone (IVMP) 3
• Intravenous immunoglobulin (IVIG) 1, 3
• Plasma exchange (PLEX), often preceding IVIG 1, 3
• Combination therapy is frequently employed 1

Second-Line Immunotherapy

For patients not responding to first-line treatment within weeks 1:

• Rituximab (B-cell targeting) 1, 6
• Cyclophosphamide 1, 5
• Both agents may be used in refractory cases 5

Tumor-Directed Treatment

• Cancer treatment has more effect on neurological outcome than immunomodulation alone 2
• Surgical resection of thymoma or testicular tumors 5, 2
• Chemotherapy for small-cell lung cancer with 75% overall cancer response rate 4
• Complete tumor removal is critical—residual tissue can cause new antibodies and recurrent syndromes 5

Supportive Care

• Antiseizure medications for seizure management 3
• Management of dysautonomia 3
• Careful correction of hyponatremia 3
• Treatment of aspiration pneumonia and respiratory complications 7

Prognosis and Response Patterns

Antibody-Specific Outcomes

• GABABR antibody patients: Better response to immunotherapy (50% improvement rate) 4
• Anti-Hu antibody patients: Poor neurological outcome despite treatment (38% improvement) 2
• Anti-Ta antibody patients: Poor neurological outcome (30% improvement) 2
• Antibody-negative patients: 64% show neurological improvement 2

Overall Outcomes

• Two-year overall survival of 74.7% in lung cancer-associated PLE 4
• 44% of patients show neurological improvement with median 8-month follow-up 2
• Limited-stage disease has better outcomes due to earlier diagnosis and prompt treatment 4

Critical Pitfalls to Avoid

Diagnostic Delays

• Delay in diagnosis and treatment leads to worse outcomes—maintain high index of suspicion in patients with unexplained neuropsychiatric symptoms 3
• Hyperacute presentations are atypical—consider vascular etiology first 1
• Subacute presentations (weeks to months) should trigger search for paraneoplastic, autoimmune, and metabolic causes 1

Treatment Errors

• Do not wait for antibody results to initiate immunotherapy 1
• Insufficient treatment or rapid interruption of immunotherapy causes relapses 1
• Failure to screen for residual tumor tissue after initial resection 5
• Not collecting blood samples before IVIG/PLEX administration 3

Monitoring for Recurrence

• New neurological symptoms require search for residual pathologic tissue or tumor recurrence causing new autoantibodies 5
• Multiple antibodies may indicate poor prognosis requiring aggressive immunosuppression 5
• Serial antibody level monitoring in serum and CSF can guide treatment weaning 1