What is paraneoplastic syndrome in the context of a brain tumor in an otherwise healthy patient?

What is Paraneoplastic Syndrome?

Paraneoplastic syndromes are remote effects of cancer that occur when the immune system mounts a cross-reactive response against antigens shared by both the tumor and the nervous system, causing neurological dysfunction without direct tumor invasion, metastasis, infection, or metabolic disruption. 1, 2

Core Pathophysiology

The mechanism involves autoimmune processes triggered by the cancer itself:

• Tumors express "onconeural antigens" - proteins normally found only in nervous tissue and sometimes testis - which provoke an immune response that inadvertently attacks the patient's own nervous system 2, 3
• The immune attack is primarily T-cell mediated for syndromes with intracellular antibodies, though autoantibodies serve as diagnostic markers 4
• Surface-binding/receptor autoantibodies can be directly pathogenic and are often more responsive to immunotherapy 4

Clinical Presentation in Brain Tumor Context

Key Distinguishing Features

Paraneoplastic syndromes typically present before the cancer is clinically apparent - in most patients, neurological symptoms develop first, prompting the search for an underlying malignancy 2, 3

The presentation is characteristically:

• Acute to subacute onset (less than 3 months duration) 5
• Polysyndromic and multifocal due to diffuse brain inflammation, affecting multiple neurological domains simultaneously 5
• Rapidly progressive and severely disabling without treatment 2

Common Neurological Manifestations

In the context of brain involvement, watch for:

• Limbic encephalitis - memory impairment, behavioral changes, seizures, psychiatric symptoms 5, 6
• Brainstem encephalitis - cranial nerve deficits, dysautonomia, respiratory failure 1
• Cerebellar degeneration - progressive ataxia, dysarthria, nystagmus 1, 6
• Encephalomyelitis - combined brain and spinal cord involvement 5, 6

Diagnostic Approach

Clinical Suspicion Criteria

Suspect paraneoplastic syndrome when you see: 5

1. Acute/subacute onset (less than 12 weeks)
2. Evidence of CNS inflammation:
   • CSF lymphocytic pleocytosis (20-200 cells, can reach 900)
   • Elevated CSF protein, IgG index, or oligoclonal bands
   • MRI showing bilateral limbic T2/FLAIR hyperintensities or other inflammatory patterns
   • Inflammatory changes on biopsy
3. Exclusion of infection, trauma, toxic, metabolic, or demyelinating causes

Critical Diagnostic Tests

Do not wait for antibody results before starting treatment - the workup should proceed in parallel with cancer screening and immunotherapy initiation 5, 1

Essential testing includes:

• Paraneoplastic antibody panel in both serum and CSF (CSF more sensitive for NMDAR, GFAP; serum more sensitive for anti-Hu, LGI1, AQP4) 5
• Anti-onconeural antibodies (anti-Hu, anti-Yo, anti-CV2, anti-Ri, anti-Ma2, anti-amphiphysin) have >90% specificity for underlying cancer 5, 2
• Brain MRI with contrast - bilateral limbic involvement alone is sufficient for definite diagnosis in the correct clinical setting 5
• CSF analysis - cell count, protein, glucose, IgG index, oligoclonal bands, viral PCR (especially HSV1/2, VZV), cytology, flow cytometry 5

Cancer Screening

Cancer screening must be performed immediately in all adult patients with suspected paraneoplastic syndrome, as the neurological syndrome often precedes cancer diagnosis 5, 1

Most Common Associated Tumors

• Small cell lung cancer (most common overall, especially with anti-Hu antibodies - >90% association) 1, 7
• Ovarian teratoma or carcinoma (especially NMDAR-antibody encephalitis in young women) 5
• Breast cancer 5, 1
• Thymoma (especially with VGKC antibodies) 5, 4
• Testicular teratoma or seminoma 5
• Neuroblastoma (in children) 5, 4

Screening Protocol

Initial approach: 5, 1

• CT chest/abdomen/pelvis with contrast as first-line (provides structural detail for biopsy planning)
• Mammogram (and breast MRI if high suspicion) for women
• Pelvic ultrasound or MRI for women of childbearing age (avoid CT contrast)
• Testicular ultrasound for men
• Consider FDG-PET if CT negative but suspicion remains high

Treatment Strategy

Primary Principle

Treating the underlying malignancy is the single most important intervention - successful tumor therapy often improves or stabilizes paraneoplastic symptoms 1, 7, 3

Immunotherapy Algorithm

Start first-line immunotherapy immediately without waiting for antibody results: 5, 1

First-line options:

• High-dose IV methylprednisolone
• IV immunoglobulin (IVIg) - most effective when given within 1 month of symptom onset
• Plasma exchange
• Often use combination therapy

Second-line therapy if no improvement after 2-4 weeks: 5, 1

• Rituximab
• Cyclophosphamide
• Both agents together for refractory cases

Critical Caveats

• Response to immunotherapy is better for surface-binding antibodies (NMDAR, LGI1, CASPR2) than intracellular onconeural antibodies (anti-Hu, anti-Yo) 1, 4
• Permanent neurological sequelae are common due to low CNS regenerative capacity and should not be interpreted as treatment failure 1
• NMDAR-antibody encephalitis can have slow response - may take weeks to months even with appropriate treatment 5
• Immunotherapy does not adversely affect cancer outcomes and should be given concomitantly 1

Prognosis

• Early recognition and treatment are critical - prompt identification can detect occult malignancies at treatable stages 1
• Neurological syndromes may have irreversible damage despite successful cancer treatment 1, 3
• Relapses are rare in idiopathic cases but can occur with insufficient treatment or rapid immunotherapy withdrawal 5
• Anti-Hu syndrome and other intracellular antibody syndromes typically have poor neurological outcomes even with treatment 1, 4