A 62-year-old woman from Mumbai with a 20-year smoking history presents with a 2-month history of progressive lower limb weakness, areflexia, and distal sensory loss in a stocking-glove distribution. Nerve conduction studies show reduced amplitudes in motor and sensory nerves with slowed conduction velocities. Serum calcium is 12.2 mg/dL (corrected). CT chest reveals a 3.5 cm right upper lobe mass with hilar lymphadenopathy. Which paraneoplastic syndrome is most likely, and what is the underlying pathophysiology?

Question

Accepted Answer

C. Paraneoplastic sensorimotor polyneuropathy due to immune-mediated demyelination and axonal degeneration. ## Diagnosis: Paraneoplastic Sensorimotor Polyneuropathy

### Clinical Presentation

**Key Point:** Paraneoplastic sensorimotor polyneuropathy is the most common paraneoplastic neurological syndrome, presenting with distal, symmetric weakness and sensory loss (stocking-glove distribution) that progresses proximally over weeks to months.

### Pathophysiology

1. **Immune-mediated mechanisms:**
   - Antibodies against neuronal antigens (e.g., anti-Hu, anti-CRMP5) cross-react with tumor antigens
   - CD8+ T cell infiltration of dorsal root ganglia and peripheral nerves
   - Demyelination and axonal degeneration

2. **Histopathological findings:**
   - Loss of dorsal root ganglion neurons (sensory > motor)
   - Demyelination in peripheral nerves
   - Axonal degeneration (primary pathology in most cases)

### Cancer Association

**High-Yield:** Lung cancer (especially small cell lung cancer, SCLC) is the most common malignancy associated with paraneoplastic sensorimotor polyneuropathy. Other associations include breast, ovarian, and gastric cancers.

### Diagnostic Criteria

| Feature | Paraneoplastic SMNP | LEMS | Hypercalcemia neuropathy |
|---------|---------------------|------|-------------------------|
| **Onset** | Subacute (weeks–months) | Acute (days–weeks) | Acute (hours–days) |
| **Weakness pattern** | Distal > proximal | Proximal >> distal | Generalized weakness |
| **Reflexes** | Reduced/absent | Reduced initially, then facilitation | Normal or reduced |
| **Sensory loss** | Prominent, distal | Absent | Minimal |
| **EMG/NCS** | Axonal or demyelinating | Reduced CMAP amplitude | Normal or mild slowing |
| **Associated antibodies** | Anti-Hu, anti-CRMP5 | Anti-VGCC | None specific |

### Mnemonic for Paraneoplastic Neuropathies

**Mnemonic:** **HU-CRMP** = Anti-Hu and anti-CRMP5 antibodies are most common in paraneoplastic sensorimotor polyneuropathy; associated with **SCLC** (Small Cell Lung Cancer)

### Clinical Pearl

**Clinical Pearl:** The presence of anti-Hu antibodies (ANNA-1) in a patient with sensorimotor polyneuropathy is highly specific for SCLC (>95% positive predictive value for malignancy). Screening for occult malignancy is mandatory even if initial imaging is negative.

### Investigation Algorithm

```mermaid
flowchart TD
  A[Subacute sensorimotor polyneuropathy]:::outcome --> B{NCS findings?}:::decision
  B -->|Axonal pattern| C[Check serum for paraneoplastic antibodies]:::action
  C --> D{Anti-Hu or anti-CRMP5 positive?}:::decision
  D -->|Yes| E[High suspicion for SCLC]:::urgent
  D -->|No| F[Consider other causes]:::action
  E --> G[CT chest + bronchoscopy]:::action
  G --> H{Malignancy confirmed?}:::decision
  H -->|Yes| I[Treat cancer + immunotherapy]:::action
  H -->|No| J[Repeat imaging in 3-6 months]:::action
```

### Management

1. **Treat underlying malignancy** (primary intervention)
2. **Immunosuppression:** Corticosteroids, intravenous immunoglobulin (IVIG), plasmapheresis
3. **Symptomatic care:** Neuropathic pain management, physical therapy

[cite:Harrison 21e Ch 397; Robbins 10e Ch 7]

Answer

A. Hyponatremia-induced peripheral neuropathy from syndrome of inappropriate antidiuretic hormone secretion

Answer

B. Lambert-Eaton myasthenic syndrome with secondary polyneuropathy

Answer

D. Hypercalcemia-induced neuropathy from osteolytic bone metastases

Explanation

Diagnosis: Paraneoplastic Sensorimotor Polyneuropathy

Clinical Presentation

Pathophysiology

Cancer Association

Diagnostic Criteria

Mnemonic for Paraneoplastic Neuropathies

Clinical Pearl

Investigation Algorithm

Management

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Feature	Paraneoplastic SMNP	LEMS	Hypercalcemia neuropathy
Onset	Subacute (weeks–months)	Acute (days–weeks)	Acute (hours–days)
Weakness pattern	Distal > proximal	Proximal >> distal	Generalized weakness
Reflexes	Reduced/absent	Reduced initially, then facilitation	Normal or reduced
Sensory loss	Prominent, distal	Absent	Minimal
EMG/NCS	Axonal or demyelinating	Reduced CMAP amplitude	Normal or mild slowing
Associated antibodies	Anti-Hu, anti-CRMP5	Anti-VGCC	None specific