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?

Explanation

## 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]