Paraneoplastic Sensory Neuronopathy Associated with Lung Cancer
The sensorimotor peripheral neuropathy most characteristically associated with lung cancer, particularly small cell lung cancer (SCLC), is paraneoplastic sensory neuronopathy (also called subacute sensory neuronopathy), which is caused by anti-Hu antibodies that cross-react with dorsal root ganglion neurons. 1
Pathophysiology and Antibody Association
Paraneoplastic sensory neuropathy results from anti-Hu antibody production that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins in the dorsal root ganglia, causing severe inflammatory destruction of these sensory neurons. 1 This antibody-mediated attack leads to degeneration of both central and peripheral sensory projections. 2
The anti-Hu antibody is almost specific for subacute sensory neuronopathy associated with SCLC. 3 When neurologic paraneoplastic syndrome is suspected, obtaining a comprehensive paraneoplastic antibody panel should be considered. 1, 4
Clinical Presentation
The clinical hallmark is distinctive and should raise immediate suspicion for underlying malignancy:
- Severe, asymmetric sensory loss that progresses subacutely over weeks to months 3, 5
- Prominent neuropathic pain and paresthesias, with striking predilection for upper limbs initially 5
- Profound proprioceptive loss leading to severe sensory ataxia that can render patients bedridden 3, 2
- Loss of deep tendon reflexes universally present 2, 5
- Perioral paresthesias may occur 2
The asymmetric onset with upper limb predominance is a critical distinguishing feature—in some patients, symptoms may be confined entirely to the arms initially. 5
Electrophysiologic and Laboratory Findings
Nerve conduction studies reveal the pathognomonic pattern of absent or severely reduced sensory nerve action potentials with normal or only minimally altered motor responses. 3, 6, 2, 5 This electrophysiologic dissociation between sensory and motor findings is diagnostically crucial.
CSF protein is typically elevated. 6, 5 Sural nerve biopsy shows severe loss of myelinated fibers and may demonstrate perivascular mononuclear cell infiltration. 6
Associated Features and Red Flags
More than half of patients have associated neurologic abnormalities beyond the peripheral sensory system, including autonomic dysfunction, cerebellar signs, or encephalomyelitis. 1, 5 The presence of these additional features should heighten suspicion for paraneoplastic etiology.
Critical red flags that should prompt aggressive cancer screening include: 5
- Prominent neuropathic pain out of proportion to examination findings
- Neurologic dysfunction involving more than just peripheral sensory nerves
- Elevated CSF protein
- Subacute progression over weeks to months
Cancer Association
Small cell lung cancer is the underlying malignancy in approximately 73% of cases (19 of 26 patients in one series). 5 Other associated cancers include breast cancer and various carcinomas. 3, 2, 5 The neuropathy frequently precedes cancer diagnosis, making it an important sentinel finding. 3
Prognosis and Treatment Response
The prognosis for neurologic recovery is poor regardless of treatment. 5 Even when the underlying cancer responds well to treatment, most patients continue to worsen neurologically or at best stabilize without improvement. 5 Treatment of the underlying malignancy may halt progression in some patients, but neurologic improvement is rare. 2, 5
Immunotherapy with high-dose intravenous methylprednisolone and/or intravenous immunoglobulin shows poor response in most cases, with only occasional transient improvement. 6, 2 Early recognition and treatment are critical to potentially limit progression, though complete reversal is unlikely. 4, 2
Other Sensorimotor Neuropathies in Lung Cancer
While sensory neuronopathy is most characteristic, other sensorimotor patterns can occur:
- Paraneoplastic sensorimotor axonal neuropathy associated with anti-CV2 antibodies and SCLC 7
- Peripheral nerve microvasculitis presenting as mononeuritis multiplex, particularly with SCLC 3
- Chronic axonal sensorimotor neuropathies that are less specific 3
However, these are less common and less diagnostically specific than the classic anti-Hu-associated sensory neuronopathy.