Paraneoplastic Peripheral Neuropathy

Paraneoplastic peripheral neuropathy is a group of immune mediated neuropathies triggered by cancer, including sensory neuronopathy (dorsal root ganglionopathy), sensorimotor polyneuropathy, vasculitic neuropathy, autonomic neuropathy and peripheral nerve hyperexcitability. It often precedes the diagnosis of the tumour by months to years.

It is uncommon: neuropathy of paraneoplastic origin affects about 1% or fewer of patients with cancer. The classic form is subacute sensory neuronopathy with anti-Hu antibodies (ANNA-1) in small cell lung cancer, which accounts for most cases. Median age is 60 to 65. Other antibodies: CRMP5 (CV2), amphiphysin, and CASPR2 or LGI1 in neuromyotonia (thymoma).

Associated tumours: small cell lung cancer, thymoma, breast, ovarian and other gynaecological cancers, lymphoma (Hodgkin), plasma cell dyscrasias (POEMS, amyloid, anti-MAG neuropathy) and renal cell carcinoma.

Pathophysiology. Cytotoxic T-cell attack on dorsal root ganglion neurons (with anti-Hu), antibody mediated mechanisms, and cross-reactivity to tumour antigens. Vasculitic neuropathy involves T-cell and immune complex injury to vasa nervorum.

Prognosis. Sensory neuronopathy leaves severe disability in most (ataxia, loss of position sense), and outcomes depend largely on tumour treatment. Neuropathies with plasma cell dyscrasias and vasculitic forms respond better to treatment.

• Sensory neuronopathy: asymmetric patchy numbness, paraesthesia and burning pain affecting the face, trunk and limbs, loss of joint position sense (sensory ataxia, pseudoathetosis), absent reflexes. Progresses over weeks to months.
• Sensorimotor polyneuropathy: distal weakness and sensory loss, subacute or chronic.
• Vasculitic neuropathy: painful asymmetric mononeuritis multiplex.
• Autonomic neuropathy: orthostatic hypotension, gastroparesis and pseudo obstruction, urinary retention, abnormal sweating.
• Neuromyotonia: muscle stiffness, cramps, fasciculations, myokymia and hyperhidrosis.

Red flags.

• Rapidly progressive weakness or respiratory involvement.
• Severe autonomic failure or pseudo obstruction.

• Nerve conduction studies: reduced or absent sensory nerve action potentials with relatively preserved motor responses (neuronopathy); axonal or demyelinating patterns in other forms. EMG for neuromyotonia.
• Antibody testing in serum (and CSF): anti-Hu, CRMP5, amphiphysin, CASPR2, LGI1, and anti-MAG. CSF shows raised protein and lymphocytes in many.
• MRI of the spine (dorsal column T2 hyperintensity in ganglionopathy). Nerve biopsy for vasculitic neuropathy.
• Tumour search: CT of the chest, abdomen and pelvis, whole body FDG-PET-CT, mammography, and pelvic imaging. Repeat every 3 to 6 months for up to 4 years if negative. Serum protein electrophoresis, free light chains and VEGF (POEMS).
• Exclusion of other causes: vitamin B12 and thiamine deficiency, diabetes, thyroid disease, drugs (platinum agents, taxanes, vinca alkaloids, bortezomib), toxins, HIV, hepatitis, Sjögren syndrome.

Differential diagnosis.

• Chemotherapy induced peripheral neuropathy
• Chronic inflammatory demyelinating polyneuropathy and Guillain-Barré syndrome
• Sjögren sensory neuronopathy and cisplatin ganglionopathy
• Diabetic and nutritional neuropathies, amyloidosis and POEMS syndrome

Treat the tumour early. Immunotherapy slows deterioration but rarely reverses established sensory neuronopathy.

Tumour treatment. Surgery, chemotherapy or radiotherapy for the tumour as soon as it is found, which is the main determinant of neurological outcome.

Immunotherapy (start early, assess response at 4 to 8 weeks).

• Methylprednisolone: methylprednisolone 1 g IV over 1 to 2 hours once daily for 3 to 5 days, then oral prednisolone 1 mg/kg daily (maximum 60 mg daily) tapered over 4 to 8 weeks in line with response; maximum 1 g daily for pulse therapy; monitoring: glucose, blood pressure, potassium, mood, infection, gastric symptoms, bone health; adjustment: give gastric protection, calcium and vitamin D, pneumocystis prophylaxis when over 20 mg prednisolone daily is expected for more than 4 weeks, reduce for psychiatric toxicity
• Immunoglobulin: immunoglobulin (human normal) 0.4 g/kg IV daily for 5 days (total 2 g/kg), started at 0.5 mL/kg/h and increased every 15 to 30 minutes to a maximum of 4 mL/kg/h as tolerated; maximum 2 g/kg in one course; monitoring: creatinine, blood pressure and heart rate during the infusion, headache, aseptic meningitis, haemolysis, thromboembolic events; adjustment: use a slower rate and a sucrose free product in renal impairment, hydrate beforehand, check IgA level (anaphylaxis in IgA deficiency), reduce the rate or avoid in patients at high thrombotic risk
• Plasma exchange (5 to 7 exchanges over 10 to 14 days) is an alternative for vasculitic and demyelinating forms.
• Cyclophosphamide for vasculitic neuropathy and severe refractory disease: cyclophosphamide 750 mg/m2 IV once monthly for 6 months; maximum 1000 mg/m2 in one dose; monitoring: FBC (nadir at 10 to 14 days), creatinine, hydration with mesna cover for haemorrhagic cystitis, urine dipstick, pregnancy test; adjustment: reduce by 25% when creatinine clearance is under 30 mL/min, hold for neutrophils under 1.0 x 10^9/L or platelets under 100 x 10^9/L, discuss fertility preservation before the first dose
• Rituximab for refractory disease, anti-MAG neuropathy and some autoantibody types: rituximab 375 mg/m2 IV once weekly for 4 doses (or 1000 mg IV on days 1 and 15), with hydrocortisone 100 mg IV, an antihistamine and paracetamol before each dose; maximum 1000 mg in one dose; monitoring: hepatitis B serology before the first dose, FBC, immunoglobulins, CD19 counts, infusion reactions, infection; adjustment: start the first infusion at 50 mg/h and increase by 50 mg/h every 30 minutes to a maximum of 400 mg/h, give antiviral prophylaxis for hepatitis B core antibody positivity, defer live vaccines, repeat at 6 months if relapse occurs and B cells have returned

Neuropathic pain.

• Gabapentin: gabapentin 300 mg orally at night on day 1, 300 mg twice daily on day 2 and 300 mg three times daily on day 3, then titrated every 3 to 7 days to 900 to 1800 mg daily in 3 divided doses; maximum 3600 mg daily; monitoring: sedation, dizziness, oedema, mood, falls, respiratory depression with opioids; adjustment: creatinine clearance 30 to 59 mL/min 400 to 1400 mg daily in 2 divided doses, 15 to 29 mL/min 200 to 700 mg once daily, under 15 mL/min 100 to 300 mg once daily, taper over at least 1 week when stopping
• Duloxetine: duloxetine 30 mg orally once daily for 1 week, then 60 mg once daily; maximum 120 mg daily (60 mg is the usual dose for neuropathic pain); monitoring: blood pressure, sodium, mood and suicidal thoughts, liver tests, nausea; adjustment: avoid when creatinine clearance is under 30 mL/min or in severe hepatic impairment, avoid with tamoxifen where possible (CYP2D6 inhibition), reduce slowly when stopping to avoid a discontinuation syndrome

Symptomatic and supportive care. Falls prevention and physiotherapy (proprioceptive training), occupational therapy and orthoses, foot care, management of autonomic features (compression stockings, fluids and salt for orthostatic hypotension; prokinetic therapy for gastroparesis), and nutritional support.

Monitoring. Neurological examination and nerve conduction studies at 3 months, then every 6 months. Repeat tumour screening for up to 4 years.

Referral and escalation.

• Urgent neurology referral for any rapidly progressive neuropathy in a smoker or patient with cancer.
• Emergency admission for respiratory involvement or severe autonomic failure.

Special groups.

• Older adults: caution with steroids and cyclophosphamide, and priority to falls prevention.
• Renal impairment: reduced doses of gabapentin and duloxetine, and caution with immunoglobulin.
• Pregnancy: immunoglobulin and plasma exchange preferred, with avoidance of cyclophosphamide.