Paraneoplastic Cerebellar Degeneration

Paraneoplastic cerebellar degeneration is a subacute, severe, bilateral loss of Purkinje cells in the cerebellum, caused by an immune response to a cancer, and often presenting before the cancer is found. It is the commonest central nervous system paraneoplastic syndrome.

It is rare, affecting about 1 in 1,000 people with breast, ovarian, lung or lymphoma cancers. Onset is usually between 50 and 70 years, and women are more often affected because of the associations with breast and ovarian cancer.

Antibodies and tumours. Anti-Yo (PCA-1) with breast and ovarian cancer; anti-Hu (ANNA-1) and anti-CV2/CRMP5 with small cell lung cancer; anti-Tr (DNER) with Hodgkin lymphoma; anti-Ri with breast and small cell lung cancer; anti-Ma2 with testicular cancer; anti-mGluR1 and anti-VGCC (P/Q-type) with small cell lung cancer.

Course. Rapid progression over weeks to months to a plateau of severe disability, with little recovery in anti-Yo and anti-Hu disease; anti-Tr disease often responds to treating the lymphoma.

Pathophysiology.

Cancer cells express onconeural antigens that also exist in Purkinje cells, and cytotoxic T cell attack leads to irreversible loss of these neurons.

Some antibodies (anti-Tr, anti-mGluR1) may act directly and are more treatable.

• Subacute gait ataxia, truncal ataxia, limb dysmetria and intention tremor, evolving over days to months.
• Dysarthria, nystagmus (often downbeat), oscillopsia and diplopia.
• Nausea, vertigo and dizziness at onset; later severe disability with inability to sit or stand.
• Absent cognitive change early; other paraneoplastic features in some (neuropathy, encephalitis).

Red flags.

• Rapid progression over weeks, especially with weight loss, a smoking history or breast lump.
• Additional brainstem, limbic or peripheral nerve involvement.
• Lambert-Eaton features (proximal weakness, autonomic dysfunction), which suggest small cell lung cancer.

• Clinical syndrome of subacute pancerebellar ataxia in a patient aged over 40 years.
• Onconeural antibody panel (serum and cerebrospinal fluid): anti-Yo, anti-Hu, anti-Ri, anti-CV2, anti-Tr, anti-Ma2, anti-amphiphysin, anti-mGluR1, anti-VGCC.
• MRI of the brain: normal early, then cerebellar atrophy; exclude stroke, tumour, demyelination and infection.
• Cerebrospinal fluid: mild lymphocytic pleocytosis, raised protein and oligoclonal bands early.
• Cancer search: CT chest, abdomen and pelvis, mammography, pelvic ultrasound, whole body PET, testicular ultrasound; repeat every 6 months for up to 4 years if negative.

Differential diagnosis. Alcoholic cerebellar degeneration, cerebellar stroke, Miller Fisher syndrome, spinocerebellar ataxia, multiple system atrophy, gluten ataxia, anti-GAD ataxia, drug toxicity (phenytoin, lithium), posterior fossa tumour and prion disease.

• Find and treat the tumour (surgery, chemotherapy, radiotherapy) as the most effective step to stop progression, working with oncology.
• Immunotherapy early (within weeks of onset): methylprednisolone 1000 mg intravenously once daily for 3 to 5 days. Maximum 5 g in a course. Monitor blood pressure, glucose, mood and infection. Avoid with active untreated infection; use caution in diabetes and peptic ulcer.
• Intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, repeated every 4 weeks for 3 to 6 cycles if there is benefit. Maximum 2 g/kg in any 4 week period. Monitor renal function, thrombosis, hypersensitivity and aseptic meningitis; check IgA before the first dose. Avoid in IgA deficiency with anti-IgA antibodies; use caution in renal impairment and heart failure.
• Plasma exchange: 5 exchanges over 10 days as an alternative or addition. Monitor calcium, blood pressure and coagulation. Avoid in unstable cardiovascular disease and sepsis.
• Second line immunosuppression for patients with progressive disease: rituximab 1000 mg intravenously on days 1 and 15 (maximum 1000 mg for each dose; screen for hepatitis B; monitor infusion reactions and infection; avoid in active infection and pregnancy), or cyclophosphamide 750 mg/m2 intravenously every 4 weeks for 6 cycles (maximum 1000 mg/m2 for each dose; give with mesna and fluids; monitor full blood count, urine for haemorrhagic cystitis, and fertility effects; reduce dose in renal impairment; avoid in pregnancy), through an oncology or neuroimmunology team.
• Symptomatic care: physiotherapy, balance and gait training, speech and swallowing therapy, occupational therapy, and aids; vestibular rehabilitation.
• Palliative care input early for patients with advanced cancer and severe disability.

Monitoring. Review at 2 to 4 weeks, then 3 monthly; track the ataxia score; cancer surveillance every 6 months for 4 years if negative.

Referral and escalation. Neurology and oncology urgently; palliative care and rehabilitation.

Special groups. Pregnancy: this is an oncology emergency needing specialist advice. Anti-Tr disease: best response to treating Hodgkin lymphoma.