Primary Spinal Cord Glioma

Primary spinal cord glioma is an intramedullary glial tumour arising within the cord, most often an astrocytoma (pilocytic, diffuse or high grade) or an ependymoma. Presentation is gradual and subtle, and management depends on grade, extent of resection and molecular type.

Intramedullary tumours form 2% to 4% of CNS tumours, and about 80% of them are astrocytomas or ependymomas. Ependymomas are commoner in adults, and astrocytomas in children (where pilocytic astrocytoma predominates). Median age is 30 to 40 for ependymomas and under 20 for astrocytomas.

Neurofibromatosis type 2 is associated with spinal ependymoma, and neurofibromatosis type 1 with pilocytic astrocytoma. Most cases are sporadic.

Pathophysiology. Spinal pilocytic astrocytomas show BRAF alterations. Diffuse midline gliomas of the cord frequently carry H3 K27 alterations and have a poor prognosis. Spinal ependymomas show NF2 loss or MYCN amplification, with the latter marking an aggressive spinal ependymoma.

Behaviour. Low grade tumours grow slowly, with a long survival (10-year survival over 80% for ependymoma after gross total resection). High grade tumours (anaplastic astrocytoma, H3 K27-altered diffuse midline glioma) have median survival of about 1 year.

• Pain (often neck or back pain, or dysaesthetic pain), usually for months before diagnosis.
• Dissociated sensory loss (loss of pain and temperature with preserved light touch) and hand clumsiness, then weakness and spasticity.
• Gait disturbance, bladder and bowel dysfunction, scoliosis in children, and torticollis.
• Rapid deterioration in high grade tumours.

Red flags.

• Rapidly progressive weakness, sphincter dysfunction or respiratory failure (high cervical lesions).
• Sudden worsening from haemorrhage into the tumour.

• MRI of the whole spine and brain with gadolinium: expansile cord lesion with syrinx or cysts, enhancement patterns and extent. Ependymoma is central, well demarcated and often has a haemosiderin cap, and astrocytoma is eccentric, long and poorly demarcated.
• Histological diagnosis by biopsy or resection with intraoperative neurophysiological monitoring, and molecular testing (BRAF, H3 K27, IDH, NF2, MYCN, TP53).
• Lumbar CSF cytology 2 or more weeks after surgery when safe.
• Baseline neurological and functional scores, bladder assessment, and scoliosis assessment in children.
• NF1 and NF2 assessment.

Differential diagnosis.

• Ependymoma and astrocytoma (the commonest entities)
• Haemangioblastoma (von Hippel-Lindau disease), cavernous malformation and metastasis
• Transverse myelitis, demyelination (multiple sclerosis, neuromyelitis optica) and abscess
• Sarcoidosis and spinal cord infarct

Surgery. Maximal safe resection by microsurgery with neurophysiological monitoring. Gross total resection is curative for most ependymomas and low grade astrocytomas with a surgical plane, and is often not possible for diffuse infiltrative tumours.

Radiotherapy. Focal radiotherapy (54 Gy in 30 fractions, or 45 to 50.4 Gy) after subtotal resection of ependymoma or high grade tumours, and for progression of low grade tumours. For H3 K27-altered diffuse midline glioma, radiotherapy 54 Gy in 30 fractions is the main treatment.

Systemic therapy. Used for progressive high grade tumours and unresectable low grade tumours.

• Temozolomide with radiotherapy for high grade tumours (benefit is uncertain in H3 K27-altered tumours): during radiotherapy temozolomide 75 mg/m2 orally once daily at the same time each day on an empty stomach for 42 to 49 days, then after a 4-week break 150 mg/m2 orally once daily on days 1 to 5 of a 28-day cycle for cycle 1, increased to 200 mg/m2 on days 1 to 5 from cycle 2 when neutrophils and platelets allow, for 6 cycles; maximum 75 mg/m2 daily during radiotherapy and 200 mg/m2 daily in adjuvant cycles; monitoring: FBC weekly during radiotherapy and on day 22 of each adjuvant cycle, liver tests, antiemetic cover; adjustment: during radiotherapy hold for neutrophils under 1.5 x 10^9/L or platelets under 100 x 10^9/L and stop for neutrophils under 0.5 x 10^9/L or platelets under 10 x 10^9/L, in adjuvant cycles reduce by 50 mg/m2 for neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L and stop if 100 mg/m2 is not tolerated, no change when creatinine clearance is 36 mL/min or more and caution when it is lower, caution in severe hepatic impairment
• Pneumocystis prophylaxis during concurrent temozolomide and while corticosteroids continue: co-trimoxazole 960 mg orally three times weekly (for example Monday, Wednesday and Friday) throughout concurrent temozolomide and radiotherapy, continued while corticosteroids are used and until lymphocytes recover above 0.5 x 10^9/L; maximum 960 mg daily; monitoring: FBC, potassium, creatinine, rash; adjustment: halve the dose when creatinine clearance is 15 to 30 mL/min and avoid under 15 mL/min, stop for rash or severe cytopenia and use a non-sulfonamide agent
• Bevacizumab for progressive disease: bevacizumab 10 mg/kg IV every 2 weeks (first infusion over 90 minutes, then 60 minutes, then 30 minutes if tolerated) until progression or toxicity; maximum 10 mg/kg each dose; monitoring: blood pressure at each visit, urine protein before each dose, FBC, bleeding, thromboembolism, wound healing; adjustment: omit for 28 days before and after major surgery, hold for urine protein over 2 g in 24 hours until it falls under 2 g, stop for gastrointestinal perforation, severe haemorrhage, hypertensive crisis, arterial thromboembolism or posterior reversible encephalopathy
• Pilocytic astrocytoma and low grade tumours with BRAF V600E: dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until progression or unacceptable toxicity, for BRAF V600E tumours in adults and in adolescents weighing 51 kg or more (weight banded doses set by a paediatric oncology pharmacist below 51 kg); maximum dabrafenib 300 mg daily and trametinib 2 mg daily; monitoring: left ventricular ejection fraction at baseline, 1 month and then every 2 to 3 months, skin and eye examination, blood pressure, liver tests, glucose, temperature; adjustment: reduce dabrafenib stepwise to 100 mg then 75 mg twice daily and trametinib to 1.5 mg then 1 mg daily, hold both for fever of 38.5 C or more, stop for a fall in ejection fraction of over 10 points to under the lower limit of normal, avoid strong CYP3A4 or CYP2C8 inducers and inhibitors, no renal adjustment for mild to moderate impairment

Symptom control.

• Neuropathic pain: 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
• Corticosteroid for cord oedema: dexamethasone 4 mg orally or IV once or twice daily for mild symptoms and up to 4 mg four times daily for marked oedema or raised intracranial pressure, for the shortest period, tapered over 1 to 2 weeks once symptoms settle; maximum 16 mg daily; monitoring: glucose, blood pressure, mood and sleep, gastric symptoms (gastric protection when combined with other risk factors), opportunistic infection, myopathy; adjustment: use the lowest effective dose, avoid prolonged courses because of myopathy, osteoporosis and infection, use lower doses in hepatic impairment

Rehabilitation. Early physiotherapy and occupational therapy, bladder and bowel care, spasticity management, and pressure area care.

Monitoring. MRI of the whole spine 3 months after surgery, then every 3 to 6 months for 2 years and then yearly. Neurological, bladder and scoliosis review, with surveillance for late recurrence in ependymoma (10 or more years).

Referral and escalation.

• Spinal neurosurgery and neuro oncology referral at diagnosis.
• Emergency admission for rapidly progressive paralysis or respiratory compromise.

Special groups.

• Children: scoliosis surveillance and spinal stability after laminectomy.
• NF2: multiple tumours need individualised strategy, with surgery delayed until symptoms or growth.
• Pregnancy: surgery in the second trimester when needed, with radiotherapy deferred.