Diffuse Midline Glioma

Diffuse midline glioma, H3 K27-altered, is a grade 4 infiltrating glioma of the pons (diffuse intrinsic pontine glioma), thalamus or spinal cord. It makes up about 10 to 15% of childhood brain tumors, with a peak at 5 to 10 years and an incidence of about 0.2 in 100,000 children a year. It also occurs in young adults.

Molecular features: H3 K27M mutation (H3F3A in about 60% and HIST1H3B in about 30%) with loss of H3 K27me3 staining, ACVR1 mutation (about 25%), TP53 mutation and PDGFRA amplification. Median survival is 9 to 12 months and 2-year survival is under 10%. Thalamic and spinal tumors behave similarly. Complications: bulbar palsy and aspiration, respiratory failure, hydrocephalus (about 15%), hemorrhage and leptomeningeal spread.

• Short history (usually under 3 months) with a triad of cranial nerve palsies (sixth, seventh and bulbar), long tract signs and cerebellar ataxia
• Diplopia, facial weakness, dysphagia, dysarthria and gait disturbance
• Thalamic tumors: hemiparesis, headache and hydrocephalus
• Red flags: apnea, aspiration, falling consciousness and vomiting from hydrocephalus

1. MRI brain and spine with gadolinium: a diffusely enlarged pons (over 50% involved) with T2/FLAIR hyperintensity, T1 hypointensity, often encasing the basilar artery, and little or no enhancement.
2. Stereotactic biopsy (morbidity 1 to 2%) for molecular confirmation: H3 K27M immunohistochemistry with loss of H3 K27me3, ACVR1, TP53 and PDGFRA. The typical imaging picture can establish the diagnosis in a child when biopsy is declined.
3. Spinal MRI at diagnosis and progression, since dissemination is common.

Differentials: brainstem encephalitis, acute disseminated encephalomyelitis, pilocytic astrocytoma of the brainstem, tectal glioma, osmotic demyelination, Bickerstaff encephalitis.

Radiotherapy is the only treatment shown to improve symptoms and delay progression.

• Focal radiotherapy: 54 Gy in 30 fractions of 1.8 Gy over 6 weeks, or 39 Gy in 13 fractions of 3 Gy over 3 weeks (equivalent, with less time in treatment). Symptoms improve in about 70 to 80%, for a median of 3 to 6 months.
• Dexamethasone: 0.1 to 0.25 mg/kg orally or IV every 6 hours (maximum 4 mg a dose) for swelling and symptoms, tapering to the lowest effective dose. Give omeprazole 1 mg/kg orally daily (maximum 20 mg) and monitor glucose, blood pressure and mood. Long courses cause Cushingoid features and myopathy.
• Re-irradiation at progression, at least 6 months after the first course: 24 Gy in 12 fractions of 2 Gy.
• Temozolomide and other chemotherapy have not extended survival. Offer a clinical trial of targeted therapy or cell-based treatment.
• Hydrocephalus: endoscopic third ventriculostomy or a ventriculoperitoneal shunt.
• Supportive and palliative care from diagnosis:
  • Gastrostomy for failing swallow.
  • Glycopyrronium 40 micrograms/kg orally every 8 hours (maximum 2 mg a dose) for drooling.
  • Levetiracetam 10 mg/kg orally twice daily, increasing to 30 mg/kg twice daily for seizures.
  • Baclofen 0.3 mg/kg a day orally in 3 divided doses, increasing weekly to 2 mg/kg a day (maximum 40 mg a day) for spasticity.
  • Morphine 0.1 to 0.2 mg/kg orally every 4 hours for pain or breathlessness in the terminal phase.
• Adult thalamic and spinal tumors: the same approach, with resection when accessible.

Follow-up: MRI every 2 to 3 months, or by symptoms. Counsel the family early about prognosis, and offer home-based palliative care and psychological support.