Complications of Therapy for High-Grade Gliomas in Children

Surgery

The potential complications after surgery for HGG, whether it be a stereotactic biopsy, open biopsy, or aggressive resection, are many.

Intraoperative

  • Blood loss: Acute, high volume blood loss, or slow, insidious loss over longer periods are major risks for children, particularly when they are very young. Even during the craniotomy, there is the danger of injury to a dural venous sinus with significant blood loss, and intraoperative venous or arterial bleeding can be catastrophic. Although AAs are typically not vascular, GBMs may be. Blood loss may lead to hypotension, cerebral hypoperfusion, or arrest.
  • Venous air embolism: This is a very rare complication in children.  It may occur when either a dural venous sinus or a large diploic calvarial venous lake is inadvertently opened during an exposure. Typically, this complication occurs when the head is significantly higher than the heart, as in the sitting position.  Consequently, these positions are used only when absolutely necessary.
  • Brain swelling: When opening the dura or working within the brain prior to debulking the tumor, an angry, edematous brain suffering from the tumor’s mass effect may be difficult to control. Preoperative or preincision EVD may be of great benefit, particularly if hydrocephalus is present.

Postoperative

  • Stroke: Stroke can be venous or arterial. Unless a dural venous sinus, large vein, or major artery is compromised, stroke is uncommon after surgery for HGG. Surgery around major arteries, however, may cause vasospasm, which can be addressed if diagnosed promptly. 
  • Seizures: Transcortical approaches or brain retraction can lead to cortical irritation and, subsequently, seizures. Preoperative seizures typically prompt the administration of preoperative anticonvulsants. Anticonvulsants should be given perioperatively for such a procedure expectantly. Postoperative seizures can complicate the examination and subsequent ICU care.
  • Neurological deficit: Weakness, numbness, paralysis, visual impairment, affect, and memory/language impairment may be expected depending on the location of the tumor and the presenting symptoms. Such expected deficits may be troubling but should not alter routine care. Unexpected symptoms should prompt urgent examination and imaging as well as appropriate blood work.
  • Hemorrhage: HGGs can be very vascular tumors. Intratumoral and intraparenchymal hemorrhage, particularly after subtotal resection, should be considered if the child’s awakening and clinical course are not as expected. In addition, brain collapse and violation of the ependyma may lead to intraventricular, subdural, or epidural hemorrhage. If there has been significant blood loss during the operation, verifying coagulation status and appropriate red blood cell and platelet levels is critical. Any mass lesion from hemorrhage should be emergently evacuated if the child’s hemodynamic or neurological function is compromised.
  • Acute hydrocephalus: A trapped ventricle or intraventricular blood may lead to acute hydrocephalus. The postoperative child, particularly one with intraventricular tumor or surgery, who does not wake up in the expected manner, or who awakens well and has a subsequent decline, should be emergently imaged to rule out a hemorrhage or hydrocephalus and the subsequent need for an emergent EVD. If there is an EVD in place, drainage should be assured and ICP measured.
  • Pituitary/hypothalamic dysfunction: Diabetes insipidus, temperature lability, and hypopituitarism are uncommon but may result from injury to the hypothalamus and/or pituitary infundibulum. Diabetes insipidus may be mistaken for postoperative diuresis. If there is a concern because of surgery in this direct location, vasopressin may be required, at least initially.
  • Spinal fluid leak: Subgaleal, transincisional, particularly after entering the ventricular system.
  • Infection: Infection after elective craniotomy is exceedingly rare. The major cause for infection would be a persistent CSF leak as mentioned above. Diagnosis may be made by lumbar puncture, enhanced, imaging studies, and serum studies including white blood cell count with differential, C-reactive protein, and estimated sedimentation rate. Treatment would include IV antibiotics with or without surgical exploration or debridement.

Medical

  • Hearing loss: Hearing may be impaired as a result of using carboplatin (29, 35).
  • Infertility: Infertility is typically a consequence of bone marrow transplantation and is more common in girls than boys (29).
  • Increased risk of secondary malignancy (29).
  • Leukoencephalopathy: This is seen after high-dose IV methotrexate and can be reversible.
  • Neutropenia and subsequent infection: Chemotherapy may adversely affect blood and bone marrow, reducing the number of white blood cells and the body’s inherent mechanism to fight infection, inflammation, and tumor cells.
  • Thrombocytopenia and subsequent bleeding: A decrease in the number of platelets impairs the ability to clot and increases the general risk of bleeding (29).
  • Death: The risk of death is small, but the toxicity of chemotherapy and the compromised immune system during high-dose chemotherapy and autologous stem cell rescue may be fatal (29).

Radiation

  • Radiation-induced tumors: Both benign meningiomas and HGGs can be caused by radiation for the initial HGG.
  • Neurocognitive/intellectual impairment: Cranial radiation is avoided in children younger than 3 years because of the potential effects to cognition and intellect. More moderate doses (50–54 Gy), fractionation, and conformal radiotherapy all contribute to fewer such neurocognitive and intellectual impairments.
  • Cerebrovascular effects: Radiation may injure the intima of arteries, particularly the carotid arteries, leading to progressive stenosis, and subsequent ischemia, leading to the risk of stroke and the development of collateral “moyamoya” vessels.
  • Eye/optic pathway effects: Radiation may cause direct damage, leading to cataracts and retinopathy, or late complications to optic nerves and pathways. The optic nerves are the most sensitive of the cranial nerves to radiation.
  • Endocrinopathies: Preferentially, growth hormone deficiency and hypothyroidism can result after craniospinal radiation in younger children.
  • Radiation necrosis: This is the most common late complication from radiation, sometimes mimicking a recurrence of HGG or a new, radiation-induced malignancy.

Immunotherapy

  • Fever, erythema, and liver dysfunction: The novelty of immunotherapy is that it targets the cancer cell and spares all the other normal cells in the body, all guided by the body’s own immune system. However, in clinical trials in adults, fever, erythema, and abnormal liver function have been described (36).