Optic nerve glioma (optic pathway glioma) is a type of glioma that arises from the optic nerve. In a narrow sense, it refers to gliomas occurring in the optic nerve anterior to the optic chiasm. In a broad sense, it includes gliomas arising anywhere along the entire optic pathway, including posterior to the chiasm.
Histologically, most are benign pilocytic astrocytomas (WHO Grade I). However, some malignant cases have been reported. Approximately 70% occur in childhood, making it a rare disease accounting for about 0.5–5% of pediatric brain tumors.
There is a strong association with neurofibromatosis type 1 (NF1, von Recklinghausen disease), and about 20–30% of optic nerve glioma cases are associated with NF1. Conversely, optic nerve glioma is the most common orbital lesion in NF1 patients.
Intraorbital optic nerve localized type
Most common form. Main symptoms are unilateral vision loss and proptosis.
Localized to the intraorbital optic nerve; observation is the basic management. Spontaneous regression has been reported in cases associated with NF1.
Chiasmal infiltration type
Type that infiltrates the optic chiasm.
Causes bilateral visual impairment and management is complex. Often occurs at a young age; evaluate extension to the hypothalamus.
Optic pathway/hypothalamic type
Type that extends from behind the chiasm to the hypothalamus.
May be associated with endocrine abnormalities (growth disorders, precocious puberty, etc.). Coordination with neurosurgery and endocrinology is necessary for treatment.
Classification by genetic background includes NF1-associated type (about 30% of all cases) and sporadic type (about 70%). Bilateral occurrence is also seen in NF1-associated type.
Young children do not complain of vision loss themselves. Therefore, parents or caregivers often notice strabismus (especially esotropia) and bring the child to an ophthalmologist for the first time.
Unilateral vision loss without strabismus is even more likely to be detected late. In some cases, optic atrophy is already present at the first visit.
Bilateral optic gliomas are more common in young children. They are first noticed due to abnormal eye movements or “not seeing” behaviors, and visual impairment may be severe.
Proptosis is not obvious, and there is no pain.
In optic glioma, young children cannot perceive or complain of vision loss, so strabismus (especially esotropia) often becomes the initial symptom leading to an ophthalmology visit. For children diagnosed with strabismus, especially unilateral strabismus, it is important to consider optic glioma and perform a thorough examination including visual acuity, fundus, and imaging studies.
Fundus examination often reveals the following findings:
In cases associated with NF1 (neurofibromatosis type 1), the following systemic findings are present:
CT findings:
MRI findings (detailed evaluation required):
Patients with NF1 have a significantly increased risk of optic glioma, and 20-30% of all optic glioma cases are associated with NF11). After an NF1 diagnosis, regular ophthalmic follow-up is recommended as screening for optic glioma. Conversely, when optic glioma is found in a child, it is important to check whether the diagnostic criteria for NF1 are met in all cases.
The main items of the diagnostic criteria for NF1 (neurofibromatosis type 1) are shown below2).
| Finding | Criteria |
|---|---|
| Café-au-lait spots | ≥6 (children: longest diameter ≥5 mm; after puberty: longest diameter ≥15 mm) |
| Neurofibromas | ≥2 (any type) or ≥1 plexiform neurofibroma |
| Iris Lisch nodules | ≥2 |
| Characteristic bone lesions | Sphenoid wing dysplasia or thinning of long bone cortex |
| Optic glioma | ≥1 |
| Axillary or inguinal freckling | Present |
| First-degree relative | With confirmed diagnosis of NF1 |
A confirmed diagnosis of NF1 requires meeting at least 2 of the above criteria.
MRI is superior to CT for evaluating tumor extent and is essential for a thorough examination.
| Finding | Details |
|---|---|
| T1-weighted imaging | Shows low signal intensity |
| Gd-DTPA contrast enhancement | Uniform enlargement with strong contrast enhancement |
| downward kinking | Characteristic in NF1-associated cases (downward kinking of the optic nerve) |
| Intracranial extension evaluation | Confirm extension into the intracranial space through the optic canal, and presence of tumor in the optic chiasm and hypothalamus |
Optic Nerve Sheath Meningioma
Most important differential diagnosis.
Common in adult women, and may be associated with NF2. CT/MRI shows a characteristic tram-track sign, useful for differentiating from optic glioma.
Optic Neuritis
Often presents with acute onset and pain on eye movement.
MRI shows contrast enhancement of the optic nerve, but enlargement is mild. Often improves with steroid therapy.
Other differential diagnoses:
Optic glioma shows uniform enlargement and downward kinking, which can be clearly distinguished from the tram-track sign of optic nerve sheath meningioma.
Optic glioma is a benign tumor (pilocytic astrocytoma) common in children, often associated with NF1. CT/MRI shows uniform enlargement and downward kinking of the optic nerve. Optic nerve sheath meningioma is more common in adult women, sometimes associated with NF2, and is differentiated by the tram-track sign (calcification or contrast enhancement along the optic nerve sheath) on CT/MRI.
Since the tumor is benign and common in children, if it is confined to the intraorbital optic nerve, surgical resection or radiation therapy is generally not performed. Careful observation with regular imaging (MRI every 3-6 months) is the basic policy.
Surgery was once performed, but due to the high risk of irreversible blindness, surgical resection is now avoided. In cases associated with NF1, spontaneous regression has been reported, so particularly careful observation is conducted.
When visual decline or tumor progression occurs, combination chemotherapy with carboplatin and vincristine (CV therapy) is used as standard first-line treatment3)4).
Standard CV therapy regimen (e.g., COG A9952):
The objective response rate (partial remission plus stabilization) of CV therapy is reported to be 60-80%4).
Second-line treatment options:
Considered for progressive cases resistant to chemotherapy. However, in children, there is concern about secondary cancer risk, endocrine dysfunction (due to hypothalamic irradiation), and cognitive effects, so it tends to be avoided as much as possible.
Currently, there is a tendency to avoid aggressive surgical resection.
Situations where surgery may be considered:
The histopathological finding of optic glioma is benign pilocytic astrocytoma (WHO Grade I). It is fundamentally different from high-grade gliomas such as glioblastoma multiforme (WHO Grade IV).
Tumor cells show a characteristic morphology with bipolar cell processes and contain Rosenthal fibers. They originate from glial cells (astrocytes) of the optic nerve and compress and replace the optic nerve from within.
Optic pathway gliomas associated with neurofibromatosis type 1 (NF1) are caused by mutations in the NF1 gene (chromosome 17q11.2).
In sporadic (non-NF1) pilocytic astrocytomas, the BRAF-KIAA1549 fusion gene is frequently observed. This fusion gene also activates the MAPK pathway and promotes tumor growth.
Some cases harbor the BRAF V600E mutation, and cases with this mutation tend to have a higher grade of malignancy6).
The majority of optic pathway gliomas are low-grade and show slow growth. The tumor enlarges the optic nerve from within and causes kinking (downward kinking) of the optic nerve within the orbit. Uniform enlargement and downward kinking on MRI are key points for imaging diagnosis.
Cases confined to the orbit:
Cases with chiasmatic/hypothalamic infiltration:
Life prognosis:
Functional prognosis:
Visual prognosis is not uniform; progressive and stable cases coexist, so longitudinal assessment of visual function is necessary in addition to tumor size. Some cases show visual deterioration despite stable MRI findings, while NF1-associated cases may exhibit spontaneous regression. 1, 8, 9)
The efficacy of MEK inhibitors for NF1-associated low-grade gliomas has been reported.
In the SPRINT trial (Phase II), selumetinib showed an objective response rate of 66% for NF1-associated progressive low-grade gliomas (plexiform neurofibromas) 7). Its application to NF1-associated low-grade gliomas including optic pathway gliomas is being investigated.
For pediatric low-grade gliomas with BRAF V600E mutation, combination therapy with dabrafenib + trametinib is being evaluated in clinical trials 6). In BRAF-KIAA1549 fusion-positive cases, the efficacy of BRAF inhibitors is limited.
With the advent of MEK inhibitors and BRAF inhibitors, there is a shift from conventional chemotherapy (CV therapy) to personalized treatment based on molecular profiles 8). In the future, treatment selection based on genetic mutation profiles (BRAF fusion, BRAF V600E, NF1 mutation, etc.) may become standard.
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