Optic Glioma

Key Points at a Glance

Key Points of This Disease

• Optic nerve glioma is a rare tumor accounting for approximately 0.5–5% of pediatric brain tumors, with a predilection for children under 10 years of age.
• Histologically, the majority are pilocytic astrocytomas (WHO Grade I), and most follow a benign course.
• Approximately 20–30% are associated with neurofibromatosis type 1 (NF1), and it is the most common tumor among NF1 orbital lesions.
• In young children, it is often noticed due to strabismus or “not seeing” behaviors, and detection tends to be delayed.
• The key imaging finding is uniform enlargement and downward kinking of the optic nerve, with MRI being essential for detailed evaluation.
• For lesions confined to the orbit, surgical resection and radiation therapy are generally not performed; regular MRI follow-up is the basic management strategy.
• Standard chemotherapy (carboplatin + vincristine) is used for progressive visual loss.

1. What is Optic Nerve Glioma (Glioma)

Optic nerve glioma (optic pathway glioma) is a type of glioma that develops in the optic nerve. In a narrow sense, it refers to a glioma arising in the optic nerve anterior to the optic chiasm. In a broad sense, it means a glioma occurring throughout the entire optic pathway, including posterior to the optic chiasm (optic pathway glioma).

Histologically, most are benign pilocytic astrocytomas (WHO Grade I). However, some malignant cases have been reported. Approximately 70% occur in childhood, and it is 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 have concurrent NF1. Conversely, optic nerve glioma is the most common orbital lesion in NF1 patients.

Classification by Site and Genetic Background

Intraorbital Optic Nerve–Limited Type

Most common form. Main symptoms are unilateral vision loss and proptosis.

Limited to the intraorbital optic nerve; observation is the basic approach. Spontaneous regression has been reported in cases with NF1.

Chiasmal Infiltrative Type

Type that infiltrates the optic chiasm.

It causes bilateral visual impairment and management becomes complex. It often occurs at a young age, and extension to the hypothalamus should be evaluated.

Optic pathway-hypothalamic type

A type that extends from behind the optic chiasm to the hypothalamus.

Endocrine abnormalities (such as growth disorders and precocious puberty) may be associated. Treatment requires collaboration with neurosurgery and endocrinology.

Classification by genetic background includes NF1-associated type (about 30% of all cases) and sporadic type (about 70%). Bilateral occurrence may be seen in the NF1-associated type.

Differences from adult malignant optic glioma

This disease is common in children, predominantly benign pilocytic astrocytoma, and the prognosis is generally good. In contrast, adult malignant optic glioma (MOGA/MONG) is a different disease that manifests as anaplastic astrocytoma or glioblastoma, with an extremely poor prognosis. The two are distinct diseases with fundamentally different histology, age groups, prognosis, and treatment strategies.

2. Main symptoms and clinical findings

Kotecha MR, et al. Idiopathic Optic Nerve Glioma: A Case Report. Cureus. 2024. Figure 2. PMCID: PMC11744336. License: CC BY.

Axial MRI shows fusiform enlargement of the right intraorbital optic nerve with homogeneous and strong contrast enhancement (red arrow), and proptosis due to mass effect posterior to the globe. This corresponds to the MRI findings (uniform enlargement of the optic nerve and downward kinking) discussed in the section “2. Main symptoms and clinical findings.”

Subjective Symptoms

Young children do not complain of vision loss themselves. Therefore, parents or those around them often notice strabismus (especially esotropia) and bring the child for an initial ophthalmology visit.

Unilateral vision loss without strabismus is even more likely to be detected late. Optic atrophy may already be present at the initial examination.

Bilateral optic gliomas are more common in cases with early onset. 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.

Q If a child is told they have strabismus, could it be optic glioma?

A

In optic glioma, young children often cannot perceive or report vision loss, so strabismus (especially esotropia) frequently becomes the initial symptom leading to an ophthalmology visit. In children diagnosed with strabismus, particularly unilateral strabismus, it is important to consider optic glioma and evaluate with visual acuity, fundus, and imaging studies.

Fundus Findings

Fundus examination often reveals the following findings.

• Optic disc edema (early finding)
• Optic disc atrophy (advanced stage finding)
• Choroidal folds

Findings in NF1-associated cases

In cases associated with NF1 (neurofibromatosis type 1), the following systemic findings are present.

• Café-au-lait spots: light brown patches on the skin
• Cutaneous neurofibroma
• Iris Lisch nodules: Important as an ophthalmologic finding confirmed by slit-lamp examination

Imaging findings

CT findings:

• The optic nerve appears hypodense to isodense and is cylindrically thickened
• Bending and tortuosity (kinking) of the optic nerve within the orbit are observed

MRI findings (for detailed examination):

• T1-weighted images: show low signal intensity
• Gd-DTPA contrast: shows uniform enlargement and strong contrast enhancement
• Downward kinking: downward bending of the optic nerve is characteristically seen in cases with NF1
• Evaluate extension from the optic canal into the intracranial space and the presence of optic chiasm/hypothalamic tumors.

Visual loss in children → Do not forget to perform a thorough examination.

In children with unilateral visual loss, it is important to rule out optic glioma. Delayed detection leads to irreversible progression of optic atrophy. In young children who cannot complain of visual loss, do not neglect behavioral observation and regular ophthalmic examinations.

3. Causes and Risk Factors

Epidemiology

• It accounts for approximately 0.5–5% of pediatric brain tumors, making it rare.
• It commonly occurs in children aged 10 years or younger, with no sex predilection.
• About 70% of cases occur in childhood (some cases occur in adulthood).
• Approximately 20–30% of cases are associated with NF1 (neurofibromatosis type 1)¹⁾.
• Optic glioma is the most common orbital lesion in NF1.

Q Does having NF1 (neurofibromatosis type 1) increase the risk of optic pathway glioma?

A

Patients with NF1 have a significantly higher risk of optic pathway glioma, and 20–30% of all optic pathway glioma cases are associated with NF1¹⁾. After an NF1 diagnosis, regular ophthalmologic follow-up is recommended for screening of optic pathway glioma. Conversely, when optic pathway glioma is found in a child, it is important to check whether the diagnostic criteria for NF1 are met in all cases.

Diagnostic criteria for NF1

The main items of the diagnostic criteria for NF1 (neurofibromatosis type 1) are shown below²⁾.

Finding	Criteria
Café-au-lait spots	≥6 (prepubertal: longest diameter ≥5 mm; postpubertal: longest diameter ≥15 mm)
Neurofibromas	≥2 of any type or ≥1 plexiform neurofibroma
Iris Lisch nodules	≥2
Characteristic bone lesions	Sphenoid wing dysplasia or thinning of long bone cortex
Optic glioma	One or more
Axillary or inguinal freckling	Present
First-degree relative	Person with a confirmed diagnosis of NF1

A confirmed diagnosis of NF1 requires meeting at least two of the above criteria.

Recommendation for NF1 screening

In children diagnosed with optic pathway glioma, the presence of NF1 should be confirmed in all cases. Checking for café-au-lait spots, cutaneous neurofibromas, and iris Lisch nodules is essential. Note that management strategies, indications for chemotherapy, and prognosis differ in cases with NF1.

4. Diagnosis and Examination Methods

Key Points for Diagnosis

• Unilateral visual loss and/or proptosis in children (even if not obvious)
• CT/MRI: Uniform enlargement of the optic nerve with downward kinking
• Always check for association with NF1
• Biopsy is usually unnecessary (diagnosis possible by imaging). Tissue confirmation is performed at the time of surgical removal.

CT Findings

• The optic nerve appears hypodense to isodense and is cylindrically enlarged.
• Kinking of the optic nerve within the orbit is observed.
• Calcification is rare.

MRI Findings (Most Important)

MRI is superior to CT in evaluating tumor extent and is essential for detailed examination.

Finding	Details
T1-weighted image	Shows low signal intensity
Gd-DTPA contrast enhancement	Uniform enlargement with strong contrast enhancement
Downward kinking	Characteristic in NF1-associated cases (downward bending of the optic nerve)
Intracranial extension assessment	Confirm extension through the optic canal into the intracranial space, and presence of tumor in the optic chiasm and hypothalamus

Differential Diagnosis

Optic Nerve Sheath Meningioma

The most important disease for differential diagnosis.

It is more common in adult women and can be associated with NF2. CT/MRI shows a characteristic tram-track sign, which is useful for differentiation from optic glioma.

Optic Neuritis

Often presents with acute onset and pain on eye movement.

MRI shows contrast enhancement of the optic nerve, but swelling is mild. Often improves with steroid treatment.

Other differential diagnoses:

• Orbital lymphoma (more common in adults)
• Orbital inflammatory pseudotumor
• Metastatic orbital tumor

Optic glioma shows uniform enlargement and downward kinking, which is clearly distinguishable from the tram-track sign of optic nerve sheath meningioma.

Q What is the difference between optic glioma and optic nerve sheath meningioma?

A

Optic glioma is a benign tumor (pilocytic astrocytoma) common in children, often associated with NF1. CT/MRI shows uniform enlargement of the optic nerve and downward kinking. 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.

5. Standard treatment

Basic Policy: Observation

Because the tumor is benign and common in children, surgical resection or radiation therapy is generally not performed when the tumor is confined to the intraorbital optic nerve. The basic policy is careful observation with regular imaging (MRI every 3–6 months).

Surgery was once performed, but due to the high risk of irreversible blindness, surgical resection is now generally avoided. In NF1-associated cases, spontaneous regression has been reported, so particularly careful observation is undertaken.

Chemotherapy (Progressive Cases or Vision Loss)

When vision loss or tumor progression occurs, combination chemotherapy with carboplatin and vincristine (CV therapy) is used as standard first-line treatment³⁾⁴⁾.

Standard CV regimen (COG A9952, etc.):

• Vincristine: 1.5 mg/m² IV, once weekly × 10 weeks
• Carboplatin: 550 mg/m² IV, every 3 weeks

The objective response rate (partial remission + stabilization) of CV therapy is reported to be 60–80%⁴⁾.

Second-line treatment options:

• Cisplatin + etoposide
• Temozolomide (alkylating agent)
• Vinblastine monotherapy (for recurrence after CV therapy ⁵⁾)

Radiation therapy

Considered for progressive cases resistant to chemotherapy. However, in children, there are concerns about secondary cancer risk, endocrine dysfunction (due to irradiation near the hypothalamus), and effects on cognitive function, so it tends to be avoided as much as possible.

Surgical Resection

There is currently a tendency to avoid aggressive surgical resection.

Situations where surgery may be considered:

• When the tumor extends intracranially in a blind eye (life prognosis prioritized over risk of blindness)
• When marked proptosis significantly impairs quality of life (for cosmetic purposes)
• When tissue confirmation is needed (biopsy)

Need for long-term follow-up

Tumors generally follow a benign course, but rare cases may show regrowth, intracranial extension, or malignant transformation. Regular imaging (MRI) and visual function assessment must be continued long-term. In cases with hypothalamic extension, follow-up of endocrine function (growth hormone, thyroid function, etc.) is also necessary.

6. Pathophysiology and detailed pathogenesis

Histological features

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 arise from glial cells (astrocytes) of the optic nerve, compressing and replacing the optic nerve from within.

NF1-related molecular mechanisms

Optic glioma associated with NF1 (neurofibromatosis type 1) is caused by mutations in the NF1 gene (chromosome 17q11.2).

• The NF1 gene is a tumor suppressor gene encoding the neurofibromin protein.
• Neurofibromin functions as a Ras-GTPase activating protein (GAP) and suppresses Ras signaling.
• NF1 mutation → loss of neurofibromin function → constitutive activation of the Ras signaling pathway → enhanced MAPK signaling → uncontrolled proliferation of glial cells.

BRAF mutation

In sporadic (non-NF1-associated) 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 higher malignancy ⁶⁾.

Growth pattern of low-grade glioma

The majority of optic gliomas are low-grade and show slow growth. The tumor enlarges the optic nerve from within, causing kinking and downward kinking of the nerve within the orbit. Uniform enlargement and downward kinking on MRI are key imaging findings.

7. Prognosis and latest research

Prognosis

Cases confined to the orbit:

• Shows a relatively good prognosis
• Cases with NF1: spontaneous regression has been reported¹⁾
• Visual prognosis largely depends on the timing of initial treatment (early detection)

Cases with optic chiasm/hypothalamic infiltration:

• High risk of bilateral visual impairment
• Hypothalamic infiltration: may be associated with endocrine abnormalities (growth disorders, precocious puberty, diabetes insipidus, etc.)

Prognosis:

• Relatively favorable due to low-grade nature (5-year survival rate >90%)
• Malignant transformation: rare but reported → justifies regular imaging follow-up
• Regrowth: can occur even after chemotherapy

Functional prognosis:

• Long-term follow-up of visual, endocrine, and cognitive functions is important
• After radiotherapy: risk of secondary cancer, endocrine disorders, and neurocognitive impairment

Long-term management

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 worsening of visual function despite stable MRI findings, while in NF1-associated cases, spontaneous regression may occur. ^{1, 8, 9)}

• Visual function evaluation: Repeatedly measure visual acuity, visual field, color vision, and RAPD according to age
• Imaging follow-up: Track regrowth, chiasmal extension, and intracranial extension with MRI⁸⁾
• Endocrine evaluation: In cases with hypothalamic extension, check for growth disorders, precocious puberty, and diabetes insipidus
• NF1 systemic management: Conduct systemic follow-up including skin lesions, other tumors, and developmental aspects^{2, 9)}

For patients: Please be sure to read

The following content is currently in the research or clinical trial stage and is not a standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

MEK inhibitors (selumetinib)

The efficacy of MEK inhibitors for NF1-associated low-grade glioma has been reported.

In the SPRINT trial (Phase II), an objective response rate of 66% was reported for selumetinib in NF1-associated progressive low-grade glioma (plexiform neurofibroma) ⁷⁾. Its application to NF1-associated low-grade gliomas, including optic pathway gliomas, is being investigated.

BRAF inhibitors

For pediatric low-grade gliomas with BRAF V600E mutation, combination therapy with dabrafenib plus trametinib is being evaluated in clinical trials⁶⁾. In BRAF-KIAA1549 fusion-positive cases, the efficacy of BRAF inhibitors is limited.

Direction of molecular targeted therapy

With the advent of MEK inhibitors and BRAF inhibitors, there is a shift from conventional chemotherapy (CV therapy) to personalized treatment based on molecular profiles⁸⁾. In the future, treatment selection based on genetic mutation profiles (BRAF fusion, BRAF V600E, NF1 mutation, etc.) may become standardized.

8. References

1. Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr. 1994;125(1):63-66. doi:10.1016/s0022-3476(94)70122-9. PMID:8021787.

2. Ferner RE, Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet. 2007;44(2):81-88. doi:10.1136/jmg.2006.045906. PMID:17105749; PMCID:PMC2598063.

3. Gnekow AK, Walker DA, Kandels D, Picton S, Giorgio Perilongo, Grill J, Stokland T, Sandstrom PE, Warmuth-Metz M, Pietsch T, Giangaspero F, Schmidt R, Faldum A, Kilmartin D, De Paoli A, De Salvo GL, of the Low Grade Glioma Consortium and the participating centers. A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioma - A final report. Eur J Cancer. 2017;81:206-225. doi:10.1016/j.ejca.2017.04.019. PMID:28649001; PMCID:PMC5517338.

4. Ater JL, Zhou T, Holmes E, Mazewski CM, Booth TN, Freyer DR, Lazarus KH, Packer RJ, Prados M, Sposto R, Vezina G, Wisoff JH, Pollack IF. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(21):2641-2647. doi:10.1200/jco.2011.36.6054. PMID:22665535; PMCID:PMC3413276.

5. Alvaro Lassaletta, Katrin Scheinemann, Shayna M. Zelcer, Juliette Hukin, Beverley A. Wilson, Nada Jabado, Anne Sophie Carret, Lucie Lafay-Cousin, et al. Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. JCO. 2016;34(29):3537-3543. doi:10.1200/jco.2016.68.1585.

6. Fangusaro J, Onar-Thomas A, Young Poussaint T, Wu S, Ligon AH, Lindeman N, Banerjee A, Packer RJ, Kilburn LB, Goldman S, Pollack IF, Qaddoumi I, Jakacki RI, Fisher PG, Dhall G, Baxter P, Kreissman SG, Stewart CF, Jones DTW, Pfister SM, Vezina G, Stern JS, Panigrahy A, Patay Z, Tamrazi B, Jones JY, Haque SS, Enterline DS, Cha S, Fisher MJ, Doyle LA, Smith M, Dunkel IJ, Fouladi M. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 2019;20(7):1011-1022. doi:10.1016/s1470-2045(19)30277-3. PMID:31151904; PMCID:PMC6628202.

7. Anuradha Banerjee, Regina I. Jakacki, Arzu Onar-Thomas, Shengjie Wu, Theodore Nicolaides, Tina Young Poussaint, Jason Fangusaro, Joanna Phillips, et al. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro-Oncology. 2017;19(8):1135-1144. doi:10.1093/neuonc/now282.

8. de Blank PMK, Orne-Ibekwe E, Packer R. International consensus recommendations for visual surveillance in optic pathway gliomas associated with neurofibromatosis type 1. J Neurooncol. 2020;148(3):571-578.

9. Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol. 1997;41(2):143-149. doi:10.1002/ana.410410204. PMID:9029062.