Glioblastoma multiforme (GBM) is an astrocytoma classified as WHO grade 4 and is the most common primary malignant brain tumor in adults. The incidence in the United States is approximately 3 per 100,000 people, with more than 10,000 cases diagnosed annually. It accounts for 12–15% of all brain tumors and 45.2% of malignant CNS tumors 3). The mean age at diagnosis is 64 years, and the male-to-female ratio is 1.5:1.
Neuro-ophthalmic signs arise from one or a combination of the following three mechanisms.
Primary optic nerve GBM is extremely rare, accounting for 0.6–1.2% of all brain tumors, with only about 70 cases reported in the literature1). Adult-type optic glioma is highly malignant and commonly occurs in middle-aged men. The prognosis is approximately 6 months, following a completely different course from the pediatric type.
The mean survival time when the visual pathway is involved is about 8 months, shorter than the 14.6 months for non-visual pathway GBM.
Primary optic nerve glioblastoma accounts for 0.6–1.2% of all brain tumors, with only about 70 cases reported worldwide 1). It is a very rare condition, and attention is needed as diagnosis is often delayed.
Characteristic neuro-ophthalmological findings are obtained depending on the affected part of the visual pathway.
Optic nerve lesion
Ipsilateral visual acuity loss: Visual impairment in the affected eye.
Visual field defect: Central scotoma, peripheral visual field loss, etc.
Color vision abnormality: May occur early.
RAPD (relative afferent pupillary defect): A finding strongly suggestive of optic nerve lesion.
Optical coherence tomography (OCT) changes: Detected as thinning of the retinal nerve fiber layer and GCL damage 1).
Optic Chiasm and Retrochiasmal
Bitemporal hemianopia: Involvement of the optic chiasm. May be accompanied by junctional scotoma.
Contralateral homonymous hemianopia: Involvement of the retrochiasmal region (optic tract and optic radiation).
Band atrophy of the optic nerve: Appears with contralateral RAPD when the optic tract is involved. Characterized by pallor of the temporal and nasal optic disc margins.
Tectal RAPD: In midbrain tectal lesions, RAPD may occur without visual impairment.
Papilledema due to increased intracranial pressure initially presents only with blurred vision and enlargement of the Mariotte blind spot. If it persists for a long time, optic atrophy occurs, and visual field narrowing and visual acuity loss progress.
The direction of MRI imaging varies depending on the lesion site. For lesions anterior to the optic chiasm, coronal orbital sections are essential; for posterior lesions, axial brain sections are useful.
The pattern of visual field defect varies depending on the tumor location. Involvement of the optic nerve causes ipsilateral central scotoma and peripheral visual field loss; involvement of the optic chiasm causes bitemporal hemianopia; involvement posterior to the chiasm (optic tract or optic radiation) causes contralateral homonymous hemianopia.
Approximately 95% of GBM cases are sporadic, and only about 5% are associated with hereditary syndromes. Occurrence is broadly divided into primary and secondary types, which have different molecular profiles.
The main molecular changes in primary and secondary types are shown below.
| Type | Main molecular changes |
|---|---|
| Primary | EGFR amplification, MDM2 amplification, PTEN mutation, CDKN2A deletion |
| Secondary | IDH1 mutation, p53 mutation, MET amplification |
| Common | RAS/PI3K pathway activation |
Factors associated with the risk of extracranial metastasis include TP53, TERT, and PTEN mutations, chromosome +7/−10, and sarcomatoid histology6). Risk factors for leptomeningeal dissemination include ventricular opening, repeat surgery, male sex, and ependymal invasion3).
Biopsy is essential for definitive diagnosis. Evaluation items include IDH1/2 mutation, GFAP, and Ki-671).
Differential diagnoses by site are shown below.
| Site | Main differential diagnoses |
|---|---|
| Optic nerve | Optic nerve sheath tumor, optic nerve sheath meningioma, optic nerve lymphoma |
| Optic chiasm | Pituitary adenoma, craniopharyngioma, meningioma |
The goal is resection to the maximum safe extent. In primary optic nerve GBM, complete resection is often difficult due to proximity to visual structures 1). In Japan, observation, surgery, chemotherapy, and radiotherapy are selected based on tumor location and progression.
Decompression of the optic chiasm may improve visual acuity. However, in cases with advanced optic atrophy, visual recovery is unlikely even after decompression, leading to a poor prognosis.
The standard irradiation protocol is 60 Gy in 30 fractions over 6 weeks 1).
The Stupp protocol (surgery + radiation + TMZ) yields a median survival of approximately 14.6 months.
Leptomeningeal seeding occurs in 2–4% (up to 15–25%) of GBM cases, with survival ranging from 0.2 to 9.7 months2). Primary LMS is extremely rare. No standard treatment exists; intrathecal chemotherapy and additional radiation have limited efficacy.
Because primary optic nerve GBM is adjacent to visual structures, complete resection is often difficult when prioritizing functional preservation 1). It is common to perform maximal safe resection followed by radiation and chemotherapy.
The central pathway of GBM proliferation, invasion, and angiogenesis is activation of the RAS/PI3K pathway via EGFR amplification. Additionally, immunosuppression in the tumor microenvironment is characteristic, with lack of T cell infiltration and increases in regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) promoting immune evasion 4).
The main route of dissemination is via the subarachnoid space 3). Autopsy reveals spinal dissemination in 25% of cases.
Effects on the optic pathway arise from the following three mechanisms.
LITT induces coagulative necrosis at temperatures above 46°C, while at 33–43°C it opens the BBB (blood-brain barrier) and induces immunogenic cell death4).
Chandar et al. (2023) performed LITT in a case of newly diagnosed GBM and confirmed a marked increase in CD8+ T cells and PD-L1 after treatment 4). The patient achieved 9-year recurrence-free survival.
Long et al. (2025) administered a triple-drug ICI regimen of nivolumab, ipilimumab, and relatlimab before surgery in newly diagnosed GBM 5). After treatment, tumor-infiltrating CD3+ T cells increased from 9.8% to 32.7%, and activated T cells increased 8.5-fold. One case showed recurrence-free survival for 17 months, and the GIANT trial is currently planned.
Immunotherapy as a standard treatment has not been established at this time. However, neoadjuvant triple-agent ICI administration has been shown to markedly increase intratumoral T-cell infiltration5), and further validation in clinical trials is expected.
Extracranial metastasis occurs in 0.4–2.0% of GBM cases, and the median survival after metastasis is extremely short at 1.5 months6). TP53, TERT, and PTEN mutations have been reported as molecular features of metastatic cases, and these are being studied as biomarkers for metastasis risk6).
