Neuro-ophthalmic Manifestations of Glioblastoma Multiforme

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 by Nagham Al-Zubidi, MD on April 25, 2022.


Introduction

Glioblastoma multiforme (GBM) is a Grade IV astrocytoma and represents the most common primary malignant brain tumor in adults. While it does not usually metastasize outside of the central nervous system (CNS),[1] it carries a poor prognosis with an average survival rate of 14.6 months despite treatment.[2] It presents clinically with headaches, focal neurologic deficits, confusion, memory loss, personality changes, and seizures.[3] Direct tumor origin in the optic pathway,[4] infiltrative or compressive GBM lesions affecting the optic pathway,[5],[6],[7],[8] and increased intracranial pressure (ICP) from tumor growth and cerebrospinal fluid flow obstruction[9],[10],[11] can also result in a variety of neuro-ophthalmic signs and symptoms, including visual field defects,[12],[13],[14] papilledema,[9],[15] relative afferent pupillary defect (RAPD),[7] ophthalmoplegia and diplopia,[16],[17],[18] exophthalmos,[18] and oculomotor nerve palsy.[16]

Epidemiology

This incidence of GBM in the United States is about 3:100,000, with over 10,000 cases diagnosed annually. GBM makes up 45.2% of malignant CNS tumors, 80% of primary malignant CNS tumors, and 54.4% of malignant gliomas. The accepted mean age at diagnosis is 64 years.[3],[19] In a single institution study of 267 cases of GBM, the patients’ ages ranged from 22-86 years, with a mean of 59.5 years and a median of 61 years.[20] It is 1.5 times more common in men compared to woman and twice as likely in whites compared to blacks.[19] With improvements in radiologic diagnosis, the incidence of GBM has slightly increased over the past 20 years, especially in the elderly population.[21]

Pathogenesis

While about 5% of GBM cases are related to hereditary syndromes,[22] most cases are sporadic.[3] In general, gliomas undergo malignant transformation through the sequential accumulation of genetic mutations and abnormal regulation of growth factor signaling pathways.[23] GBM has two clinical forms – primary and secondary GBM. Primary GBM usually arises de novo and often has amplified, mutated epidermal-growth factor receptor (EGFR), whereas secondary GBM arises from prior low-grade astrocytoma and often has increased platelet-derived growth factor A (PDGF-A) receptor signaling. Both mutations lead to increased tyrosine kinase receptor (TKR) activity and subsequent activations of the RAS and PI3K pathways.[24]

Primary and secondary GBM also have other mutations commonly involved in the pathogenesis of these tumors. Primary GBM commonly has amplification of the MDM2 gene, PTEN mutations, and homozygous deletions of CDKN2A. Secondary GBM often has prevalent p53 mutations, IDH1 mutations, and MET amplification, and the transformation of low-grade astrocytoma to high-grade astrocytoma like GBM via the secondary pathway is associated with the inactivation of the retinoblastoma gene (RB1) and increased activity of human double minute 2 (HDM2).[24]

Even though primary and secondary GBM have different mutations in their pathogenesis, they both result in aberrations in the same signaling pathways, ultimately resulting in increased cell proliferation, inhibition of apoptosis, invasion, and angiogenesis.[24],[25]

Neuro-ophthalmologic Manifestations

GBM can present with various neuro-ophthalmic symptoms, which result from malignant glioma originating in the optic pathway, non-optic GBM invading or compressing the optic pathway or cranial nerves III through VIII pathways, and increased ICP.

GBM can arise in the optic nerve, optic chiasm, or optic tract as a malignant optic glioma.[5],[6],[7] Malignant optic glioma affecting the optic nerve can present as loss of visual acuity or visual field deficits in the ipsilateral eye, loss of color vision, and RAPD.[8] Orbital involvement can also present with proptosis.[26]

Malignant glioma arising in the optic chiasm or non-optic GBM infiltrating or compressing the optic chiasm can presents with bilateral, progressive visual loss. It often presents as either a bitemporal hemianopsia when only the chiasm is involved, or as a junctional scotoma or junctional scotoma of Traquair when the junction of the optic nerve and chiasm is involved.[27],[28]

GMB affecting the post chiasma pathways, including the optic tract, optic radiations in the temporal or parietal lobes, and occipital cortex will present as contralateral homonymous hemianopsia.[15] Involvement of the optic tract can produce contralateral RAPD with band-type optic atrophy in the contralateral eye with temporal visual field.[29]

As with any mass lesion in the brain, elevated ICP can present with papilledema and subsequent bilateral vision loss. Rarely, a tectal lesion in the midbrain can produce a tectal RAPD without vision loss due to the visual afferent pathway remaining unaffected with only involvement of pupillary afferent fibers in the midrain.[8],[30]

Although it is uncommon, there have been case reports documenting GBM presenting with efferent visual symptoms such as diplopia. Cho et al. reported a patient with GBM and leptomeningeal gliomatosis who presented with diplopia and photophobia.[17] Reifenberger et al. reported a patient with transient diplopia and incomplete left-sided oculomotor nerve (CN III) palsy due to GBM at the left pontomesencephalic junction with destruction of the left CN III.[16] Yu et al. reported a patient with GBM extending to the left temple and sphenoid, ethmoidal, and frontal sinuses who presented with diplopia and left-sided exophthalmos.[18]

Prognosis

The prognosis of GBM is poor, and GBM affecting the optic apparatus further reduces prognosis compared to GBM affecting other brain locations. The survival rate of non-optic pathway GBM is a mean of 14.6 months, while the survival rate is reduced to a mean of 8 months with optic pathway GBM.[2],[4] While GBM rarely metastasizes outside of the CNS,[1] leptomeningeal spread (LMS) of GBM within the CNS is another severe complication of GBM. This represents end-stage disease with a prognosis of 2-5 months.[31]

Management

Treatment of GBM involves maximal safe surgical resection followed by adjuvant radiotherapy and temozolomide chemotherapy, which is a DNA alkylating agent that crosses the blood-brain barrier in order to cause cell cycle arrest at the G2/M boundary and subsequent apoptotic tumor cell death.[31],[32],[33] There is currently no clear consensus on a standard treatment for LMS in GBM, with intrathecal chemotherapy and additional radiotherapy having shown limited efficacy.[31]

Summary

Glioblastoma multiforme is a malignant astrocytoma that can present with various neuro-ophthalmic symptoms relating to direct optic tumor origin, infiltration or compression of the optic apparatus, and increased ICP. Involvement of the anterior, chiasmal, and posterior afferent pathways can result in unilateral vision loss, bitemporal hemianopsia/junctional scotoma/junctional scotoma of Traquair, and contralateral homonymous hemianopsia, respectively. Increased ICP can result in papilledema and subsequent bilateral vision loss. Rarely, involvement of the efferent visual system, such as the oculomotor nerve, can result in diplopia. Loss of color vision, RAPD, and proptosis are other ophthalmic presentations of GBM. Involvement of the optic pathway reduces the already poor prognosis of GBM from an average of 14.6 months survival to an average of 8 months. Despite, maximal treatment with surgical resection, radiotherapy, and temozolomide chemotherapy, prognosis of the disease remains poor.

References

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