Introduction

Optic pathway gliomas (OPGs) are astrocytic neoplasms that are typically low-grade tumors arising from the optic nerve, chiasm or posterior tract [1••]. They account for approximately 2 % of gliomas in the central nervous system and 3 %‒5 % of childhood intracranial tumors. OPGs commonly present in childhood with 75 % of patients being diagnosed prior to the age of 10 and 90 % by the age of 20 [2]. Classification is based on anatomic location and concomitant diagnosis of neurofibromatosis type 1 (NF1) [3]. The pathogenesis of OPGs may be related to allelic chromosomal loss such as loss of chromosome 17q that can occur in pilocytic astrocytomas or loss of neurofibromin in patients with NF1 [4].

Tumors arise in the anterior visual pathway in 25 %‒30 % and can be further subdivided into orbital, intracanalicular, or intracranial prechiasmal lesions. These tumors are almost exclusively pilocytic astrocytomas, and growth is almost universally slow. Tumors may be infiltrative or demarcated from the normal optic nerve and invasion of the leptomeninges can often be seen. Compression of the optic nerve may occur as the tumor enlarges, resulting in demyelination and atrophy of the nerve. In contrast, posterior visual pathway tumors arising in the optic chiasm, hypothalamus, or anterior third ventricle, are a more heterogeneous group of tumors and are more often nonpilocytic astrocytomas. Therefore, their behavior is also more heterogeneous and their prognosis is significantly poorer [5, 6].

Presenting symptoms depend upon the location in which the tumor arises. Patients with orbital lesions most commonly present with proptosis and less likely with strabismus or spasmus nutans. Because of the young age at diagnosis, visual impairment is a relatively uncommon presenting symptom although fundoscopic examination may exhibit edema or pallor of the optic disc. Chiasmal lesions most often present with visual symptoms but can also present with symptoms arising from obstructive hydrocephalus. Hypothalamic gliomas may present as diencephalic syndrome such as failure to thrive in an alert and cheerful child. Children may present with endocrinopathies leading to precocious puberty or accelerated linear growth. Patients with NF1 should have annual ophthalmologic screening for identification of optic pathway gliomas until age 10 [1••, 7].

The diagnosis of OPG should be considered in situations of unexplained visual loss, monocular or asymmetric nystagmus, diencephalic syndrome, or optic nerve atrophy. Brain magnetic resonance imaging (MRI) including fine cuts through the orbit and optic pathway is the diagnostic imaging of choice. Findings may include tubular thickening of the optic nerve and chiasm, a suprasellar lesion, or optic nerve/tract involvement. Differential diagnoses include suprasellar germinoma, craniopharyngioma, glioma, sarcoidosis, lymphoma, or Langerhans histiocytosis [8]. The natural history of OPGs varies dependent on the histologic findings, location, and the genetic background of NF1 [9, 10].

Overall, OPGs are associated with an indolent clinical course and long-term survival, underscoring the need for addressing long-term treatment complications in treatment decisions [11]. Patients with NF1 and a more anterior location of the tumor are associated with the most favorable outcomes. Visual acuity loss is the most significant morbidity associated with OPGs, with blindness developing in almost 20 % of affected individuals. For this reason, treatment should be based on patient’s age, genetic predisposition (NF1), location of the lesion, and growth rate and is best rendered by a multidisciplinary team including ophthalmology, radiation oncology, neuro-oncology, neuroradiology, and neurosurgery (Table 1) [12–15].

Table 1 Presentation, pathology, and treatment options based on anatomic location
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Treatment

Diet and lifestyle

Although no specific studies have looked at OPGs and diet, there have been some studies looking at the use of ketogenic diets and gliomas in general. The use of the ketogenic diet derives from the Warburg hypothesis that tumor tissue relies mostly on glycolysis rather than oxidative phosphorylation for metabolism. In using the ketogenic diet, which provides low carbohydrates, high fat, and moderate protein, glucose levels in the blood are decreased and ketone bodies that bypass glycolysis are funneled directly into oxidative phosphorylation for metabolism. Mouse studies have shown that a ketogenic diet led to smaller tumor size, increased survival, and alterations in gene expression and reactive oxygen species [16]. Anecdotally, there have been some case reports on patients who have had success with tumor control on a ketogenic diet, but one clinical trial in patients with glioblastoma multiforme on ketogenic diets showed some difficulty with diet tolerability and minor differences in overall progression free survival [17].

Pharmacologic treatment

There have been no definitive studies establishing the superiority of one specific chemotherapeutic agent over others for OPGs. At our institution, we prefer starting with temozolomide given its favorable side effect profile, but all other chemotherapy options listed have been used for OPG treatment both alone and in conjunction.

Standard dosage :

150 mg/m2 once daily for 5 days of a 28 day cycle.

Contraindications :

Hypersensitivity to temozolomide or any component of the formulation; hypersensitivity to dacarbazine; myelosuppression.

Main drug interactions :

Valproic acid.

Main side effects :

Myelosuppression, moderate emetic potential, Pneumocystis jirovecii pneumonia, constipation.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents. At our institution, this is our first line agent due to tolerability of side effect profile.

Cost/cost effectiveness :

100 mg (5) capsules, $1261.45

Standard dosage :

450 mg/m2 in 1 h infusion on day 1 in a 3-week cycle.

Contraindications :

Allergic reaction to carboplatin, cisplatin, or other platinum-containing formulations, mannitol, or any component of the formulation; myelosuppression or bleeding.

Main drug interactions :

May enhance effect of immunosuppressant drugs, ototoxic effects of aminoglycosides, and neurotoxic effects of cisplatin (ie, peripheral neuropathy).

Main side effects :

Myelosuppression, electrolyte abnormalities, renal impairment, hepatic impairment, ototoxicity.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

450 mg/45 mL (45 mL) intravenous solution, $120.

Standard dosage :

30 mg/m2/d in a 3-h infusion with mannitol and saline on day 1 and 2 out of 3-week cycle.

Contraindications :

Hypersensitivity to cisplatin, other platinum-containing compounds, or component of the formulation; pre-existing renal impairment; myelosuppression; hearing impairment.

Main drug interactions :

Aminoglycosides, immunosuppressants, myelosuppressive agents.

Main side effects: nausea, vomiting, hypersensitivity/anaphylactoid reactions, hyperuricemia, infusion site reactions, neurotoxicity, ototoxicity, renal toxicity.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

200 mg/200 mL (200 mL) $86.64.

Standard dosage :

1500 mg/m2 in a 1-h infusion on day 1 out of 3-week cycle

Contraindications :

Hypersensitivity to cyclophosphamide or any component of the formulation

Main drug interactions :

Vitamin K antagonists, immunosuppressants, CYP3A4 inhibitors, CYP2B6 substrates, cardiac glycosides.

Main side effects :

Myelosuppression, cardiotoxicity, fertility, nausea, vomiting, hemorrhagic cystitis, hypersensitivity, immunosuppression, pneumonitis, secondary malignancies, wound healing impairment.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

1 g (1) cyclophosphamide reconstituted solution $879.00.

Standard dosage :

150 mg/m2/d in 1-h infusion on day 1 and 2 out of 3-week cycle.

Contraindications :

Hypersensitivity to etoposide or any component of the formulation.

Main drug interactions :

May decrease the metabolism of CYP3A4 substrates and enhance the anticoagulant effect of vitamin K antagonists (ie, warfarin).

Main side effects :

Myelosuppression, hypersensitivity reaction (anaphylactic-like reactions), hypotension with rapid administration, secondary malignancies.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

1 gm/50 mL (50 mL) intravenous solution, $105.60.

Standard dosage :

120 mg/m2/d, days 1‒7 in a 3-week cycle.

Contraindications :

Hypersensitivity to procarbazine or any component of the formulation; myelosuppression.

Main drug interactions :

Inhibits monoamine oxidase thus enhancing the effects of multiple classes of medications that are metabolized by these enzymes. Patients should be placed on a diet that minimizes exposure to tyramine.

Main side effects :

High emetic potential, myelosuppression, CNS toxicity (paresthesia, neuropathy), hypersensitivity.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

100 capsules (matulane oral) 50 mg, $6434.81.

Standard dosage :

1.5 mg/m2 in a 1-h infusion on day 1 out of 3-week cycle.

Contraindications :

Patients with the demyelinating form of Charcot-Marie-Tooth syndrome, pre-existing neuropathy.

Main drug interactions :

May decrease the metabolism of CYP3A4 substrates.

Main side effects :

Constipation, infusion site reactions from extravasation, neurotoxicity, respiratory distress or bronchospasm, uric acid nephropathy.

Special points :

Unlabeled use; Dosage varies depending on its use with other chemotherapeutic agents.

Cost/cost effectiveness :

Vincasar PFS intravenous 1 mg/mL (1 mL) $18.06.

Interventional procedures

Ophthalmological screening [20–23]

Patients with known OPGs and those diagnosed with NF1 should be serially screened for progressive visual loss. Although visual acuity is the primary screening test, it is difficult to perform in younger children. Visual evoked potentials and optical coherence tomography (OCT) are tools that can be helpful in the screening visit.

Contraindications :

None.

Complications :

None.

Special points :

More thorough testing may be necessary in younger children given inconsistencies in their acuity exam.

Cost/cost effectiveness :

High

MRI brain [24]

Cases with characteristic imaging findings on MRI can obviate biopsy of suspected lesions for diagnosis. MRI is the preferred method of imaging although head CT can be used as an initial screening tool at the time of presentation or when MRI is contraindicated. Lesions are often isodense to brain and contrast enhancement may be variable.

Contraindications :

Renal impairment may preclude contrast use.

Complications :

None.

Special points :

Sedation is often necessary for children to complete MRI.

Cost/cost effectiveness :

High.

Surgery

Surgery is typically considered only in the event of single nerve involvement, progressive and disfiguring proptosis, blindness, and significant mass effect or hydrocephalus. Complete resection of a tumor would only be considered and possible if the lesion is limited to one optic nerve because the procedure may cause blindness. Tumor resection or ventricular shunting may be needed in the setting of obstructive hydrocephalus.

Contraindications :

Diffuse or bilateral optic nerve involvement.

Complications :

Blindness.

Special points :

Patients with NF1 often have diffuse disease burden with increased failure rate after surgical intervention.

Cost/cost effectiveness :

Variable.

Assistive devices

Dependent on degree of vision loss and best evaluated by blind rehabilitation service experts.

Therapy and exercise

Blind rehabilitation services and vision therapy.

Usage :

Indicated when visual loss may be impairing independent functioning.

Special points :

Consider school for the blind for implementation of multidisciplinary approach to therapy.

Cost/cost effectiveness :

High.

Other treatments :

[25–28].

Radiation

Once utilized as the primary treatment modality, radiotherapy is typically deferred until at least age 5‒7 because of the potential for late risks including endocrinopathy, vasculopathy, and cognitive decline. Radiotherapy is considered a viable option in children older than age 5‒7 whose tumors are not amenable to surgery and/or tumors that have progressed despite other treatments. Conventionally, external-beam fractionated radiation therapy has been the treatment of choice. Radiotherapy is associated with 10-year relapse-free survival rates of 71 %‒90 % and stabilization of vision of 69 %‒81 % [29–32]. Indeed with regard to tumor stabilization and visual outcomes, radiotherapy is the modality with which other options are compared and remains the fall-back option when others fail. The results of a number of studies have suggested that using early introduction of radiotherapy rather than after visual decline or chemotherapy progression is associated with better visual outcomes [29–32]. For example, in a study of 27 patients with OPG treated at St. Jude Children’s Cancer Hospital on a prospective trial of conformal radiotherapy as the first treatment, patients were more likely to have useful vision before and after radiotherapy. [25] Although radiotherapy is effective, given the long-term survival for these patients, early radiotherapy has to be counterbalanced with development of complications later in life. Highly conformal techniques of radiation including proton beam radiotherapy and fractionated stereotactic radiotherapy have shown promise to limit the radiation exposure to surrounding brain tissue and minimize associated late risks [29, 30, 33, 34].

Contraindications :

Relative contraindication in age less than 5 years.

Complications :

Visual loss, edema, cognitive dysfunction, endocrine abnormalities, vasculopathy.

Special points :

Maximal effect of radiation may take years to be observed. Irradiation is associated with an increased incidence of secondary tumor development occurring years later and can result in the development of secondary Moyamoya disease, especially in NF1 patients.

Cost/cost effectiveness :

Variable.

Emerging therapies

Standard procedure :

Chemotherapy.

Contraindications :

Hemorrhage, wound healing difficulty, recent surgery.

Complications :

Hemorrhage, gastrointestinal perforation, hypertension, wound dehiscence.

Special points :

Most effective if edema associated with lesion contributing to symptoms or clinical presentation. Figure 1 demonstrates an example of OPG treated with bevacizumab at our institution with prolonged tumor control.

Fig. 1
figure 1

Tumor control following bevacizumab. A, Contrast enhancing MRI axial slices from a patient with an optic tract glioma previously treated with surgical debulking, carboplatin, vincristine, etoposide, vinblastine with progression noted at next scan 3 months later. B, Patient was started on bevacizumab with continued tumor stabilization over 4 years later (C).

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Cost/cost effectiveness :

400 mg/16 mL (16 mL), $3115.87.

Pediatric considerations

The information provided in this manuscript applies mostly to children given the fact that the mean age of patients at diagnosis is 8.8 years.