ORRT Journal

1. Introduction

Radiation-Induced Injury (RII) of the visual pathways is an infrequent, iatrogenic and devastating phenomenon, occurring in patients who have undergone radiation therapy in sites near the visual pathways [1]. Its occurrence is rare but increasing with improved long-term cancer survival [2]. The time to disease onset displays a wide range. The earliest response manifests several weeks after the initiation of radiotherapy and may be reversible. The later manifestations are generally irreversible [3]. The latency period between radiation exposure to the onset of symptoms is related to the radiation dose and additional predisposing risk factors. Once Radiation-Induced Injury (RII) of the visual pathways becomes established, it typically follows a fulminate course. Prompt diagnosis and early treatment is essential to prevent complete visual loss. Magnetic resonance imaging (MRI) with Gadolinium-Diethylenetriamine Pent Acetic Acid (Gd-DTPA) enhancement is the preferred modality to differentiate RII from a recurrent tumor though the diagnosis may not always be forthcoming [1].

2. Case Description

A 46-year-old woman presented in June 2010 with a 2-week history of bilateral painless visual loss. Her medical history revealed a symptomatic amenorrhea for the preceding months. There was no history of head trauma or other associated symptoms. Two years previously the patient had been diagnosed with an anaplastic astrocytoma World Health Organization (WHO) grade II (partially grade III) of the medial part of the right temporal lobe with progression into the temporal Uncas. The tumor initially presented in August 2008 with a one day history of headache, nausea and vomiting followed by a status epileptic’s. After admission to the emergency department she was incubated, sedated and hospitalized. An intracranial lesion was found and the patient was referred for neurosurgical assessment. The ophthalmologic examination was normal. Her Best-Corrected Visual Acuity (BCVA) was log MAR 0 in the right eye and log MAR 0 in the left eye and Goldman V-4 visual field examination was within normal limits. Treatment included a surgical resection in October 2008 followed by radiotherapy combined with 6 months of chemotherapy (Temozolomide). In the interim, the patient did not have any ocular complaints and the neurologic examinations, which included a confrontation visual field, were normal. In the absence of complaints, she was not referred for formal ophthalmological assessment.

On ophthalmologic presentation in 2010, her best-corrected visual acuity was log MAR 0.6 in the right eye and log MAR 0.6 in the left eye. The anterior segment examination was normal. Fundoscopy demonstrated bilateral pale optic discs, particularly at the temporal rims, while Goldman V-4 visual field revealed a left homonymous hemianopia with also on the left eye nasal defects in the upper part with whole nasal constriction (Figure 1).

Visual Evoked Potentials (VEP) showed delayed latency in both eyes (right > left). The MRI scan showed a thickened optic chiasma and diffuse enhancement of the optic nerve, the left more than the right (Figure 2). There were no signs of tumor recurrence of the temporal lobe. The blood investigations were non-contributory and there was no evidence of hypopituitarism.

The most likely diagnosis based on clinical and radiologic data was radiation-induced chiasma injury, but at that time, it was not possible to definitively out-rule tumor infiltration. Oral prednisolone therapy was started at an initial dose of 64milligram/day (mg/day) tapering over three weeks to a maintenance dose of 8milligram, based on the provisional diagnosis of RII however the discrepancies between the MRI findings, original tumor location and the visual functions were a concern. A concise radiotherapy history revealed that the cumulative radiation dose was 55.8Gray (Gy), with a maximum single dose of 1.8Gy. The right optic nerve and the chiasma received a total (100%) radiation dose, while the left optic nerve received a maximum of 30-50% of the total dose. The exposure to the left optic nerve was restricted to the proximal part (Figure 3).

Despite the evidence in support of RII, tumor extension could not be ruled out. Three weeks after her initial presentation, BCVA declined to log MAR 1.3 in the right eye and log MAR 1.3 in the left eye. The patient expressed concerns at this stage about the inability to establish a definitive diagnosis and worsening of her vision despite oral corticosteroid therapy and a new MRI scan was performed in greater detail of the pituitary region.

The images were reviewed by a panel, which included a neuro-ophthalmologist, a radiologist and a neurosurgeon. The MRI showed tumoral in growth of the chiasma and left optic nerve. The consensus was that the visual symptoms were also due to tumoral in growth and not only RII, as was previously suspected. The oral prednisolone therapy was continued at the maintenance dose of 8mg/day and a bilateral optic nerve sheath fenestration was performed to decompress the nerves in order to preserve any residual visual potential. The surgery confirmed a thickened and gliomatous optic nerve, chiasma and optic tract, indicating tumor growth. No further action was taken, nor was a biopsy performed to preserve the already impaired optic nerve function. Over the following week’s visual acuity dropped to nil perception of light bilaterally. No further therapeutic options were available and all subsequent care measurements were palliative. The patient died a six months later as a result of tumor progression.

3. Discussion

The diagnosis of RII is difficult, particularly since a tissue biopsy of the optic nerve is not often feasible. Clinicians rely on symptoms, examination and imaging to establish the diagnosis. In this case, the patient reported a new onset of visual symptoms two years after her surgical resection. There was equal visual loss in both eyes, a left sided homonymous hemianopia and VEP showed delayed latency in both eyes (right > left). These clinical findings appeared to contradict the initial MRI findings. The MRI imaging showed gadolinium-DPTA enhancement of the chiasma and the optic nerve (left > right), which typically manifests as a central and bitemporal field defect, however the interpretation of the MRI was impaired by the previous surgical history and radiotherapy. The differential diagnosis must therefore consider both the clinical and MRI findings. For this patient, we elected to record her optic nerve function using a manual kinetic perimetry (Goldman) and a VEP protocol to provide an objective quantitative result. Automated static perimetry and standard colour vision assessment could also be helpful as a convenient and economic means of documenting optic nerve function but was not possible at that period in our patient.

The most likely diagnosis, based on the acute presentation and imaging was RII or idiopathic chiasmal neuritis. Patients with idiopathic chiasmal neuritis typically stabilize and improve over a period of days to weeks [4]. The fulminate course and subsequent loss of vision in this case, especially on the left side- with also on the nasal side visual field defects- make this diagnosis unlikely. The clinical findings also suggested a post-chiasmatic pathology at the right side, related to the left sided homonymous hemianopia, the most likely being caused by the irradiation. Even a small vascular infarct could result in a complete homonymous defect, no matter what the size of the lesion, due to the small size of the tract [5]. In the contrary, the left thickened chiasma and depressed central vision suggested a recurrence of the original tumor. Differentiating between RII and tumoral recurrence was the key decision point in the management of these patients.

Typical MRI findings in RII include gadolinium-DTPA enhancement of the optic nerve, chiasma or tracts as in this patient [1]. The accumulation of contrast is thought to be due to an occlusive vasculitis associated with delayed radio necrosis. Subsequent damage and depletion of the vascular endothelium leads to ischemic demyelination [6-8]. Patients often present themselves within 8 to 16 months with progressive vision loss over weeks to months [3]. The medical history of the patient, the timing after radiation exposure, the symptoms of bilateral progressive vision loss and the gadolinium-DPTA enhancement on MRI made RII seem the most likely diagnosis and oral prednisone therapy was initiated [1-3]. Unfortunately, there is still no consistently successful treatment for RII. Corticosteroids and anticoagulants are frequently used but don’t affect the final outcome. Furthermore, Hyperbaric Oxygen therapy (HBO) has been reported to be successful, but only when the therapy is applied < 72h of the onset of visual loss and when it is instituted at ≥ 2.4 atmospheres [1]. The use of intravitreal injections of triamcinolone acetonide and anti-vascular endothelial growth factor (anti-VEGF) injections with bevacizumab have been reported though they may only be of benefit to anterior neuritis and papillitis, but long-term injections are required for sustained effect [9,10]. Reversal of visual deficits through treatment with systemic bevacizumab has been reported, but until controlled studies are performed, the side effect profile of stroke and myocardial infarction should limit its use in a population with predisposing cardiovascular risk factors [10]. There are also promising results in animals using angiotensin-converting enzyme inhibitors as a medical prophylaxis of RII, which may be potentially applicable to humans [11].

The diagnosis of RII naturally requires a history of radiation consistent with a high risk of exposure to the tissue involved. Hence a review of the original radiotherapy protocol to determine the degree of optic nerve and chiasma exposure was requested. The right optic nerve, the chiasma and optic tract received 100% of the radiation dose while the left optic nerve received 30-50%. The threshold for developing RII has been reported as over 50 Gy, with the risk increasing at higher doses [1]. The exposure of 55.8 Gy, as was seen in this case, confers a very low risk of RII. Other causes that could have aggravated the radiation effect were taken into consideration [4]. Predisposing risk factors associated with a higher risk for developing RII and at a lower total dose of radiation were age, diabetes mellitus, and prior radiation exposure [6], which were not factors in this case. At the time of radiation, the patient’s age was 38 and she did not suffer from diabetes. Female gender has not been found to be a significant risk factor for RII [12]. She did have concomitant chemotherapy with Temozolomide, which could be a radio sensitizer and may increase the likelihood of RII of the right optic tract [8].

Despite the evidence for RII, some of the data were conflicting. RII is typically accompanied by optic tract atrophy, which was not seen in this case [12]. In addition the involvement of the left optic nerve and chiasma, which was not exposed to a sufficiently high radiation dose (approx. 27 Gy), displayed enlargement on the MRI. These findings were therefore more suggestive of a compressive or infiltrative growth. Tumor recurrence has already been described in the literature in the absence of MRI findings [13,14]. Other articles describe a role for PET scanning with 18-F-desoxyglucose in the diagnosis of RII [15,16]. PET scans show high metabolic activity in neoplasm’s and low activity in necrotic changes such as RII, though this has not been widely replicated in the literature. The definitive diagnosis may be made by optic nerve biopsy or optic nerve exploration [7,13]. As surgery is associated with some risks, exploration and biopsy were initially deferred. In this case, the patient expressed concerns about the inability to establish a definitive diagnosis and worsening of her vision despite oral corticosteroid therapy. A new MRI scan was performed in greater detail of the pituitary region. The images were reviewed by a panel and tumoral in growth was really suspected and not only RII. An optic nerve sheath fenestration was performed to decompress the nerves and provide the greatest potential for preservation of vision. During surgery, the tumor was visualized. The size and infiltration of the lesion confirmed that the lesion was not amenable to treatment and the surgery was concluded without biopsy to preserve visual function for palliative care.

4. Conclusion

In patients who presents with bilateral visual loss, thickened optic chiasma and nerves on MRI scan, tumor extension should still be the first consideration for the ophthalmologist. Although MRI scans is the most important imaging method to differentiate other causes. Clinical examination and patient history should be applied to critically interpret MRI findings and especially radiation schedules should be revised in the first acute phase by the radiotherapist. Thereafter the problems discussed with the other neuro-ophthalmological and neuro-oncological specialists to ensure accurate and prompt diagnosis and treatment of this debilitating condition.

Figure 1: Goldmann V-4 visual field revealed a left sided homonymous hemianopia. (A-B) Preoperative fields, (C-D) presentation fields.

Figure 2: MRI on clinical presentation. Coronal T2 image shows a thickened optic chiasm and diffuse enhancement of the optic nerve, see arrow (left (L) > right (R)).

Figure 3: Radiation dose schematic diagram. The right optic nerve and the chiasm received a total (100%) radiation dose (white area). The radiation to the left optic nerve was restricted to the proximal part.

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