Vaphiades, Michael S DO; Spencer, Sharon A MD; Riley, Kristen MD; Francis, Courtney MD; Deitz, Luke MD; Kline, Lanning B MD
Departments of Ophthalmology (MSV, CF, LD, LBK), Neurology (MSV), Neurosurgery (MSV, KR), and Radiation Oncology (SAS), University of Alabama, Birmingham, Alabama.
Supported in part by an unrestricted grant from the Research to Prevent Blindness, Inc, New York, NY.
The authors report no financial conflicts of interest related to this article.
Address correspondence to Michael S. Vaphiades, DO, Department of Ophthalmology, University of Alabama, Suite 601, 700 South 18th Street, Birmingham, AL 35233; E-mail: firstname.lastname@example.org
Background: Radiation therapy is often used in the treatment of pituitary tumor. Diplopia due to radiation damage to the ocular motor cranial nerves has been infrequently reported as a complication in this clinical setting.
Methods: Retrospective case series of 6 patients (3 men and 3 women) with pituitary adenoma, all of whom developed diplopia following transsphenoidal resection of pituitary adenoma with subsequent radiation therapy. None had evidence of tumor involvement of the cavernous sinus.
Results: Five patients developed sixth nerve palsies, 3 unilateral and 2 bilateral, and in 1 patient, a sixth nerve palsy was preceded by a fourth cranial nerve palsy. One patient developed third nerve palsy. Five of the 6 patients had a growth hormone-secreting pituitary tumor with acromegaly. Following transsphenoidal surgery in all 6 patients (2 had 2 surgeries), 4 had 2 radiation treatments consisting of either radiosurgery (2 patients) or external beam radiation followed by radiosurgery (2 patients).
Conclusions: Patients with pituitary tumors treated multiple times with various forms of radiation therapy are at risk to sustain ocular motor cranial nerve injury. The prevalence of acromegalic patients in this study reflects an aggressive attempt to salvage patients with recalcitrant growth hormone elevation and may place the patient at a greater risk for ocular motor cranial nerve damage.
The onset of diplopia in a patient following treatment of a pituitary tumor raises the concern of tumor recurrence particularly with involvement of the ocular motor cranial nerves within the cavernous sinus. However, in patients who have undergone radiotherapy as part of their treatment regimen, radiation damage to the ocular motor cranial nerves must also be considered. This complication has been infrequently reported and when described often poorly characterized. Previously reported cases have been included in large series of patients with various skull base tumors, looking mostly at prevalence but not describing the clinical features of this disorder (1-4). We report 6 patients who developed radiation-induced ocular motor cranial neuropathy following treatment of pituitary tumor. In all cases, neuroimaging excluded tumorous involvement of the cavernous sinus. Our report documents the clinical profile, risk factors, pathophysiology, and treatment of this clinical entity.
We retrospectively evaluated 6 patients who developed diplopia following transsphenoidal resection of pituitary tumor with subsequent radiation therapy. Patients were excluded if their tumors involved the cavernous sinus or if an ocular motor palsy was detected prior to radiation. All patients underwent gadolinium-enhanced MRI of the brain. One patient (Case 1) also had cranial CT angiography (CTA) and MRA to exclude an aneurysm. All patients received complete examination by 1 of 2 neuro-ophthalmologists (M.S.V. or L.B.K.). A PubMed literature review using the terms “radiation,” “ocular motor palsy,” and “pituitary adenoma” was performed from the year 1948 until the present. References were reviewed in the articles discovered. In addition, textbooks and their references were reviewed, and interviews with neuro-oncologists and radiation oncologists were undertaken to assess the frequency of radiation-induced damage to the ocular motor cranial nerves.
Table 1 summarizes the clinical course of our 6 patients. Two illustrative cases are presented.
A 35-year-old woman was diagnosed with acromegaly due to a growth hormone-secreting pituitary tumor. She underwent transsphenoidal resection that was repeated 6 months later for residual tumor. Twenty-one months later, she underwent radiosurgery to the sella turcica for residual tumor (Fig. 1). With this treatment, 20 Gy was delivered to each cavernous sinus. Subsequently, the patient developed pituitary insufficiency and was placed on hormone replacement therapy. Twenty-four months following radiation, she developed left pupil-involving third nerve palsy.
At that time she was found to have incomplete left ptosis, a dilated left pupil that was poorly reactive to light, and an exotropia of 55 prism diopters and a left hypotropia of 6 prism diopters in primary gaze. Eye movements on the left were limited in adduction, supraduction, and infraduction while abduction was normal. Brain MRI as well as MRA and CTA revealed no evidence of tumor or aneurysm. Three years and 9 months following radiosurgery, the patient underwent left eye muscle surgery and has remained orthophoric in primary gaze over 11 months of follow-up.
A 25-year-old woman presented with amenorrhea, hypothyroidism, and hypoadrenalism and was subsequently diagnosed with pituitary macroprolactinoma. She underwent transsphenoidal resection and postoperatively received external beam radiation. With this treatment, both cavernous sinuses were exposed to a total dose of 46 Gy over 23 sessions.
Eight years later, the patient developed right optic neuropathy with acuity of 20/40, diminished color vision, right relative afferent pupillary defect, and temporal visual field loss. At that time, she also reported diplopia and was found to have limited abduction on the right consistent with a sixth nerve palsy. Visual acuity in the right eye declined to 20/200 and then stabilized, and the sixth nerve palsy remained unchanged.
Twenty-seven years after radiation therapy, the patient underwent right eye muscle surgery for an esotropia of 20 prism diopters with resolution of her diplopia. She has remained free of double vision over 1 year of follow-up, and MRI showed complete regression of the pituitary tumor. The patient remains on hormone replacement and has regained a normal serum prolactin level without suppressive medication.
Our patient cohort consisted of 3 women and 3 men ranging in age from 25 to 45 years. Five of the 6 patients had growth hormone-secreting pituitary tumor and developed acromegaly. None were diabetic. Table 1 summarizes the form and chronology of therapy each received. All had transsphenoidal surgery prior to receiving radiation therapy. Only 1 patient (Case 2) had 1 surgical procedure followed by a single course of radiotherapy. Two patients had 1 surgical procedure followed by 2 types of radiotherapy (Cases 3 and 6: external beam radiotherapy followed by radiosurgery; Case 4: radiosurgery performed twice). Two patients had 2 surgical procedures followed by radiotherapy (Case 1: radiosurgery; Case 5: radiosurgery performed twice). In the 2 patients who underwent 2 surgical procedures, the interval between surgeries ranged from 6 months to 6 years while the time between completion of radiation therapy and onset of diplopia ranged from 4 months to 8 years.
At our institution, during the period reviewed (1980-2009), a total of 181 patients received radiation therapy for pituitary tumors. Injury to the ocular motor cranial nerves occurred in the following: 1 of 159 patients (0.6%) receiving 1 radiosurgery series, 2 of 10 patients (20%) receiving 2 radiosurgery series, and 2 of 12 patients (17%) treated with both external beam and radiosurgery. In our experience, it appears that multiple radiotherapy sessions put the patient at an increased risk for radiation damage to the ocular motor cranial nerves.
Onset of diplopia in a patient treated for pituitary tumor raises the suspicion of tumor recurrence involving the cavernous sinus. However, none of our patients had cavernous sinus involvement clinically or on neuroimaging studies. Rather, they all developed diplopia due to radiation damage to the ocular motor cranial nerves.
The first documentation of radiation-induced ocular motor nerve injury was in the late 1960s and early 1970s following proton-beam hypophysectomy (5-8). This heavy particle radiation was used at that time because conventional radiotherapy was unable to suppress hormone levels in pituitary disorders. The largest series of patients was from the study by Kjellberg and Kliman (7), who reported oculomotor palsies in 37 of 128 proton-treated acromegalic patients followed for 6 months or more. Braunstein and Loriaux (8) reported 3 acromegalic patients, 2 patients with a third cranial nerve palsy and 1 with a sixth cranial nerve palsy, following protein beam therapy, and Dawson and Dingman (5) reported 3 patients with oculomotor palsies following protein beam therapy. Two of the patients had acromegaly, 1 with Cushing syndrome who also developed sixth nerve palsy in addition to the oculomotor palsy.
A decade later, another heavy particle modality, alpha-particle radiation, was used to irradiate the pituitary gland for the treatment of diabetes. Price et al (9) examined 161 diabetic patients who received this form of therapy and documented 11 cases of damage to the third, fourth, and sixth cranial nerves. Radiation dose to the cavernous sinus ranged from 14 to 151 Gy.
Currently, these forms of heavy particle radiation are not widely used in treating pituitary adenoma, supplanted by external beam radiation and radiosurgery. Within the past 2 decades, radiosurgery has become the preferred method of radiation therapy for pituitary tumor. There are scattered reports of patients developing ocular motor neuropathy following this form of therapy, yet the clinical details of the cases are poorly documented, and in some, there was tumor involvement of the cavernous sinus. Movsas et al (10) reported 1 patient with “transient right ophthalmoplegia” following treatment with a linear accelerator. The other documented cases occurred following gamma knife therapy: Landolt and Lomax (11) reported 1 patient with a sixth cranial nerve palsy; Jagannathan et al (12) reported 4 patients with “ophthalmoplegia,” including third and sixth cranial nerve palsy; Mauermann et al (13) reported 1 patient with a third nerve palsy; and Much et al (14) reported 3 patients, 1 with a third nerve palsy, 1 with a sixth nerve palsy, and 1 with both a third nerve palsy and a sixth nerve palsy. In contrast, none of our patients had clinical or neuroimaging findings of cavernous sinus involvement from their pituitary tumor.
We propose 2 potential causes for radiation injury to the ocular motor nerves in our patient population. First, the repeated use of radiotherapy increases the likelihood of radiation-induced complications. For example, Shaw et al (15) examined the maximum tolerated dose of single fraction radiosurgery in patients with previously irradiated primary brain tumors and metastases. They found a dose-dependent increased risk of developing radiation injury to central nervous system. Four of our 6 patients received either a combination of external beam and radiosurgery or radiosurgery on 2 separate occasions. Combining both modalities may have predisposed our patients to radiation injury to the ocular motor nerves. We estimate a combined total dose of radiation delivered to the cavernous sinus in our patient cohort ranged from 20 to 68 Gy. The second explanation may relate to the fact that 5 of our 6 patients had growth hormone-secreting pituitary tumors and acromegaly. Although such pituitary tumors are virtually always benign, elevated levels of growth hormone and insulin-like growth factor-1 may lead to a variety of cardiovascular, respiratory, endocrine, and metabolic morbidities. Thus, an aggressive treatment, including radiotherapy, is essential in this patient population (16), and this factor may have contributed to radiation-induced cranial neuropathy.
Why does ocular motor injury not occur more often in patients receiving radiation for pituitary tumor? There appears to be a significant difference in the sensitivity of the anterior visual pathways (optic nerves, chiasm) to the effects of radiation compared to the ocular motor cranial nerves. The anterior visual pathways, as extensions of the brain, are myelinated by oligodendrocytes. These cells are highly radiosensitive. In contrast, ocular motor cranial nerves are myelin free and their function depends on the integrity of Schwann cells, which appear to be more radioresistant.
In many instances, MRI has facilitated the diagnosis of radiation injury to the central nervous system. For example, with radiation damage to the optic nerves and/or chiasm, there is enhancement of these structures with contrasted MRI (17). However, enhancement of the ocular motor cranial nerves due to radiation damage cannot be detected because the cavernous sinus, being a venous structure, fills with contrast, preventing visualization of these cranial nerves.
As our series illustrates, patients with growth hormone-secreting pituitary tumors treated multiple times with various forms of radiation therapy are at risk to sustain ocular motor cranial nerve injury. However, the management of these patients is generally favorable. Once eye position has stabilized, prismatic spectacles or eye muscle surgery are successful therapeutic options.
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