Radiation-Induced Multiphasic Demyelination

Radiation-induced brain injury encompasses a wide range of neurotoxic effects varying in severity and ranging from transient edema to progressive white-matter necrosis. Classification is based on the timing of onset of symptoms after radiotherapy: 1) acute injury that occurs within days to weeks, 2) early delayed injury develops within weeks to months, and 3) late delayed injury that manifests after 6 months or longer (1). One of the proposed mechanisms of the early delayed injury is acute demyelination, which has been reported in 6 patients without history of demyelinating disease. In these cases, demyelination developed within 1-4 months after radiotherapy (2-5). We describe a case of demyelination in a patient following a course of radiotherapy targeted at the residuum of a pituitary macroadenoma.

Clinical Correspondence Radiation-Induced Multiphasic Demyelination Oi Yean Wong, MBBS, Yih-Horng Tham, FRCOphth, Michelle Lai, FRCOphth, Indran Davagnanam, FRCR, Fion Bremner, FRCOphth R adiation-induced brain injury encompasses a wide range of neurotoxic effects varying in severity and ranging from transient edema to progressive white-matter necrosis. Classification is based on the timing of onset of symptoms after radiotherapy: 1) acute injury that occurs within days to weeks, 2) early delayed injury develops within weeks to months, and 3) late delayed injury that manifests after 6 months or longer (1). One of the proposed mechanisms of the early delayed injury is acute demyelination, which has been reported in 6 patients without history of demyelinating disease. In these cases, demyelination developed within 1-4 months after radiotherapy (2-5). We describe a case of demyelination in a patient following a course of radiotherapy targeted at the residuum of a pituitary macroadenoma. One year previously, a 31-year-old woman underwent trans-sphenoidal pituitary resection of a macroadenoma. Eight months later, visual acuity was 20/40, right eye, and 20/25, left eye; eye movements were full and visual fields demonstrated a bitemporal hemianopia. At that time, the patient was treated with intensity-modified radiotherapy (IMRT) with total dose of 50.4 Gy given in 28 fractions (Fig. 1) and cabergoline for residuum of a growth hormone-secreting pituitary tumor. Three weeks after initiating radiotherapy, she complained of numbness in her left arm, which resolved spontaneously. However, 4 months after radiation therapy, the patient reported decreased vision. Visual acuity was 20/40 bilaterally. In addition, she noted vertical diplopia, left lower facial numbness, and loss of sensation on the left side of her tongue. Brain magnetic resonance imaging (MRI) showed bilateral T2 hyperintensities in the middle cerebellar peduncles, left cerebral peduncle, pons, midbrain, and the temporal periventricular and subcortical white matter (Fig. 2). The neuroparenchymal structures affected were within the field of radiation treatment with relative sparing of the rest of the brain. MRI of the spine was unremarkable. A diagnosis of radiation-induced demyelination was made, and treatment with corticosteroids was planned. However, before steroids could be started and now 5 months after IMRT, the patient developed painful, bilateral simultaneous retrobulbar optic neuropathy with visual acuities of light perception, right eye, and counting fingers, left eye. She was prescribed oral prednisolone (30 mg/day). FIG. 1. Computed tomography images of radiotherapy planning map for treatment of pituitary tumor residuum. Lysholm Department of Neuroradiology (OYW, ID), National Hospital for Neurology and Neurosurgery, London, United Kingdom; Department of Neuro-Ophthalmology (Y-HT, ML, FB), National Hospital for Neurology and Neurosurgery, London, United Kingdom; and Department of Brain Repair and Rehabilitation (ID), UCL Institute of Neurology, London, United Kingdom. The authors report no conflicts of interest. Address correspondence to Fion Bremner, FRCOphth. Department of Neuro-Ophthalmology, National Hospital for Neurology and Neurosurgery, London, United Kingdom; E-mail: [e-mail] Wong et al: J Neuro-Ophthalmol 2019; 39: 111-114 Over the next 2 weeks, the retrobulbar pain resolved and vision began to improve. Within 2 months, the ocular motor examination was normal and visual acuity improved to 20/80, right eye, and 20/30, left eye. Visual field testing was unchanged. Optical coherence tomography showed a pattern of bow-tie retinal nerve fiber layer loss in the right eye and temporal sector atrophy in the left eye. Visual evoked potentials demonstrated significant delay in the 111 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. Axial T2 MRI. A. Scans appear unremarkable before radiation therapy. B. Four months after radiotherapy, areas of hyperintensity are present in the left cerebral peduncle and the middle cerebellar peduncles. C. Twelve months after radiation therapy, the areas of abnormal signal are less conspicuous. 112 Wong et al: J Neuro-Ophthalmol 2019; 39: 111-114 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Wong et al: J Neuro-Ophthalmol 2019; 39: 111-114 Reference Age/Sex Milic and Rees (2) 39/F Milic and Rees (2) Redjal et al (3) 44/F 42/F Reason for Radiotherapy Left temporal oligodendroglioma *Radiologically isolated syndrome prior to radiotherapy Left parietal oligodendroglioma *Clinically isolated syndrome before radiotherapy Right optic nerve sheath meningioma Radiation Dose Onset of Symptoms After Radiotherapy 56 Gy 3 months Cerebellum, brainstem, 1 g IV methylprednisolone Left gaze palsy, for 3 days, 60 mg basal ganglia, corpus nystagmus, right partial prednisolone with callosum, and whiteptosis, left facial gradual tapering over matter, right inferior weakness, and ataxia 6 weeks frontal gyrus Confirmed on MRI N/A 2 months Dizziness, vertigo, ataxia, Right and left parietal left-sided weakness, left subcortical white hemianopia, and sensory matter neglect Signs and Symptoms Areas Affected Treatment 1 g IV methylprednisolone for 3 days, 60 mg prednisolone with gradual tapering over 6 weeks Confirmed on MRI 45 Gy 2 months 18/F Right frontal embryonic tumor 55.8 Gy 3 months Murphy et al (4) 5/M Right frontotemporal embryonic tumor 55.8 Gy 4 months Kemp et al (5) 65/F Right trigeminal neuralgia Stereotactic radiosurgery 90 Gy to right root entry zone with 50% isodoseline tangential to pons 3.5 months Decreased sensation in lower extremities and perianal region, loss of bowel and bladder control Right frontal lobe Confirmed on MRI and histology Cervical spinal cord Confirmed on MRI Lumbar spinal cord Weakness in lower extremities, bowel, and bladder dysfunction Confirmed on MRI Right trigeminal root Right facial numbness, ataxia, and left leg entry zone and paresthesia cervical spinal cord *History suggestive of but not confirmed demyelination before radiotherapy. F, female; Gy, gray; IV, intravenous M, male; N/A, not applicable. Steroids IV methylprednisolone and gamma globulin IV methylprednisolone and gamma globulin Steroids Clinical Correspondence Murphy et al (4) Decreased right visual acuity and color perception Confirmed on MRI 113 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Published cases of early, delayed demyelination after radiotherapy Clinical Correspondence P100 component (right worse than left) consistent with demyelination. Brain MRI 12 months later showed significant but not complete resolution of the T2 hyperintensities and no new lesions (Fig. 2). Cerebrospinal fluid examination was normal without evidence of IgG production or oligoclonal bands. Acute demyelination after radiotherapy has been described in 6 other patients without history of confirmed demyelinating disease (2-5) (Table 1). The onset of symptoms typically ranges from 1 to 4 months after the initiation of radiotherapy, fitting the time frame for early delayed injury. The affected areas of the brain correlate with the field of radiation, and these have been confirmed on neuroimaging, histologically or both. Treatment with corticosteroids has led to complete or significant clinical improvement. We are unaware of other reports of a multiphasic presentation of radiotherapy-induced acute demyelination. Our patient, who had no previous history of demyelinating disease, developed different neurological deficits that occurred over 3 separate time points at least 1 month apart. Lesions on MRI were found in the pons, cerebellar peduncles, and left cerebral peduncle, which correlated with her symptoms as well as multiple asymptomatic nonenhancing lesions in the temporal subcortical and periventricular areas, suggesting that demyelination was disseminated in time and space. Of the 6 previously reported cases, only 1 patient went on to develop multiple sclerosis (5). We hypothesize that acute demyelination occurs in individuals with susceptibility to developing de novo multiple sclerosis, and that a diffuse preceding insult, such as radiotherapy, lowers the brain parenchymal threshold required to develop a demyelinating 114 disease, albeit monophasic or multiphasic. Long-term follow-up of our patient is required to determine whether she develops future episodes of demyelination. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: I. Davagnanam and F. Bremner contributed to the conception and design of the manuscript; b. acquisition of data: O.Y. Wong, Y.-H. Tham, and M. Lai contributed to the acquisition of data; c. analysis and interpretation of data: O.Y. Wong, Y.-H. Tham, M. Lai, and I. Davagnanam analyzed and interpreted the data. Category 2: a. drafting the manuscript: O.Y. Wong and I. Davagnanam drafted the manuscript; b. revising it for intellectual content: I. Davagnanam and F. Bremner revised the manuscript for its intellectual content. Category 3: a. final approval of the completed manuscript: I. Davagnanam and F. Bremner approved the final version of the completed manuscript. REFERENCES 1. Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD. Radiation-induced brain injury: a review. Front Oncol. 2012;2:73. 2. Milic M, Rees J. Acute demyelination following radiotherapy for glioma: a cautionary tale. Pract Neurol. 2017;17:35-38. 3. Redjal N, Agarwalla PK, Dietrich J, Dinevski N, StemmerRachamimov A, Nahed BV, Loeffler JS. Remote acute demyelination after focal proton radiation therapy for optic nerve meningioma. J Clin Neurosci. 2015;22:1367-1369. 4. Murphy CB, Hashimoto SA, Graeb D, Thiessen BA. Clinical exacerbation of multiple sclerosis following radiotherapy. Arch Neurol. 2003;60:273-275. 5. Kemp S, Allan RS, Patanjali N, Barnett MH, Jonker BP. Neurological deficit following stereotactic radiosurgery for trigeminal neuralgia. J Clin Neurosci. 2016;34:229-231. Wong et al: J Neuro-Ophthalmol 2019; 39: 111-114 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.