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Abstract
Radiotherapy is the mainstay of treatment after surgery for high-grade gliomas and is usually well tolerated. Radiation toxicity in the brain is usually classified according to the timing of side effects in relation to treatment, as either acute (during radiotherapy), early delayed (within 12 weeks of radiotherapy) or late delayed (months to years after radiotherapy). We report two cases of young women who developed severe acute demyelination within 4 months of radiotherapy for glioma, one of whom had a previous history of transverse myelitis. Both improved with corticosteroids and remain in tumour remission. These cases emphasise the importance of careful discussion with patients before starting radiotherapy if there is a previous history of central nervous system demyelination or multiple white matter lesions on MRI.
- MULTIPLE SCLEROSIS
- brain tumour
- acute demyelination
- glioma
- RADIOTHERAPY
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Case 1
A 39-year-old woman presented with seizures in 2001 and was found to have a left temporal oligodendroglioma (WHO grade II), which was surgically resected. She had been previously well. She underwent further surgical resection in 2004 and again in April 2013 for radiological progression. Histology of the third resection specimen confirmed malignant transformation to an anaplastic oligodendroglioma (WHO grade III). In July 2013, following surgery, she completed a course of adjuvant radiotherapy (56 Gy in 30 fractions over 6 weeks).
In October 2013, she presented with 3 weeks of progressively worsening gait, headache, double vision and drowsiness. On admission to hospital, she was somnolent and confused. She had a complex ophthalmoplegia with left gaze palsy, bilateral nystagmus on lateral and up gaze, a mild right-sided ptosis and a left lower motor neurone facial weakness. She had normal power and sensation. Reflexes were brisk in the lower limbs and plantar responses were flexor. There was bilateral heel-shin ataxia. Her general physical examination was normal.
MR scan of brain on admission showed multiple new foci of signal change within the cerebellum, brainstem, basal ganglia, corpus callosum and hemispherical white matter. The largest of these, within the right inferior frontal gyrus, exerted mild mass effect, showed faint ring enhancement and subtle restricted diffusion of the enhancing component (Figure 1). Many of the other lesions also showed restricted diffusion. The extensive left frontotemporal glioma was less bulky than on the preradiotherapy scans (Figure 2). The attending physicians initially suspected that she had multifocal tumour progression, and treated her with dexamethasone (4 mg) with minimal improvement; they informed her family that she would probably die of progressive disease.
Multiple white matter lesions (axial T2 and T1 postgadolinium MRI). (A) February 2012—two small subcortical white matter lesions (Ai) with no enhancement (Aii). (B) October 2013—multiple white matter lesions, with surrounding oedema (Bi), the largest of which in the right frontal lobe shows ring enhancement (Bii).
Left temporal glioma, before and after radiotherapy treatment. (A) June 2013. Before radiotherapy. (B) October 2013. Four months following radiotherapy showing reduced tumour bulk and mass effect.
She was transferred to neurology for further investigation and treatment. A neuroradiologist subsequently reviewed the imaging, including earlier scans from 2012, which showed numerous white matter lesions in a periventricular and juxtacortical location, and concluded that the appearances were more in keeping with demyelination rather than tumour progression.
Cerebrospinal fluid (CSF) examination showed a normal white cell count of 1/µL (≤5) and protein concentration. CSF cytology showed only small numbers of lymphocytes and macrophages with no atypical cells. Oligoclonal bands were positive in CSF and negative in serum. We gave intravenous methylprednisolone 1 g/day for 3 days followed by oral prednisolone 60 mg daily with a gradual taper over 6 weeks. This resulted in clinical improvement over the next 3 months. Two and a half years later, she is alive and disabled mainly by fatigue, lethargy, limb ataxia and weight loss. She has had no further neurological relapses. Her last imaging in June 2015 showed a single small enhancing lesion in the left juxtatrigonal white matter, with no tumour recurrence.
Case 2
A 44-year-old woman was diagnosed with transverse myelitis in June 2010 and treated with intravenous corticosteroids. She had residual dysaesthesia in her left leg. MRI showed one or two non-specific white matter lesions in the brain and a single lesion within the cervical cord at C1/2. There were oligoclonal bands in CSF but not in serum. She was diagnosed with a clinically isolated syndrome. There was an incidental left posterior parietal lesion presumed to be a low-grade glioma. No further treatment was offered at that time other than MRI surveillance.
Two years later, while on holiday abroad, she had two generalised tonic-clonic seizures and was started on antiepileptic medication. In 2014, there was a slight increase in tumour size. A biopsy in December 2014 confirmed an oligodendroglioma (WHO grade II).
As she was becoming symptomatic, with frequent episodes of loss of coordination and sensation over the right side of her body, and she was anxious to be treated, she underwent radiotherapy; this was completed in March 2015, 3 months after the biopsy.
Two months later, following a sinus infection, she was admitted with an acute onset of dizziness, vertigo, unsteadiness and left-sided weakness over a few days. On examination, there was a dense left hemianopia and sensory hemineglect. Tone was increased in the left arm and leg with preserved power. She had ankle clonus and asymmetrical brisk reflexes.
The MR scan of brain showed a slight reduction in the parietal tumour but new extensive enhancing periventricular lesions in the right and left parietal subcortical white matter, consistent with acute demyelination (Figure 3). We did not undertake a further lumbar puncture.
MR scan of brain before biopsy and 2 months after completing radiotherapy. (A) October 2014. There is a diffuse left parietal lesion and one tiny non-specific white matter lesion in the left frontal subcortical white matter (Ai), neither of which enhances (Aii). (B) May 2015. There are now larger bilateral white matter lesions (Bi) and an enhancing right peritrigonal lesion with surrounding oedema, discrete from the primary tumour (Bii).
We treated her with intravenous methylprednisolone 1 g/day for 3 days, followed by an oral prednisolone taper; she completely recovered functionally after 2 months, and 1 year later is well, with minor gait ataxia. She has had no further neurological relapses and her tumour remains stable.
Discussion
We report two cases of women with cerebral glioma who deteriorated neurologically 4 months and 2 months after radiotherapy treatment, in whom the imaging and subsequent clinical course suggested acute demyelination, rather than tumour progression. Neither had a previous diagnosis of multiple sclerosis, although case 2 had a previous diagnosis of clinically isolated syndrome and case 1 had white matter lesions without previous clinical symptoms.
Acute demyelination may occur in rat brains exposed to radiation, through breakdown of the blood-brain barrier, probably caused by white matter injury targeting glial cells and the vascular endothelium.1 It can cause delayed neurological symptoms that may manifest several months after radiotherapy. A postmortem study of 25 patients dying of glioma reported selective demyelination in tissue adjacent to the tumour, suggesting early delayed necrosis following radiation.2
In a retrospective study of 15 cases of patients with multiple sclerosis who received brain radiotherapy at the Mayo Clinic, none experienced a relapse, but 6 had serious neurotoxicity a median of 1 year after radiotherapy.3 This suggests that patients known to have multiple sclerosis have an increased risk of neurotoxicity. The authors were careful to emphasise that this risk occurred with older treatment techniques and may not apply to modern conformal radiotherapy techniques.
In conclusion, we present two cases of early acute demyelination following brain radiotherapy and emphasise the importance of considering demyelination in the differential diagnosis of rapid neurological deterioration after treatment, even in those without a history of inflammatory neurological episodes.
Learning points
Consider acute demyelination in the differential diagnosis of a patient who deteriorates rapidly shortly after completing brain radiotherapy, when there are new multifocal enhancing lesions on MR brain imaging.
Patients with a brain tumour referred for radiotherapy who have a history of multiple sclerosis or a clinically isolated syndrome should be counselled about the increased risk of an acute relapse in the months following radiotherapy.
Footnotes
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Fiona McKevitt, Sheffield, UK.