Review

Radiation and the nervous system

Pract Neurol: first published as 10.1136/pn-2022-003343 on 22 August 2022. Downloaded from http://pn.bmj.com/ on October 19, 2023 by guest. Protected by copyright.
Michael Kosmin,1,2 Jeremy Rees ‍ ‍ 3,4

1
Clinical Oncology, University Abstract delivery platforms include Gamma Knife
College London Hospitals NHS
Radiation therapy is widely used for benign (Elekta, Stockholm, Sweden) or
Foundation Trust, London, UK
2
NIHR University College and malignant brain tumours as it is effective Cyberknife (Accuray, California), which
London Hospitals Biomedical and well tolerated. However, damage to the can provide more conformal radiation
Research Centre, London, UK
3
surrounding healthy nervous system tissue leads dose distributions to smaller targets.
Neurology, National Hospital
for Neurology and Neurosurgery,
to a variety of complications both in the short However, techniques for undertaking
London, UK term and long term, ranging from mild and stereotactic treatments on standard linear
4
National Hospital for Neurology self-­limiting to irreversible and fatal. Radiation accelerator platforms have also been
and Neurosurgery, London, UK neurotoxicity is due to a combination of early developed and continue to evolve.
Correspondence to inflammation and oligodendroglial damage Proton beam therapy uses the specific
Dr Jeremy Rees, Neurology, followed later by brain tissue necrosis, white physical properties associated with the
National Hospital for Neurology matter damage, accelerated vascular disease and dose deposition of a particle beam in
and Neurosurgery, London, UK;
the development of secondary tumours. This tissue, namely, that most of the energy
j​ eremy.​rees@​ucl.​ac.​uk
article explains the basic principles of radiation is delivered at the distal end of its range,
Accepted 24 July 2022 physics, the different modalities used in clinical immediately before the particle comes to
Published Online First practice, how radiotherapy is planned and rest—known as the Bragg peak. When
22 August 2022
delivered and the scientific basis of radiation planned accordingly, this can increase
damage. The main body of the article focuses the dose deposited in the clinical target
on the clinical features of radiation toxicity in the and minimise the dose to normal tissues
brain, spinal cord, cranial and peripheral nerves beyond the Bragg peak. There are two
​pn.​bmj.​com
with an emphasis on the distinction between main indications for proton beam therapy
early and delayed complications. in clinical practice1: for dose escalation
to radioresistant tumours such as skull
base chordoma or chondrosarcoma, at
Introduction sites where standard photon radiotherapy
Radiation therapy is used to treat a range cannot deliver the necessary dose due to
of malignant and benign conditions of the proximity of critical structures2; to
the brain, skull base and adjacent struc- reduce radiation therapy toxicities to the
tures with curative and palliative intent. brain and surrounding soft tissues, partic-
The treatment can be delivered using ularly in children, teenagers and young
various techniques, taking advantage of adults, for whom the negative effects of
the specific characteristics of the different irradiating the developing brain are more
modalities and platforms for delivery. The pronounced.
most commonly used modality is external
beam radiation with photon therapy, in Mechanisms of radiation damage
the form of X-­rays or gamma rays. X-­ray Irradiation of tissue causes different types
photon treatments can easily penetrate of DNA damage through the production
through tissues and are usually prescribed of highly reactive free radicals: single-­
in daily sessions (fractions) using a linear strand break, double-­ strand break (the
accelerator, with the total radiation dose major lethal lesion), base damage and
being delivered over several weeks. The DNA crosslinks. A range of DNA damage
precise dose fractionation depends on repair mechanisms operate to help main-
the type of target and clinical indication. tain genomic stability. However, some
Some smaller tumours, such as vestibular lesions fail to repair adequately, and it is
© Author(s) (or their schwannomas and meningiomas, can be the accumulation of these lesions that may
employer(s)) 2022. No
commercial re-­use. See rights
treated with radiation therapy in a single eventually lead to cell death, either by a
and permissions. Published treatment session (stereotactic radiosur- programmed mechanism such as apoptosis
by BMJ. gery) or a number of sessions (stereo- or autophagy or via mitotic catastrophe
To cite: Kosmin M, Rees J. tactic radiotherapy), while larger tumours at a future cell division. If the damage
Pract Neurol 2022;22:450– such as gliomas require multiple frac- does not cause cell death, it may lead to
460. tions, usually over 3–6 weeks. Alternative a late manifestation of radiation such as

Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343 1 of 12

Review

the development of a secondary tumour, sometimes

several years or decades after radiation exposure.1

Pract Neurol: first published as 10.1136/pn-2022-003343 on 22 August 2022. Downloaded from http://pn.bmj.com/ on October 19, 2023 by guest. Protected by copyright.
The precise mechanisms responsible for radia-
tion toxicity of the nervous system are incompletely
understood. For example, several processes have been
hypothesised to explain radiation-­induced neurocog-
nitive decline with a range of preclinical and clinical
data to support them. There is evidence that radia-
tion reduces neurogenesis in the hippocampus, with
preclinical models showing a depletion of neural
progenitor cells occurring over the course of multiple Figure 1 Radiation treatment planning CT scan of head
cell divisions. Changes in the cellular microenviron- showing a right temporal glioblastoma. (A) Volume delineation
ment are also a major factor in the determination of of target and organs at risk (OARs): brown=postoperative
cell fate and reduction in neurogenesis. The oxidative tumour bed and residual enhancing gross tumour (GTV);
stress induced by radiation results in upregulation of yellow=clinical target volume (CTV), area at risk of microscopic
proinflammatory pathways and an increase in number disease infiltration, defined as GTV+2 cm for glioblastoma,
edited off barriers to spread (eg, bone); red=planning target
of activated microglia, which act as potent inhibitors
volume (PTV), CTV+geometric 3 mm margin for positional
of neurogenesis. Radiation can also trigger the death of inconsistencies within immobilisation device; pink=optic
endothelial cells, causing thrombus formation on the chiasm; dark green=3 mm margin around chiasm for positional
exposed matrix and small vessel occlusion. Further- inconsistencies; orange=brainstem; light green=3 mm
more, accelerated atherosclerosis and microangiop- margin around brainstem for positional inconsistencies. (B)
athy after radiation can lead to vascular insufficiency Radiotherapy dose distribution >50Gy: prescription dose to
and infarction.2 PTV of 60 Gy. Note compromise of PTV dose coverage medially
due to the location of the brainstem and optic chiasm within
the high dose volume. This radiotherapy plan was designed
Radiotherapy treatment planning
to ensure that no dose >55 Gy was delivered to these critical
There are multiple linked processes involved in the OARs.
planning and delivery of a course of radiation therapy.
Initially, the patient undergoes CT imaging while
immobilised in the treatment position, usually via radiation-­induced optic neuropathy: <3% at 5-­year
a thermoplastic head shell. Diagnostic MR images postradiation therapy when <55 Gy delivered rising
obtained previously are coregistered with the planning to 7% at 5 years at 55–60 Gy.3
CT scan and used to delineate the treatment targets
and relevant organs at risk. This is known as the gross Radiotherapy dose fractionation
target volume. Depending on the underlying tumour The relationship between radiation dose and cell
histology, the radiotherapist will delineate an appro- survival varies between tissues. Cells may be killed
priate margin around the visible tumour to account by a single lethal radiation hit or by a succession of
for possible microscopic infiltration (Clinical Tumour sublethal hits. In addition to the overall radiosensi-
Volume), and a small additional margin is then added tivity of certain tissues, there is also a difference in
to account for small movements that can occur even sensitivity to treatment fraction size. For example, the
within the immobilisation device. This final volume is difference in biological effect of treating to a dose of
called the planning target volume. The radiotherapy 20 Gy in 10 daily fractions (2 Gy per fraction) versus
dosimetrists and physicists create a treatment plan that 20 Gy in 5 daily fractions (4 Gy per fraction) will
delivers the prescribed dose homogenously to the plan- vary between tissues depending on their sensitivity
ning target volume, while ensuring that the organs at to fraction size.4 This fraction size sensitivity is most
risk do not receive more than the maximum allowed. commonly expressed using the alpha–beta ratio, which
Figure 1 shows an illustrative case. incorporates a linear component (alpha) of lethal cell
The constraints on radiation dose owing to organs kill and a quadratic component (beta) of sublethal cell
at risk are defined from the literature based on clinical kill. Fractionating treatment, that is, splitting the total
and preclinical radiobiological data. Each major struc- dose up into multiple smaller radiation doses, allows
ture within the nervous system has a particular dose for repair to sublethal damage between fractions. This
constraint associated with it, and these constraints are is more effective in normal tissues than in tumour
often given greater priority in the radiotherapy plan- tissue, so fractionating treatment can increase the
ning process than treating the target, meaning that therapeutic ratio between tumour control and normal
planning target volume dose coverage is compromised tissue damage. Unlike many tumour cell types, the
to avoid the risk of significant radiation-­induced toxic- normal tissues of the nervous system are particularly
ities. For example, the dose constraint to the optic sensitive to changes in fraction size. Therefore, split-
chiasm is 55 Gy. Published data reveal that doses ting radiation treatment into multiple fractions over
above 55 Gy lead to an incrementally higher risk of several weeks facilitates more sublethal damage repair

2 of 12 Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343

 Review

in these normal tissues than if the same overall radi- oncologists continue corticosteroids during and after
ation dose was delivered over a shorter overall treat- radiotherapy.

Pract Neurol: first published as 10.1136/pn-2022-003343 on 22 August 2022. Downloaded from http://pn.bmj.com/ on October 19, 2023 by guest. Protected by copyright.
ment time.5
Pseudoprogression
About 6–12 weeks after the end of radiation therapy,
Radiation complications in the brain patients may experience worsening of pre-­ existing
Early complications
Acute radiation encephalopathy
neurological deficits, leading to the suspicion of tumour
Acute radiation encephalopathy appears within 2 progression. Imaging is usually unhelpful as the MRI
weeks of the start of brain radiation therapy and may show appearances of tumour progression that
occasionally a few hours after the first fraction. The resolve over the next few months without any specific
most common symptoms are drowsiness, headache, antitumour intervention. This phenomenon is known
nausea and vomiting together with a worsening of as ‘pseudoprogression’ and occurs in up to 30% of
pre-­existing neurological deficits. The main risk factor patients with glioblastoma treated with concomitant
is the size of the tumour and the dose per fraction temozolomide and radiotherapy. Ironically, pseudo-
(usually >3 Gy/fraction). It rarely occurs nowadays as progression may be associated with a better tumour
dose fractionation is restricted and large tumours are response.9 Patients usually improve within a few weeks
routinely debulked before radiation therapy. Patients or months associated with slow radiological improve-
usually recover quickly although herniation and death ment. Advanced imaging techniques such as perfusion-­
have been reported. In an older series, acute radiation weighted imaging and MR spectroscopy may help to
encephalopathy occurred in half of patients with brain distinguish pseudoprogression from true progression
metastases treated with 15 Gy in two fractions.6 As the but interpretation is limited by the presence of residual
conventional dose fractionation for whole brain radio- tumour within the irradiated area.
therapy nowadays is either 20 Gy in five fractions over Some patients report poor attention and memory
for up to 6 months following brain radiation therapy,
1 week or 30 Gy in 10 fractions over 2 weeks,7 this
which reassuringly does not predict the develop-
complication almost never occurs.
ment of long-­term cognitive decline. We, therefore,
Sometimes patients report nausea and moderate
warn patients who are keen to resume work immedi-
headache on the evening after the first fraction of
ately after radiation therapy that they should inform
radiation therapy. Corticosteroids may help espe-
employers about the possibility of a delayed or phased
cially in patients with large tumours or with consider-
return.
able oedema particularly at risk of herniation. Where
surgical debulking is not possible, these patients
Brainstem syndrome
should be prescribed dexamethasone 16 mg per day
An early-­delayed subacute brainstem syndrome can
2–3 days before the first fraction and the dose per frac-
occur 1–3 months after radiation therapy for pitu-
tion ideally limited to 2 Gy. The pathophysiology of
itary or head and neck cancer, where the treatment
acute radiation encephalopathy probably results from
fields overlap the brainstem. Clinical features include
radiation-­induced blood-­ brain barrier disruption,
ataxia, dysarthria, diplopia and/or nystagmus as well
accounting for a rise in intracranial pressure.
as hearing loss. MR brain scan sometimes shows high
signal change within the white matter of the brainstem
Early-delayed radiation encephalopathy and the cerebellar peduncles, which may enhance. This
Early-­delayed radiation encephalopathy is so called as condition usually responds to corticosteroids within a
it starts from 2 weeks to 6 months after completing few weeks; very rarely it results in coma and death.
radiation therapy. The pathophysiology is probably
transient demyelination caused by blood-­brain barrier Late complications
disruption and/or oligodendroglial injury. The most Late complications usually start 6–12 months after
common symptoms include fatigue, drowsiness, leth- completing radiation therapy but can be delayed by
argy, memory and attentional deficits. At its worst, many years or even decades. The two main compli-
patients may be asleep for most of the day. Somno- cations are radionecrosis and late-­
delayed radiation
lence syndrome, characterised by hypersomnolence, encephalopathy.
nausea and anorexia, was first described in children
receiving low-­dose radiation therapy for scalp ring- Radionecrosis
worm and after prophylactic cranial radiation therapy Radionecrosis is the most common late complication
for leukaemia; it occurs less commonly in adults. and was first described pathologically in 1948 in a
The diagnosis is clinical as neither MR imaging nor series of patients, one of whom had a recurrent ‘rodent
EEG shows specific changes. Patients usually improve ulcer of the scalp’ and a normal brain.10 It can be
within a few weeks. There may be a biphasic course difficult to distinguish from tumour recurrence both
with symptoms appearing from days 11 to 21 and clinically and radiologically. Nowadays, radionecrosis
then again from days 31 to 35.8 As a result, many most commonly follows focal radiation therapy for

Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343 3 of 12

Review

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Figure 2 Radiation necrosis. A 37-­year-­old patient presenting
with severe amnesia 4 years following proton beam therapy for
a pituitary adenoma. Axial T2W (A), T1W+gad (B) images show
bilateral temporal signal change and oedema with irregular
enhancement in medial temporal lobes, typical of radiation
necrosis. There was no improvement with corticosteroids and
the patient remained severely incapacitated by fatigue and
amnesia.

a brain metastasis but can also occur in patients who

have had radiation therapy for extracranial and extra-­
axial tumours, in whom normal brain was included
within the radiation field (eg, head and neck cancer,
skull osteosarcoma, pituitary adenoma, clival chor- Figure 3 Treatment response assessment maps (TRAMS)/
doma). A typical example is bilateral medial temporal contrast clearance analysis maps contrast-­enhanced T1-­
lobe necrosis following radiation therapy for pituitary weighted MRI (T1-­Gd, top) and the calculated TRAMS image
(bottom) of a patient receiving stereotactic radiosurgery for a
tumours (figure 2) or nasopharyngeal cancer. It is seen
malignant melanoma brain metastasis. Before the radiosurgery
less often nowadays due to reduction in dose per frac- (left) the enhancing lesion on T1-­Gd appears blue in the
tion and improvements in the delivery of radiation TRAMS scan. Follow-­up MR scan of brain 10 months following
therapy. It is now recognised that the upper limits stereotactic radiosurgery (right) shows significant shrinkage
of a ‘safe dose’ of 55–60 Gy administered to a focal of the enhancing lesion on T1-­Gd, appearing red, suggesting
field with fractions of 1.8–2 Gy per day are associated radiation necrosis. (Courtesy of Prof Yael Mardor, Sheba
with a less than 5% risk of radionecrosis. Patients with Medical Centre, Israel).
vascular risk factors such as hypertension, diabetes and
old age are at higher risk of radionecrosis, as are those to the poor clearance of contrast in non-­viable tissue-­
who have concomitant chemotherapy. Some patients containing irradiated vessels, while tumour recurrence
without any particular risk factors may develop radio- shows up as blue due to the rapid clearance through
necrosis, probably because of increased sensitivity to tumour vasculature (figure 3).
radiation, such that they develop this complication at Refractory cases of radionecrosis are treated with
conventional dose fractionation.11 dexamethasone and resection of necrotic foci. Corti-
Radionecrosis nowadays most commonly occurs after costeroid dependence can occur. Other treatments
stereotactic radiosurgery, for example, Gamma Knife such as hyperbaric oxygen or drugs such as pentoxi-
treatment for brain metastases (5%–25% of cases) and fylline, alpha-­tocopherol and pentobarbital have also
also for non-­neoplastic conditions such as arteriove- been tried but without clear evidence of efficacy. A
nous malformations (up to 20% of cases). Symptoms recent systematic review concluded that bevacizumab
of radionecrosis are indistinguishable from those of appeared to be more effective and just as safe as
tumour recurrence or progression and brain imaging is corticosteroids.13
likewise similar. More recently, an MRI sequence with
delayed contrast sequences known as TRAMS (treat- Late-delayed radiation encephalopathy
ment response assessment maps) or contrast clearance It has been known for many years that radiotherapy
analysis has become routinely available in clinical can cause delayed cognitive impairment that varies
practice as it is both sensitive and specific.12 It requires from mild memory loss to a severe dementia.14 This
the acquisition of two standard 3D T1-­weighted MR complication develops more frequently in adult survi-
brain scans—one 5 min after injection of gadolinium vors of childhood brain tumours and in patients with
and another after an hour. The first series is digitally low-­grade gliomas where the tumour remains in remis-
subtracted from the second. The analysis results in sion for many years.15 MRI shows variable degrees
high-­resolution, volumetric maps that can distinguish of high T2W signal change in the subcortical white
regions of contrast clearance (blue) from contrast matter and brain atrophy. Some patients deteriorate
accumulation (red). Radionecrosis shows up as red due slowly while most remain stable. Cerebral atrophy

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Figure 4 Delayed radiation encephalopathy. A 55-­year-­old patient treated with bifrontal parallel fields to a right frontal glioma in
1997, presenting with progressive cognitive and behavioural decline 25 years later. Sagittal (A) and coronal T1W (B) shows striking
bifrontal and perisylvian atrophy with relative preservation of the parietal and occipital lobes. Note the enhancing residual tumour.

may also be strikingly focal where specific lobes of the radiosurgery, but these techniques have not yet been
brain have been irradiated (figure 4). This syndrome shown to provide a consistent cognitive advantage
has no recognised treatment although some authors In patients with primary CNS lymphoma who have
have advocated using anticholinesterases for symp- been traditionally treated with combined high-­ dose
tomatic benefit.16 intravenous methotrexate chemotherapy followed
The long-­term cognitive effects of radiotherapy in by whole brain radiotherapy, the incidence of severe
patients with low-­grade gliomas have been reported in cognitive impairment increases with age, reaching
a study comparing 195 patients with low-­grade glioma 83% in patients over 60 years.20 Based on the results
(of whom 104 had been treated with radiotherapy) of a randomised phase 2 study by a European consor-
with a matched series of patients with low-­ grade tium (the IELSG-­32 study), the standard of care across
haematological malignancies and healthy controls, Europe for fit patients with primary CNS lymphoma
followed up for at least 6 years. Patients with low-­ aged under 70 years is now a chemotherapy regimen
grade glioma experienced significant problems across known as Methotrexate, Ara-­C, Thiotepa and Ritux-
a range of Health-­Related Quality of Life domains, imab (MATRIX) followed by autologous stem cell
including neurocognitive deficits, but these were transplantation, a strategy that avoids using whole
associated with tumour changes. Only high dose per brain radiotherapy altogether, thus reducing poten-
fraction (>2 Gy) resulted in significant added cogni- tially fatal neurotoxicity.21
tive decline.17 Interestingly, the same group published
their findings after a follow-­up of 12 years and found Radiation-induced secondary normal pressure hydrocephalus
that the patients who had received radiotherapy even Radiation-­ induced dementia is characterised by a
at doses less than 2 Gy/fraction showed a progres- ‘subcortical dementia’ pattern associated with diffuse
sive decline in attentional and executive functioning white matter injury, usually starting within 2 years
and speed of information processing. Fifty-­three per of treatment. Patients may present with a picture
cent patients who had radiotherapy developed cogni- similar to normal pressure hydrocephalus and develop
tive deficits in at least five of 18 neuropsychological progressive memory loss, reduced attention, gait diffi-
test areas compared with 27% patients who had not culties, urinary incontinence and fatigue. There may be
received radiation therapy.18 emotional lability and apathy that is difficult to distin-
Whole brain radiotherapy was the standard treat- guish from depression. Antidepressants are frequently
ment for brain metastases until the last decade but tried but do not improve cognitive function. Eventu-
causes cognitive decline in over 60% of patients ally, patients may develop akinetic mutism. MR scan of
within 2–6 months of treatment. It has now been brain shows ventricular enlargement, diffuse confluent
replaced by stereotactic radiosurgery for fit patients subcortical white matter change, with cortical and
with stable or controlled extracranial disease and a subcortical atrophy.
reasonable prognosis from their underlying cancer (at There is no specific treatment for radiation-­induced
least 6 months).19 Hippocampal sparing techniques are dementia. However, ventriculoperitoneal shunting
gaining in popularity for patients with brain metastases is sometimes tried with incomplete and short-­ lived
who are not suitable for treatment with stereotactic improvement (figure 5).22 Deterioration occurs in

Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343 5 of 12

 Review

10 000 patients treated for tinea capitis with low-­dose

(1.5 Gy) radiation, the relative risk for all tumours was

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6.9 and the risk for glioma was 2.6.23 This has been
confirmed in several other studies. In patients treated
for childhood acute lymphoblastic leukaemia, the rela-
tive risk is so high22 as to justify screening MR brain
imaging for adult survivors.24
In order to diagnose a radiation-­induced tumour,
there must be a long interval between the treatment
and the occurrence of the second tumour (there have
been cases developing over 60 years later), the tumour
has to grow within the radiation field or at its margins,
Figure 5 Secondary normal pressure hydrocephalus. A
and be of a different histological subtype to the primary
66-­year-­old with left occipital glioblastoma treated with
concomitant chemoradiation. Within a year of radiotherapy (54 tumour. These tumours have a poor prognosis as such
Gy in 30 fractions) she became increasingly unsteady due to an patients have limited reserve for further radiotherapy.
apraxic gait with urinary incontinence and mild memory loss. However, the longer the gap between the original
Her condition improved with ventriculoperitoneal shunting but treatment and the secondary tumour, the more scope
the improvement was short-­lived and she died of progressive there may be due to normal tissue recovery.
disease 9 months later. Coronal T1W post-­Gd immediately after
radiotherapy (A) showing normal ventricular dimensions and 1
Radiation-Induced vasculopathy
year later (B) showing dilatation of posterior horns and fourth
ventricle and sulcal effacement. Note tumour recurrence around Radiation can damage the intracranial vasculature
the left lateral ventricle with surrounding oedema. leading to ischaemic stroke or haemorrhage. The
carotid artery can become stenotic after cervical radio-
therapy for lymphomas or head and neck cancers and
about 80% of cases and death generally occurs within occasionally can rupture a few weeks after radiation
4 years after the onset of the disorder. therapy causing death. However, late-­delayed compli-
cations are more frequent and generally occur many
Radiation-Induced brain tumours years after treatment (median time about 20 years for
Irradiated patients are more prone than the general extracranial arteries, 7 years for intracranial arteries).
population to developing second brain and spine Radiation-­induced vasculopathy is an accelerated form
tumours. Meningiomas (70%) (figure 6), gliomas of atherosclerosis and often occurs in unusual loca-
(20%) and sarcomas (10%) are the most common tions, for example, the distal internal carotid artery.
tumours and develop many years (mean onset 12 It has been described within 2 years of proton beam
years) or decades after treatment. In a study of over therapy for childhood brain tumours.25 The lesions
consist of one or more arterial stenoses or occlusions
of the carotid or cerebral arteries within the radia-
tion portal. Pathological findings include destruction
of the internal elastic lamina and replacement of the
normal intima and media with fibrous tissue. Treat-
ment includes managing vascular risk factors and,
where appropriate, carotid endarterectomy. However,
surgery may be more difficult because of vascular
fibrosis and poor wound healing. If a patient with
previous radiation therapy develops a stroke, it should
not be assumed to be due to radiation vasculopathy
unless it is within the radiation portal, and other risk
factors should be sought.

Moyamoya disease
Moyamoya disease is a progressive occlusive cranial
vasculopathy characterised by abnormal anastomoses
and netlike blood vessels at the apices of the intra-
Figure 6 Radiation induced meningiomas. A 48-­year-­old cranial internal carotid arteries, the proximal ante-
patient presenting with new onset generalised seizures; she
rior cerebral arteries and middle cerebral arteries.26
had received whole brain radiotherapy 30 years previously for
a pineal germinoma. Coronal contrast-­enhanced T1W image
It results in decreased cerebral blood flow with an
shows two meningiomas both within the midline, one arising increased risk of stroke, transient ischaemic attacks
from the falx and one from the tentorium, with no evidence of and focal seizures. It often develops in patients who
tumour recurrence in the pineal gland. had cranial radiation therapy as young children,

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particularly those treated for optic chiasm glioma, a neurological deficits can persist even after radiological
condition often associated with neurofibromatosis improvement.28 There is imaging evidence (from CT

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type 1, which is a risk factor for vasculopathy in itself. perfusion studies) that SMART syndrome is caused by
The strong association between neurofibromatosis reversible hemispheric hypoperfusion,29 but there is
type 1 and moyamoya is one of the reasons why radia- often elevated relative cerebral blood volume in the
tion has been replaced with chemotherapy in younger acute phase on dynamic susceptibility contrast perfu-
children with optic pathway gliomas. Treatment is sion MR imaging (figure 7). There is no known treat-
aimed at preventing further strokes through surgical ment for SMART syndrome although anecdotally,
revascularisation procedures. L-­arginine has been used to good effect in two reported
acute cases. One of our patients who had four previous
Radiation-induced cavernomas, angiomatous malformations and severe attacks of SMART every 15 months has not had
aneurysms an attack for 3 years since taking L-­arginine, which is
Vascular malformations such as telangiectasias and available without prescription and non-­toxic.
cavernomas are increasingly being recognised as a
long-­term complication of brain radiotherapy, due to
the routine inclusion of gradient-­echo and suscepti- Radiation complications in the spinal
bility weighted sequences in modern MRI protocols. cord
When present, their main risk is intracranial haemor- Radiation therapy damages the cord in much the
rhage, but this is rare.27 There have been occasional same way as with the brain although is less commonly
cases of radiation-­ induced intracranial aneurysms encountered, due to the relative rarity of spinal cord
reported with fatal outcomes. tumours compared with brain tumours. However,
the spinal cord is a critical organ at risk in the plan-
SMART syndrome ning and delivery of radiation therapy for non-­CNS
Stroke-­like migraine attacks after radiation therapy tumours, including head and neck and paravertebral
(SMART syndrome) is a poorly understood late cancers. Early and late-­ delayed myelopathy, lower
complication of brain radiation therapy for both motor neurone disorder and spinal haemorrhage have
primary and secondary brain tumours. It presents with all been described.
a combination of migraine-­like headaches and cortical
dysfunction including seizures and focal neurological Early-delayed radiation myelopathy
deficits, for example, aphasia, neglect and hemipa- This usually follows radiation to the cervical or thoracic
resis. Seizures may be prolonged and respond poorly cord, most commonly after mantle radiation therapy
to antiseizure medication. Corticosteroids do not seem for Hodgkin’s disease within the cervical cord. The
to help. It has a distinctive radiological appearance clinical symptoms include Lhermitte’s phenomenon,
with pial enhancement and cortical high signal change presumably caused by transient demyelination in the
within the radiotherapy field. It is now recognised that posterior columns, secondary to oligodendroglial cell

Figure 7 SMART syndrome. A 68-­year-­old patient who had received radiation therapy 8 years previously for a left frontal
astrocytoma. He subsequently developed a rapid onset of continuous focal motor aware seizures, loss of speech and right
hemiparesis that gradually improved over the next 3 months, leaving him with moderate dysphasia and mild hemiparesis. There was
no response to high-­dose intravenous corticosteroids. Imaging at the onset shows swollen left hemisphere with diffuse high signal
and sulcal effacement on axial T2W (A) and pial enhancement (B) with high relative cerebral blood volume on perfusion-­weighted
imaging (C). The appearances had resolved and returned to baseline 3 months later (D and E).

Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343 7 of 12

Review

loss. There is no specific treatment for this condition conventional radiotherapy (60 Gy in 2 Gy daily frac-
and recovery is the norm. It is important to reassure tions). Having said that, patients who have previously

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patients that this does not evolve to a progressive received more than 50 Gy to the posterior fossa have
myelopathy. a higher likelihood of developing hearing impairment.
Current radiotherapy planning techniques allow for
Late-delayed radiation myelopathy
this risk to be minimised.
Late-­delayed radiation myelopathy occurs 1 to 10
years after exposure to radiation therapy and, as with Optic nerve
brain neurotoxicity, risk factors include older age, total The most clinically important cranial nerve impli-
radiation dose (above 60 Gy), higher dose per fraction cated in delayed radiation toxicity is the optic
and the volume of cord irradiated. Late-­delayed radia- nerve, which can be damaged many years after
tion myelopathy presents with a combination of slowly treatment for orbital, pituitary or suprasellar
progressive sensorimotor deficits, a hemicord (Brown-­ tumours. The optic nerve apparatus is regarded as
Séquard) syndrome, with bladder involvement eventu- a major organ at risk when planning treatment to
ally leading to paraparesis or tetraparesis. MR imaging nearby targets. Radiation therapy-­ induced optic
may be initially normal but usually the cord becomes neuropathy usually presents with subacute painless
swollen and, in about half of cases, there is gadolinium visual loss, progressing to monocular or binocular
enhancement. Eventually, there is cord atrophy with blindness with optic atrophy. Funduscopy of ante-
occasional cystic cavitation. The diagnosis can be made rior lesions shows papilloedema and peripapillary
only if the cord signal change lies within the radiation-­ haemorrhage, sometimes associated with radiation-­
exposed area and if having excluded all other potential induced retinal lesions, but is usually normal in
causes of myelopathy. The natural history varies—in posterior lesions. MR imaging of the anterior visual
some patients, the symptoms stabilise, in others, they pathways with fat saturation can help in these cases,
progress to a complete deficit. showing enlargement and signal change in the optic
Neuropathological findings include demyelination, nerve and chiasm, with contrast enhancement.
focal necrosis and axonal loss, together with fibrinoid As with late-­ delayed radiation myelopathy,
necrosis of the vessel walls, perivascular fibrosis and steroids are useful in the acute setting, but there are
sometimes vasculitis. no proven treatments for progressive optic neurop-
Corticosteroids can help in the subacute stages to athy. Optic nerve sheath fenestration has been used
reduce the inflammatory component of the disorder; in a few patients with some success.31
however, patients often become steroid dependent and
only a few experience long-­term improvement. There Eye movement disorder
is no current proven treatment although hyperbaric Transient sixth nerve palsy occasionally follows
oxygen and anticoagulation have both been tried in radiation to the pituitary gland and cavernous
small series. sinus and very occasionally to the nasopharynx.
Neuromyotonia may also occur, characterised by
spontaneous eye muscle spasm and intermittent
Lower motor neurone syndrome diplopia, usually lasting a few seconds, occurring
A lower motor neurone syndrome resembling motor up to several times an hour. This may respond to
neurone disease has been described after radia- phenytoin or carbamazepine.
tion therapy to the distal spinal cord and cauda
equina, mainly as treatment for testicular cancer and Trigeminal nerve
lymphoma. It presents with progressive proximal and/ Facial numbness due to trigeminal neuropathy has
or distal symmetrical leg weakness associated with been reported after radiosurgery for trigeminal
muscle fasciculation and wasting, but with normal neuralgia, trigeminal and vestibular schwannomas.
sensation.30 Sphincter disturbance and sensory loss may
appear much later. MR imaging is usually normal, but Facial nerve
contrast enhancement of the roots of the cauda equina Patients irradiated for head and neck cancer
occasionally occurs. The CSF is usually acellular, with a commonly report ageusia. Facial motor neuropathy
high protein concentration. Electromyoagraphy shows almost never develops after fractionated radiation
denervation with preserved sural action potentials. therapy and its development should prompt suspi-
This is best regarded as a motor neuronopathy rather cion of perineural invasion. Facial palsy follows
than a radiculopathy based on the neurophysiology. stereotactic radiosurgery for vestibular schwan-
noma in fewer than 5% of cases.
Radiotherapy complications in the
cranial nerves Vestibulocochlear nerve
Late-­delayed complications of radiation therapy in the Early–delayed hearing loss is usually due to otitis
cranial nerves arise in fewer than 1% of cases after media, caused by oedema of the eustachian tube and

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 Review

temporary build-­up of fluid within the middle ear.

In contrast, late-­onset hearing loss due to cochlear

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damage is characterised by high-­frequency hearing
loss and tinnitus.

Lower cranial nerves

The glossopharyngeal, vagus, spinal accessory and
hypoglossal nerves can all be damaged by large radi-
ation doses for head and neck cancer; this damage
typically arises months to years after treatment. The
hypoglossal nerve is the most commonly involved
nerve presenting with unilateral asymptomatic or Figure 8 Early-­delayed lumbosacral plexopathy. A 73-­year-­old
bilateral disabling paralysis with tongue atrophy. man with subacute distal lower limb oedema, bilateral foot
Unilateral vocal cord and palatal palsy give rise to drop and loss of distal sensation, 4 months after completing
dysarthria and dysphagia. Spinal accessory nerve radical radiotherapy for prostate cancer. EMG suggested a
lumbosacral plexopathy rather than a sensorimotor neuropathy.
palsy presents as painless shoulder drop.
Motor function improved completely with corticosteroids
Dropped head syndrome may occur as a poten- although a year later, there was persistent sensory impairment
tial late-­delayed complication of radiation therapy distally. Axial (A) and coronal (B) T1W post-­gadolinium scans
due to weakness of the neck extensors several years of lumbosacral spine showing diffuse contrast enhancement
after irradiation involving the cervical region, for in the proximal L5 nerves, particularly on the left (arrow),
example, mantle radiation therapy for Hodgkin’s in the lumbosacral plexus and the proximal S1 roots, again
disease. The differential diagnoses include myas- more on the left consistent with an early-­delayed lumbosacral
plexopathy. EMG, electromyography.
thenia gravis, motor neurone disease or isolated
neck extensor myopathy. Such extensive radio-
therapy fields are much less commonly used today.
small arterioles and perineural fibrosis accounting
Radiotherapy complications in the for the severe and irreversible nerve damage.
peripheral nerves Initial symptoms include distal paraesthesiae
Plexopathy and dysaesthesiae, muscle weakness and atrophy
Brachial and lumbosacral plexopathies are the most confined to specific myotomes, dermatomal sensory
important late-­ delayed complications of radiation loss and early loss of reflexes. The lack of pain
therapy in the peripheral nervous system but are and presence of myokymia, when present, strongly
rarely seen nowadays, with the use of smaller doses suggest the diagnosis and help to differentiate from
and a greater awareness of the long-­term effects of malignant infiltration of the plexus. There may
radiation. Brachial plexopathy is the more common also be visible skin complications such as radiation
and occurs after radiation therapy to the supracla- dermatitis, painful induration of the axillary region
vicular, infraclavicular or axillary nodes, usually and/or lymphoedema. During the later stages, there
for breast cancer and sometimes Hodgkin’s disease. is progressive motor loss that can vary from localised
Lumbosacral plexopathy much less commonly muscle weakness to an almost complete paralysis of
develops after radiation therapy for pelvic or lower the limb.
abdominal and pelvic cancer (uterus, ovary, cervix, Neurophysiology shows normal motor and sensory
testis, rectum or prostate). conduction velocities. F waves may be absent or
Occasionally, patients can present with an early– delayed. Electromyography shows fasciculation,
delayed plexopathy within a year of treatment, fibrillations and positive sharp waves. The most
which usually improve within a few months, thought important neurophysiological finding that favours
to be due to direct radiation toxicity on the Schwann radiation-­induced plexopathy is the presence of
cells inducing demyelination. This responds to corti- myokymic discharges, present in about two-­thirds of
costeroids (figure 8). patients, but this almost never occurs with tumour
Late-­delayed radiation plexopathies appear 3–20 infiltration. MR scanning is the imaging modality of
years after treatment. As with other radiation therapy choice in differentiating between radiation fibrosis—
toxicity, the most important risk factors are the total in which there is thickening of the brachial plexus
radiation dose (>60 Gy) and dose per fraction (>2 with occasional contrast enhancement—and tumour
Gy), the use of overlapping fields and combined infiltration, in which there are nodular mass lesions
chemoradiotherapy. There are two phases in the along the branches of the brachial plexus (figure 9).
pathophysiology: during the first phase, direct radi- Rarely, MR imaging is inconclusive, and a biopsy
ation damage to the nerves causes acute inflamma- may be indicated. In radiation plexopathy, this shows
tion that then resolves; later on, there is injury to the fibrosis and the absence of tumour infiltration.

Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343 9 of 12

Review

Pract Neurol: first published as 10.1136/pn-2022-003343 on 22 August 2022. Downloaded from http://pn.bmj.com/ on October 19, 2023 by guest. Protected by copyright.
Figure 9 Radiotherapy-­related plexus changes versus malignant infiltration (Upper part)—radiation plexopathy. MR images of the
brachial plexus (coronal T1W (A) and STIR (B)) showing STIR hyperintense signal changes predominantly involving the divisions and
cords of the left brachial plexus with mild associated distortion and loss of the perineural fat planes (arrowheads). Note the pleural
thickening and adjacent parenchymal scarring within the left lung apex (short arrows) secondary to previous radiotherapy. (Lower
part) Malignant infiltration. MR images of the brachial plexus (coronal STIR (C) and fat-­suppressed post-­contrast T1w (D)) showing
nodular thickening and enhancement of the right brachial plexus (arrowheads) and adjacent supraclavicular lymphadenopathy
(curved arrow) consistent with metastatic infiltration in a patient with known breast carcinoma. (Courtesy of Dr Sachit Shah,
Consultant Neuroradiologist, National Hospital for Neurology and Neurosurgery.) STIR, short inversion time inversion recovery.

The treatment is supportive involving physio-

Further reading
therapy, lymphoedema massage and bandaging and
pain management. ►► Wilke C, Grosshans D, Duman J, et al. Radiation-­
induced cognitive toxicity: pathophysiology and
Radiation-induced malignant peripheral nerve sheath tumours
interventions to reduce toxicity in adults. Neuro-­
Radiation-­induced nerve malignant peripheral nerve
Oncology. 2017;20(5):597–607.
sheath tumours can develop 4–40 years after radi-
►► Dominguez M, Malani R. Stroke-­like migraine
ation therapy, particularly in patients with neuro-
attacks after radiation therapy (SMART) Syndrome: a
fibromatosis type 1. Patients report localised pain
comprehensive review. Curr Pain Headache Rep 2021;
followed by sensorimotor deficit, and diagnosis
25:33.
is made on imaging. Treatment is surgical with
►► Kraik SF, Watson GA, Shih S-­F, et al. Radiation-­induced
complete resection of the tumour. The prognosis
large vessel cerebral vasculopathy in pediatric patients
of malignant peripheral nerve sheath tumours that
with brain tumors treated with proton radiation
result from radiation therapy is worse than those
therapy. Int J Radiat Oncol Biol Phys 2017;99:817–24
that develop de novo.32

10 of 12 Kosmin M, Rees J. Pract Neurol 2022;22:450–460. doi:10.1136/pn-2022-003343

 Review
Provenance and peer review Provenance and peer review.
Key points Commissioned. Externally peer reviewed by Robin Grant, Edinburgh, UK
and Fiona McKevitt, Sheffield, UK.

Pract Neurol: first published as 10.1136/pn-2022-003343 on 22 August 2022. Downloaded from http://pn.bmj.com/ on October 19, 2023 by guest. Protected by copyright.
►► Radiation therapy for brain and spinal tumours is most Data availability statement No data are available.
commonly delivered as photons in the form of X-­rays
ORCID iD
or gamma rays; proton beam therapy is used mainly Jeremy Rees http://orcid.org/0000-0001-5320-9551
for tumours in children to minimise long-­term toxicity,
and in adults for radioresistant tumours that require
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cognitive toxicity: pathophysiology and interventions to reduce
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16 Cramer CK, Cummings TL, Andrews RN, et al. Treatment
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of radiation-­induced cognitive decline in adult brain tumor
Competing interests None declared.
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