MR imaging findings in some rare neurological complications of paediatric cancer
Insights into Imaging
MR imaging findings in some rare neurological complications of paediatric cancer
Tetsuhiko Okabe 0 1 2 4 5 6
Taiki Nozaki 0 1 2 4 5 6
Noriko Aida 0 1 2 4 5 6
Jay Starkey 0 1 2 4 5 6
Mikako Enokizono 0 1 2 4 5 6
Tetsu Niwa 0 1 2 4 5 6
Atsuhiko Handa 0 1 2 4 5 6
Yuji Numaguchi 0 1 2 4 5 6
Yasuyuki Kurihara 0 1 2 4 5 6
0 Department of Radiology, Kanagawa Children's Medical Center , Kanagawa , Japan
1 Department of Radiology, Yokohama City University , Kanagawa , Japan
2 Department of Radiology, St. Luke's International Hospital , 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560 , Japan
3 Tetsuhiko Okabe
4 MassGeneral Hospital for Children and Harvard Medical School , Boston, MA , USA
5 Department of Radiology, Tokai University School of Medicine , Kanagawa , Japan
6 Department of Radiology, National Center of Neurology and Psychiatry , Tokyo , Japan
Neurological complications of paediatric cancers are a substantial problem. Complications can be primary from central nervous system (CNS) spread or secondary from indirect or remote effects of cancer, as well as cancer treatments such as chemotherapy and radiation therapy. In this review, we present the clinical and imaging findings of rare but important neurological complications in paediatric patients with cancer. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Paraneoplastic neurological syndromes, hyperviscosity syndrome, haemophagocytic lymphohistiocytosis and infection are found in the pre-treatment phase, while Trousseau's syndrome, posterior reversible encephalopathy syndrome and methotrexate neurotoxicity are found in the treatment phase; though some complications overlap between the pre-treatment and treatment phases. Hippocampal sclerosis, radiation induced tumour, radiation induced focal haemosiderin deposition and radiation-induced white matter injury are found in the post-remission phase. With increasingly long survival after treatment, CNS complications have become more common. It is critical for radiologists to recognise neurological complications related to paediatric cancer or treatment. Magnetic resonance imaging (MRI) plays a significant role in the recognition and proper management of the neurological complications of paediatric cancer. Teaching Points Neurological complications of paediatric cancer include various entities. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Radiologists should be familiar with clinical and imaging findings of neurological complications. MRI features may be characteristic and lead to early diagnosis and proper treatments.
Paediatric cancer; Treatment; Neurological complication; MRI; imaging
Malignant tumours are the most common disease-related
cause of death for the people under 20 years of age. With
survival rates rapidly increasing with new treatments,
currently two-thirds of children who suffer from paediatric cancers
become long-term survivors. As survival rates for children
with cancer have improved, so have the number of people
who develop complications, with at least 70% of paediatric
cancer survivors having some complication within 30 years
from the onset their disease  (Table 1). Leukaemia and
central nervous system (CNS) tumours make up the majority
of paediatric malignancies. The most common types of brain
tumours of children are astrocytoma, medulloblastoma and
ependymoma . Because current treatments for brain
tumours and leukaemia include intrathecal chemotherapy and
cranial irradiation, which are potentially neurotoxic,
neurological complications are often found in patients with paediatric
cancer . It is necessary to be familiar with the complications
that can be seen on imaging related to cancers and their
treatment, as imaging is essential for early diagnosis and proper
treatment to minimise adverse effects. In this review, we
present the clinical and imaging findings of rare but important
neurological complications in paediatric patients with cancer
in the pre-treatment, treatment and post-remission phases.
Paraneoplastic neurological syndromes
Paraneoplastic neurological syndromes are defined as
neurological syndromes caused by an autoimmune mechanism in
cancer patients. Diagnosis of a paraneoplastic syndrome in
pre-treatment patients must exclude local neuropathy due to
metastasis, opportunistic infections accompanying decreased
immune response, vascular disorders with coagulopathy and
neuropathy accompanied by malnutrition. It should be noted
that paraneoplastic syndromes are also sometimes found in the
treatment phase. Although paraneoplastic syndromes can
affect any part of the neuraxis in children, the CNS is the most
commonly affected .
The most common paraneoplastic syndromes in children
are: (1) opsoclonus myoclonus syndrome (OMS), (2) limbic
encephalitis, and (3) anti-N-methyl-D-aspartate (NMDA)
receptor encephalitis . Regarding OMS, neuroblastoma is
found in as many as 50% of children with the disease,
although OMS occurs in just 2-3% of children with
neuroblastoma . The most frequently associated neoplasms with
limbic encephalitis in children are neuroblastoma, Hodgkin
lymphoma, ovarian teratoma and testicular tumour. Manifestation
of paraneoplastic limbic encephalitis precedes the detection of
cancer in 60% of patients . Anti-NMDA receptor
encephalitis is a paraneoplastic syndrome associated with teratomas.
Most patients with anti-NMDA receptor encephalitis have full
or substantial recovery after treatment. Although the most
frequently associated neoplasm is ovarian teratoma, others
such as mediastinal teratomas, testicular tumours and small
cell lung cancers have been reported.
Typical features of limbic encephalitis include personality
changes, irritability, seizures, cognitive dysfunction and
memory deterioration. Children with anti-NMDA receptor
encephalitis have behavioural or personality changes, sleep
dysfunction, dyskinesia, dystonia and/or dysautonomia.
Magnetic resonance imaging (MRI) demonstrates high
signal intensity on T2-weighted images in one or both mesial
temporal lobes. MRI may have abnormal signal intensities in
other regions, such as the brainstem, hypothalamus, thalamus
and cingulate gyrus (Fig. 1) . The diagnosis of
paraneoplastic limbic encephalitis must be made
comprehensively in combination with the imaging and clinical findings,
including cerebrospinal fluid examination, because it is
difficult to distinguish from other diseases such as herpes simplex
encephalitis or convulsive encephalopathy which have similar
imaging features. In anti-NMDA receptor-related
encephalopathy, MRI may demonstrate hyperintensities in the medial
temporal lobes, cortical and subcortical regions, basal ganglia,
brain stem and cerebellum on fluid attenuated inversion
recovery (FLAIR) images. These regions may also show
contrast enhancement .
Treatment is usually with immunomodulators such as
steroids or intravenous immunoglobulins and plasmapheresis,
along with treatment of the primary tumour.
Hyperviscosity syndrome (HVS)
H V S h a s b e e n r e c o g n i s e d i n p a t i e n t s w i t h
macroglobulinaemia, a type of non-Hodgkin lymphoma, since
it was first described by Waldenstrom in 1944 . When the
serum viscosity rises, blood flow is delayed and peripheral
circulation disturbance occurs. The classic triad for HVS
consists of bleeding, neurological symptoms and visual
disturbances. However, in addition to these symptoms, a variety
of end organ damage can be observed.
Primary macroglobulinaemia is the most common cause of
HVS, which accounts for 85-90% of HVS. Multiple myeloma
is the second leading cause overall. While multiple myeloma
can occur in children, it is exceedingly rare. HVS can also be
caused by leukaemia because hyperleukocytosis, which can
l e a d t o l e u k o s t a s i s , i s o f t e n f o u n d i n l e u k a e m i a .
Hyperleukocytosis is found in 5-13% patients with acute
myeloid leukaemia and 10-30% patients with acute lymphocytic
Fig. 1 Paraneoplastic limbic
encephalitis. A 17-year-old boy
with recurrent medulloblastoma
presented with seizure and altered
mental status. a FLAIR image
shows hyperintensities in the
mesial temporal regions (arrows).
b Contrast enhanced
fatsuppressed T1-weighted image
shows nodular meningeal
enhancements in the left Sylvian
fissure (arrowheads), suggestive
In patients with HVS, congestive heart failure, renal
dysfunction, anorexia, fatigue and weakness may occur in
addition to the classic triad. The most frequent symptom is
bleeding, especially gingival and nasal. Although the number of
platelets is usually near-normal, repetitive bleeding is
characteristic. Bleeding may result from blood vessel wall
abnormality caused by an intravascular friction phenomenon due to the
increased blood viscosity. Neurological symptoms are
common in hyperviscosity syndrome, including headache,
dizziness, vision disorder, gait disturbance, sensory deafness,
convulsions, coma and cerebral infarction. MRI may show
multifocal parenchymal microhaemorrhages or frank haematoma
formation [10, 11] (Fig. 2).
Plasma exchange therapy is widely used for the treatment
of hyperviscosity syndrome, and clinical symptoms improve
by decreasing blood viscosity . In primary
macroglobulinaemia and multiple myeloma, it is necessary to use
chemotherapy in addition to plasma exchange.
Haemophagocytic lymphohistiocytosis (HLH)
HLH is a disease characterised by systemic proliferation of
histiocytes. HLH is divided into the familial/primary and the
In both primary and secondary HLH, cytokinaemia
associated with excessive activation of NK cells and cytotoxic T
cells and accompanying tissue damage is the hallmark of the
disease. When severe, infiltration into the central nervous
system occurs. Histopathological findings of CNS invasion of
HLH are classified into stages I-III. Stage I primarily shows
only leptomeningeal infiltrates of lymphocytes and
histiocytes/macrophages. Stage II shows additional parenchymal
involvement with perivascular infiltrations. Stage III reveals
cerebral tissue necrosis and demyelination in addition to
massive white matter infiltration . Familial HLH is genetic,
mainly due to abnormality of perforin, MUNC13-4, syntaxin
or MUNC18-2 . Secondary types are associated with
malignancy, infection, autoimmune disease and drugs. Although
the most common cause of malignancy associated HLH is
lymphoma and leukaemia, malignant solid tumours also cause
HLH [15, 16]. Malignancy associated HLH is usually seen in
the pre-treatment phase; however, it may also be seen in the
HLH is associated with fever, hepatosplenomegaly,
lymphadenopathy, rash and bleeding tendency. Laboratory and
pathological examinations reveal blood cell phagocytosis of bone
marrow, pancytopenia, liver dysfunction,
hypertriglyceridaemia, low fibrinogen plasma and high value of serum
MRI include diffuse leptomeningeal and perivascular
enhancement, which corresponds to meningeal and perivascular
infiltrations of histiocytes and lymphocytes, patchy areas of an
increased T2 signal intensity in the white matter of the both
cerebral hemispheres, and diffuse cerebral and cerebellar
parenchymal volume loss (Fig. 3). In some cases, nodular or ring
enhancement of parenchymal lesions occurs due to the
compromised blood-brain barrier in areas of active demyelination.
Diffusion-weighted imaging (DWI) shows diffusion
restriction in white matter lesions during the acute phase .
Differentiation from posterior reversible encephalopathy
syndrome (PRES) is often a problem both clinically and
Although treatments of HLH have not been established,
initial goals of treatments in HLH have been to suppress the
overactive immune system, thus preventing
immunemediated organ damage. Patients with malignancy associated
HLH require control of the HLH followed by treatment of the
Control of infection is central in the management of cancer.
Even before treatment, paediatric patients with malignant
tumours are prone to infection because of decreased
granulocytes, mucositis and reduced mucociliary clearance
Fig. 2 Hyperviscosity syndrome.
A 10-year-old girl with acute
lymphocytic leukaemia, whose
white blood cell count reached
400,000, presented with headache
and vomiting. a A T1-weighted
image shows hyperintensity in the
pons and bilateral cerebellar
hemispheres (arrows). b These
lesions show hyperintensity with
a hypointensity rim on
T2weighted image (arrows),
indicating haemorrhage in the
subacute phase. c T2*-weighted
image demonstrates a number of
microhaemorrhages which are not
seen on T1- and T2-weighted
or depletion of physiological flora, together with
immunosuppression due to primary disease.
Intracranial infection may result from direct spread from
sinusitis or from haematogenous spread, especially in the form
of septic emboli complicating endocarditis. Such infections
may be fungal, bacterial or viral.
Fungal infection Fungal infection typically affects children
having absolute granulocyte counts of less than 100/mm3 for
longer than 2 weeks .
The MRI appearance varies with the causative agent.
Aspergillus may cause an infectious vasculopathy, leading
initially to acute multiple infarctions or haemorrhage and later to
extension into surrounding tissue as an infectious cerebritis or
occasionally evolving into an abscess . Fungal abscesses
may have central restricted diffusion because of proteinaceous
fluid and cellular infiltration in the lesions . Haemorrhage
is found in 25% of patients . The contrast enhancement of
the lesion is strong in immunocompetent patients but is often
characteristically weak in immunocompromised patients .
Typical sites of involvement in Aspergillus vasculopathy
include the basal ganglia, thalami and corpus callosum,
reflecting a predisposition to involve the perforating arteries,
as well as the subcortical regions. Encasement of intracranial
arteries and vasculitis is found on MR angiography.
Candidiasis may cause numerous microabcesses at the
greywhite matter junction, basal nuclei and cerebellum, while
haemorrhage and infarction are relatively rare .
Formation of numerous abscesses can be seen in nocardiosis,
resulting in hydrocephalus, epistaxis and meningitis.
Because fungal culture tests are time-consuming and often
do not lead to definitive diagnosis, empirical antifungal
treatments are recommended for high-risk patients.
Bacterial infection Although bacterial infections of the CNS
are less common than fungal disease in immunocompromised
patients with cancer, infection with Listeria monocytogenes
and Bacillus cereus is well known [23, 24]. Clinical
symptoms, cerebral spinal fluid (CSF) examination and laboratory
data are important for the diagnosis of bacterial meningitis.
MRI is useful for detecting cerebral oedema, subdural
effusions/abscess and arterial or venous infarction
associated with meningitis. On MRI, hyperintensities are shown
in the subarachnoid spaces on the FLAIR imaging,
r e f l e c t i n g a n i n c r e a s e i n p r o t e i n c o n c e n t r a t i o n s .
Meningeal enhancement is observed on contrast MRI
Fig. 3 Haemophagocytic
14-yearold girl with myelodysplastic
syndrome presented with seizure.
a A T2-weighted image shows
patchy hyperintensities with
swelling in the frontal and parietal
lobes (arrows). b FLAIR image
shows hyperintensity of these
lesions (arrows). c T2*-weighted
image shows a number of
microhaemorrhages in these
lesions (arrowheads). d
Postcontrast image shows nodular
enhancement along the
leptmeninx (white arrows)
(Fig. 4), and it may progress to brain abscess if meningeal
inflammation spreads to the brain parenchyma. In brain
abscess, sudden onset headache and focal nervous
disturbance like motor paralysis, convulsions, visual
disturbance and cerebellar ataxia are observed. Progression of
clinical symptoms in a matter of hours is characteristic for
brain abscess. Fever is recognised only in about half of
cases. MRI shows iso- or hyper-intensity on T1-weighted
images with a low signal intensity rim on T2-weighted
images. Post-contrast images show ring enhancement.
Marked central diffusion restriction and rapid growth
can help to differentiated abscess from neoplasm.
Treatment with broad-spectrum antibiotics with narrowing
of coverage as possible is the general approach to treatment.
Fig. 4 Pyogenic meningitis. An
8-year-old boy with acute
myeloid leukaemia, who had
received chemotherapy including
presented with esotropia. a
FLAIR image shows
hyperintensities along the surface
of the brain stem (arrows).
Communicating hydrocephalus is
also seen (white arrows). b These
lesions show enhancement
Viral infection The most common pathogen in viral infection
in patients with haematological malignancy is the herpes
virus. Among the herpes subtypes, HHV-6 is important as an
opportunistic infection in immunosuppressed patients .
HHV-6 infection is present in 90% of children by 2 years of
age. While inactive at sanctuary sites in the parotid gland and
brain, HHV-6 activation leading to encephalitis occurs in
MRI findings of HHV-6 encephalitis are similar to acute
disseminated encephalomyelitis, and scattered hyperintensities
are seen in cerebral white matter on T2 weighted images .
Treatment is using with anti-viral agents such as acyclovir
and gancyclovir, which are often started empirically when the
imaging and clinical findings are suggestive.
Trousseau’s syndrome (cancer-associated thrombosis)
Trousseau’s syndrome was first reported in 1865 by Armand
Trousseau as a condition of cerebral infarction and pulmonary
embolism due to multiple venous thrombosis associated with
gastric cancer. In 1977, Sack et al. reported that Trousseau’s
syndrome is chronic disseminated intravascular coagulation
(DIC) associated with non-bacterial thrombotic endocarditis and
arterial thrombosis in patients with malignancy. Currently, the
term BTrousseau’s syndrome^ is often used to describe a
hypercoagulation disorder associated with various malignancies.
It is reported that the risk of venous thromboembolism, including
both deep vein thrombosis and pulmonary embolism, is fourfold
to sevenfold higher in patients with cancer than those without
cancer . Neurological symptoms depend on the infarcted
area; however, altered mental status and convulsion are often
observed. Although Trousseau’s syndrome is classified as a
treatment phase complication in this article, it can occur as a primary
symptom in some patients with paediatric cancer.
The brain is abundant with thromboplastin, which triggers
the exogenous coagulation cascade and is thought to be a
target of DIC due to the lack of thrombomodulin, a thrombin
antagonist. Although the mechanism of hypercoagulability in
patients with cancer has not been fully elucidated, it is thought
that tumour cells express tissue factors that activate the
coagulation cascade, including cellular procoagulants such as
tumour procoagulant and factor X receptors. These lead to
thrombosis by inducing cell-cell interactions with platelets,
monocytes and endothelium via inflammatory cytokines,
tumour antigens, and their immunoconjugates, which promote
coagulation activation. Although malignant tumours that
cause Trousseau’s syndrome tend to be solid, children with
any malignancy are at increased risk .
Certain MRI features can suggest this entity. Trousseau’s
syndrome should be considered, particularly when cerebral
infarction involves three or more vascular territories.
Microemboli are usually scattered in multiple vascular territories
[29, 30]. In addition, MRI with MR venography is useful for the
diagnosis of dural sinus thrombosis. MR venography can show
loss of the flow void in an affected dural sinus  (Fig. 5). Since
there are no clear diagnostic criteria for Trousseau’s syndrome, it
is important to search for malignant tumours when unexplained
cerebral infarction or sinus thrombosis are found.
Regarding therapy, in addition to treating the underlying
cancer, anticoagulant therapy using heparin is also usually
necessary; warfarin is usually ineffective.
Posterior reversible encephalopathy syndrome (PRES)
PRES is an acute neurotoxic syndrome of characteristically
reversible subcortical vasogenic brain oedema in patients with
acute neurological symptoms. The pathophysiology of PRES
is thought to be due to failure of cerebral blood flow
autoregulation from endothelial dysfunction . Predisposing
conditions associated with PRES in patients with cancer include
chemotherapeutics or immunosuppressant administration,
infection and autoimmune disorders. Hypertension is associated
with paediatric PRES, but because the cerebral blood flow
autoregulation threshold is lower in children than in adults,
the mean blood pressure at the onset of PRES is also lower
. The mean blood pressure at the onset of paediatric PRES
was reported to be 140/85 mmHg . The spectrum of
neurological features observed in patients with PRES includes
headache, seizure, visual disturbances and nausea.
Although the subcortical white matter and cortex are often
involved, distribution of abnormal imaging findings in PRES is
classified into four patterns: holohemispheric watershed,
superior frontal sulcus, dominant parietal-occipital and partial or
asymmetric . The basal ganglia, brain stem and cerebellum are
also sometimes involved. MRI shows regions of high signal
intensity on T2-weighted or FLAIR images. Restricted diffusion
can be seen in 15-30% of cases, which is generally associated
with irreversible change  (Fig. 6). Contrast enhancement is
seen in about 20% of patients with PRES. Intraparechymal or
subarachnoid haemorrhage around cortical or subcortical lesions
is seen in 10-25% of cases. Intraparenchymal haemorrhage is
often multifocal; however, mass effect is rare. Subarachnoid
haemorrhage spares the basilar cisterns [32, 36]. Additionally,
temporal lobe involvement, restricted diffusion on MRI, and
associated multi-organ failure are more frequent in paediatric
PRES compared with adults .
Treatment of PRES depends on its cause. Anti-epileptic
medication may also be appropriate.
Abnormalities of the cerebral white matter are seen in some
patients following treatment with chemotherapeutic agents.
Fig. 5 Trousseau’s syndrome.
(dural sinus thrombosis). A
5year-old boy with acute
lymphocytic leukaemia presented
with seizure and altered mental
status. a A T2*-weighted image
shows hypointensity in the
superior sagittal sinus (arrows). b
MR venography shows signal
loss in the superior sagittal sinus
Although several drugs cause leukoencephalopathy,
methotrexate (MTX) is the most common one in children. MTX is
an antifolate drug used for treatment of diseases such as acute
lymphoblastic leukaemia, malignant lymphoma and sarcoma.
MTX neurotoxicity is found in 3-10% of recipients.
It is believed that MTX can induce direct toxic effects to the
CNS by damaging the neuronal tissue. Moreover, MTX
interferes with the metabolic pathways of folate and induces
biochemical alterations in excitatory amino acids, homocysteine,
and biopterins , which can lead to neurological symptoms.
High-dose intravenous administration, intrathecal
administration, teenage and a history of radiation therapy are risk factors.
Its neurotoxicity can be classified as acute, subacute and
chronic. Acute or subacute neurotoxicity can present with
stroke-like symptoms such as aphasia, muscle weakness,
sensory disturbance and ataxia, occurring within 2-14 days after
initiation of MTX. Neurological symptoms are usually
transient. In contrast, the chronic type can cause a slowly
developing leukoencephalopathy and may progress to permanent
impairment of neurological function.
MRI of acute neurotoxicity shows diffusion restriction on
DWI in cerebral white matter, especially in the centrum
semiovale or corona radiata, indicating intramyelinic oedema
(Fig. 7). Although T2-weighted and FLAIR images show
hyperintensities, they may be quite subtle. DWI findings are
normal after recovery, while T2 and FLAIR images usually
show slight residual abnormalities. The cerebral cortex and
cerebellum are also involved in atypical cases . When
imaging findings resembling cerebral infarction appear in
patients receiving MTX, MTX neurotoxicity should be
After cessation of MTX and resolution of the associated
neurotoxicity, subsequent intrathecal MTX administration is
not associated with recurrence of MTX neurotoxicity.
Hippocampal sclerosis is a neuropathological condition
with severe neuronal cell loss and gliosis in the
hippocampus, specifically in the cornu ammonias area 1 and
subiculum of the hippocampus. Although hippocampal
sclerosis is generally associated with biphasic seizures of
the infantile period, cerebritis, head trauma and perinatal
brain injury, there are also some reports of hippocampal
Fig. 6 Posterior reversible
(PRES). A 5-year-old boy with
acute lymphocytic leukaemia,
who received bone marrow
lethargy during administration of
tacrolimus. a A T2-weighted
image shows hyperintensities in
the occiptal lobes (arrows). b A
(SWI) shows punctate signal loss
in these lesions, suggestive of
Fig. 7 Methotrexate
neurotoxicity. (acute phase). A
14-year-old girl with acute
lymphocytic leukaemia, who
received intrathecal methotrexate,
presented with left hemiplegia. a
Diffusion-weighted image shows
a small area of hyperintensity
within the right centrum
semiovale (arrow). b Apparent
diffusion coefficient map shows
restricted diffusion in this lesion
sclerosis in patients with haematological malignancy .
Various factors are thought to underlie the sclerosis seen
in haematological malignancies, such as neurotoxicity due
to methotrexate or cyclosporine, radiation exposure and
bone marrow transplantation. Hippocampal sclerosis
accounts for a large portion of refractory temporal lobe
epilepsy in children. Although hippocampal sclerosis is
highly associated with mesial temporal lobe epilepsy, it
is not known whether hippocampal sclerosis causes
temporal lobe epilepsy or temporal lobe epilepsy causes
On MRI, coronal FLAIR and short tau inversion recovery
images perpendicular to the hippocampus are useful. Atrophy
and high signal intensity of the hippocampus and amygdala
are observed (Fig. 8). In temporal lobe epilepsy, slight
abnormal signal may be observed in the white matter at the temporal
lobe tip, leading to the diagnosis of hippocampal sclerosis in
the initial stages .
Medial temporal lobe epilepsy is usually refractory to
anticonvulsant drugs; brain surgery is effective in such patients.
Hence, early detection of hippocampal sclerosis in patients
with haematological cancer is important, because these
children are likely candidates for brain surgery.
Radiation induced tumours
Development of a secondary neoplasm is an important
late complication of radiation therapy. Childhood cancer
survivors who received cranial radiation therapy have an
8.1–52.3 times higher incidence of subsequent CNS
neoplasms compared with the general population . In
adult patients with radiation induced brain tumours,
meningiomas represent approximately 70%, gliomas 20%
and sarcomas 10% . In paediatric populations,
highgrade gliomas and meningiomas are the two most
common subsequent CNS neoplasms, although
medulloblastomas, primitive neuroectodermal tumours (PNETs),
schwannomas and low-grade gliomas have also been
reported . Initial studies from the early 1990s had
suggested that high-grade gliomas occur in the 1st decade
after primary cancer diagnosis, but more recent studies
with longer follow-up have shown that high-grade
gliomas also occur in the 2nd decade after primary cancer
therapy. Moreover, survivors of brain tumours who had
not developed meningiomas at 20 years after diagnosis
of their original cancer still had a 5.3% incidence of
meningiomas in the subsequent decade . Thus, deciding
on an optimal screening regimen is challenging.
There is a recommendation that secondary brain tumour
screening by MRI should be performed annually for the initial
5 years after completion of the radiotherapy, and thereafter
repeated MRI screening should be performed only for the
patients with neurological symptoms, such as headache,
cognitive changes and seizures, particularly in those with a history
of haematological malignancy or radiotherapy at a young age
. However, large sample, prospective randomised studies
Fig. 8 Hippocampal sclerosis. A 24-year-old-man, who received bone
marrow transplantation for malignant lymphoma at the age of six,
presented with temporal lobe epilepsy. FLAIR image shows atrophy
with high signal intensity in the bilateral amygdalae and hippocampi
Fig. 9 Radiation induced atypical
teratoid/rhabdoid tumour. A
21year-old man, who received
radiation therapy for optic glioma
during infancy, presented with
headache, appetite loss and
somnolence. a A T2-weighted
image shows a lobulated, solid
mass with internal low signal
intensity, indicating a small
haemorrhage in the middle cranial
fossa to basal ganglia (arrows). b
Diffusion weighted image shows
hyperintensity in the tumour
(arrows). c Apparent diffusion
coefficient map shows restricted
diffusion in the tumour (arrows)
are needed in this regard. Radiation-induced gliomas are
associated with high-grade gliomas in young people,
multiplicity of gliomas and earlier age at presentation . The
neuroimaging appearance of radiation-induced tumours does not
differ from that of other types (Fig. 9).
Radiation induced focal haemosiderin deposition (RIFHD)
RIFHD is a late complication of radiation therapy, which
represents haemorrhagic or proliferative microangiopathies such
Fig. 10 Radiation induced focal
haemosiderin deposition. A
29year-old woman, who received
radiation therapy for acute
lymphocytic leukaemia, had no
symptom. a A T2*-weighted
image shows focal haemosiderin
deposition in the right insular and
left temporo-parietal lobe
(arrows). b FLAIR image shows
slight low intensity area in the
right insular (arrowheads). Left
temporo-parietal small lesion is
not apparent (arrow)
as capillary telangiectasias and cavernous malformations .
Pathologically, telangiectasias and cavernous malformations
differ only in the presence or absence of intervening brain
parenchyma among the dilated, thin-walled vascular channels.
Because these similarities and transitional forms of these
vascular malformations have been observed in some patients,
r a d i a t i o n - i n d u c e d t e l a n g i e c t a s i a s a n d c a v e r n o u s
malformations have been proposed to exist along a spectrum
driven by a common proliferative pathway .
The mechanism of RIFHD probably involves vascular injury,
proliferation and dilation of vascular endothelium, hyalinisation
and fibrinoid necrosis of blood vessel walls due to radiation
therapy, and finally ischaemia and infarction due to narrowing
of the vascular lumen . The influence of age at the time of
radiation therapy varies by report, and there is no consensus [46,
49, 50]. Radiation dose of 6-12 Gy has been reported as the
minimum threshold level for development of RIFHD, and
radiation dose positively correlates with frequency of RIFHD .
Although most patients with RIFHD are asymptomatic,
symptomatic bleeding may occur. Infratentorial RIFHD is more prone
to symptomatic bleeding compared with supratentorial RIFHD
[51, 52]. RIFHD is associated with neurocognitive dysfunction
in primary brain tumour survivors .
On MRI, RIFHD shows mixed intensity with an enhancing
c y s t i c a n d / o r s o l i d c o m p o n e n t a n d a n i n c o m p l e t e
haemosiderin rim, which would be insufficient for a diagnosis
of de novo cavernous malformation . Small RIFHD
lesions are best seen on iron-sensitive sequences such as
gradient recalled echo imaging or susceptibility weighted imaging
 (Fig. 10).
The treatment algorithm for RIFHD is not well established
because the natural course of RIFHD has yet to be elucidated.
Surgery may be considered in patients with repeated bleeding
episodes and progressive neurological symptoms.
Radiation induced white matter injury
White matter injury is also an important late complication of
radiotherapy. Radiation-induced white matter injury is divided
into acute, early-delayed and late-delayed injury . Acute
and early-delayed reactions are often mild. Late-delayed
injury is found as early as 3-4 months or as late as several years
after completion of therapy.
It is believed to result mainly from permanent damage to blood
vessels. Patients may develop progressive neurological symptoms.
Pathologically, the affected white matter exhibits necrosis, with
rarefaction and fragmentation of myelin and cellular disruption.
Imaging studies show variable patterns of injury, such as
focal lesions or diffuse white matter abnormality. MRI
demonstrates hypointensity on T1-weighted images and
hyperintensity on T2-weighted images (Fig. 11). In
wholeFig. 11 Radiation induced white matter injury. A 5-year-old boy, who
received radiation therapy for anaplastic ependymoma, was
asymptomatic. A T2-weighted image shows hyperintensity in the right
frontal lobe which was irradiated (arrows)
brain radiation, signal changes occur in the periventricular
region and may progress in size and signal intensity over time,
extending peripherally to the subcortical fibres .
Telencephalic commissural fibres are typically spared .
White matter volume loss may occur as a result of diffuse
radiation injury . Central necrosis within the lesions is
uncommon in children .
Neurological complications of paediatric cancer are a
substantial problem and are associated with significant morbidity and
loss of quality of life for long-term survivors of paediatric
cancer. It is critical for radiologists to recognise the imaging
findings of these rare but important complications related to
disease and treatment. MRI plays a significant role in the
recognition and proper management of neurological
complications of paediatric cancer.
Compliance with ethical standards
Conflict of interest
We declare that we have no conflicts of interest.
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