Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Jun; 166(2):236-241.

Very late complications of oncotherapy in glioblastoma patients: A case series
Ondrej Kalitaa, Lumir Hrabaleka, Matej Halaja, Pavel Hokb, David Francb, Yvona Klementovac, Martin Dolezelc,
Eva Cechakovad, Zuzana Sporikovae, Jiri Drabeke, Marian Hajduche, Lucie Tuckovaf
Background. Stroke-like syndrome is defined as a rare, delayed complication of brain oncotherapy. Cases with more
favorable brain cancer diagnoses and longer life expectancy have been previously reported, but here we present, for
the first time, three long-term survivors of glioblastoma with stroke-like syndromes.
Methods and Results. Three young or middle-aged patients underwent tumor resection and chemoradiotherapy.
They received regular clinical and imaging follow-up with stable neurological status and no signs of tumor recurrence.
They exhibited varied signs and symptoms (motor and sensory deficits, aphasia, memory and cognitive disorders, seizures, and headache) accompanied by imaging abnormalities. Stroke-like syndromes developed within 2-5 days and
resolved in 2-6 weeks. Diffusion-weighted MRI and T2 brain perfusion abnormalities were demonstrated in all patients.
In addition, there was focal T1 MRI contrast enhancement due to blood-brain barrier disruption. In addition to tumor
recurrence, classic stroke, encephalitis, metabolic and mitochondrial disorders, and post-seizure swelling should be
excluded. The imaging indicated intensive MRI scanning and symptomatic medication (steroids supplemented by
antiepileptics, vasoactive agents, etc.) for judicious management. With respect to the course, an invasive procedure
was still considered an option.
Conclusion. All stroke-like syndromes are diagnoses of exclusion. To avoid misinterpretation of imaging findings as
glioblastoma recurrence and avert recall oncotherapy or redundant interventions, better understanding of delayed
complications of brain tumor therapy is crucial.
Key words: stroke-like syndrome, glioblastoma, oncotherapy, corticosteroid
Received: November 28, 2020; Revised: January 14, 2021; Accepted: January 29, 2021; Available online: February 22, 2021
https://doi.org/10.5507/bp.2021.012
© 2022 The Authors; https://creativecommons.org/licenses/by/4.0/
Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech
Republic
b
Department of Neurology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
c
Department of Oncology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
d
Department of Radiology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic
e
Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky
University Olomouc, Czech Republic
f
Department of Pathology and Laboratory of Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine
and Dentistry, Palacky University Olomouc, Czech Republic
Corresponding author: Ondrej Kalita: e-mail: ondrej.kalita@fnol.cz
a

BACKGROUND
Despite advanced imaging, surgical, and oncological
techniques, the prognosis of patients with glioblastoma
(GBM) remains dismal. However, some signs of improvement in treatment outcomes of patients with GBM can
be traced over the last decades1.
The best outcomes are yielded by aggressive multimodal therapy involving safe and maximal resection followed by chemoradiotherapy1. However, side effects of
this aggressive treatment seriously impact not only GBM
patients’ quality of life, but also their overall survival. The
ensuing follow-up involves MRI and clinical status review,
assessment of tumor recurrence or residuum, and distinguishing between true progression, pseudoresponse, and
pseudoprogression. Temporary and permanent surgical
complications are obvious immediately after resection and
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within several months, respectively. By contrast, side effects of oncological treatment commonly have a gradual
presentation, some occurring after months or even years.
In particular, very late complications are the most difficult
to identify. Several diagnostic items have been defined.
“SMART” - stroke-like migraine attacks after radiotherapy is an uncommon, very late complication of cranial
radiotherapy. It typically presents as reversible, unilateral
cortical signs on MRI and symptoms such as confusion,
hemiparesis, seizures, and headaches2.
“PIPG” – peri-ictal pseudoprogression refers to transient seizure-related MRI changes that could mimic disease progression3.
“ALERT” – a syndrome characterized by acute lateonset encephalopathy after radiotherapy4.

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CASE 1 – SMART
In 2010, a 37-year-old woman presented with a two-week
history of fluctuating left-sided hemiparesis and sensory
symptoms. Brain MRI revealed a contrast-enhanced tumor in the parasagittal region of the right parietal lobe.
She received radical resection in January 2010, followed
by chemoradiotherapy (Stupp regime). Histological diagnosis confirmed GBM, immunohistochemistry detected
IDH1 canonical R132H mutation, and PCR revealed
MGMT promoter methylation and IDH1 canonical
R132H mutation, retrospectively5. She was followed by
regular clinical and imaging check-ups, with stable neurological status and no signs of tumor recurrence. Despite
her left hemiparesis, she had independent gait, and permanently looked after her blind husband. In January 2019, a
follow-up MRI disclosed a new, contrast-enhanced lesion
in the periventricular region of her right temporal lobe,
relatively far from the original resection cavity (Fig. 1a,b).
In February 2019, a PET FLT scan showed no radiotracer
uptake in brain tissue (Fig. 1c). Surprisingly, another follow-up MRI showed effacement of the contrast-enhanced
lesion in March 2019 (Fig. 1d). In May 2019, there was
disability progression, with worsening of hemiparesis,
accompanied by development of anxiety and depressed
mood, migraine and mild epileptic seizures. A new MRI,
in June 2019, revealed new multiloculated contrast-enhanced lesions around the original resection cavity in
the right parietal lobe and a blurred contrast-enhanced
region in the right temporal lobe (Fig. 1d). EEG showed
a nonspecific abnormal pattern consistent with a lesion,
with no signs of epileptic activity. The patient received
antiepileptics, corticoids, and anxiolytics, rehabilitation
services and psychiatric interventions. Another follow-up
MRI, in September 2019, again showed lesion disappearance. Based on an incidental MRI finding, complementary CT angiography confirmed a radiation-related basilar
tip aneurysm, which was managed with endovascular coil
embolization (October 2019) (Fig. 1e,f). The next followup MRI (September 2020) detected no enhanced lesion
(Fig. 1g,h). There was an incomplete recovery. The patient
was free from migraine, anxiety, and epileptic seizures,
but continued to use a wheelchair due to severe left hemiparesis.
CASE 2 – SMART/PIPG
In 2009, a 16-year-old male patient presented with a short
history of right-sided hemiparesis. Brain MRI revealed a
contrast-enhanced tumor in the left TP cerebral region. He
underwent radical resection, followed by chemoradiotherapy (Stupp regime). The histological diagnosis was GBM,
and retrospective immunohistochemical analysis detected
IDH1 mutation. He was followed by regular clinical and
imaging check-ups with no signs of tumor recurrence or
neurological deterioration. He was fully independent, with
no epileptic seizures, and no motor or sensory deficits. He
graduated from the Faculty of Law of a local university in
June 2018. In December 2018 he suffered from sudden
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onset of right-sided hemiparesis, hemihypesthesia, and
speech disorder. Emergency MRI showed a hyposignal
and hypersignal lesion in the frontal periphery of the resection cavity, visible in T1 and FLAIR scans, respectively
(Fig. 2a,b), suggestive of acute ischemia. Accordingly, MR
angiography revealed acute ischemia in the MCA region.
PET FLT, echocardiography, Holter ECG, and extracranial vessel ultrasonography yielded no tumor recurrency
or cardiovascular emboligenic perturbation. After conservative treatment (anticoagulant and antiplatelet therapy,
anxiolytics) for a month, he recovered uneventfully. MRI
revealed no tumor recurrence in May 2020.
CASE 3 – PIPG/ALERT
In 2012, a 39-year-old man presented with his first epileptic seizures. Brain MRI revealed a contrast-enhanced
tumor in the parasagittal region of the right parietal lobe.
He underwent radical resection, followed by chemoradiotherapy (Stupp regime). The histological diagnosis was
GBM. Retrospective immunohistochemical analysis detected canonical R132H mutation of IDH1, and PCR
revealed MGMT promoter methylation and canonical
R132H mutation of IDH1 (ref.5). He was followed by
regular clinical and imaging check-ups with no signs of
tumor recurrence or neurological deterioration. Despite
only partial epileptic control (with a few remaining mild
episodes per month), he was independent, with no mobility impairment. In January 2018, disclosure by a follow-up
MRI of a new, blurred, small contrast-enhanced lesion in
the resection cavity wall and the adjacent cortex was followed by a rise in convulsive activity (Fig. 3a,b). A PET
FLT scan showed no radiotracer uptake in brain tissue.
His clinical status stabilized following modification of
antiepileptic therapy and corticoid administration. The
patient recovered completely. MRI indicated no tumor
recurrence in June 2020 (Fig. 3c).
DISCUSSION
All our patients shared common features, including a
radically resected, IDH-mutated, and MGMT-methylated
GBM, a history of chemoradiotherapy, young to middle
age tumor presentation, and long survival. For a long period in the regular follow-up, they were in relatively good
health and showed no evidence of tumor recurrence. Both
patients 1 and 3 had a stable, radiation-induced leukoencephalopathy. The onset of neurological deterioration was
characterized by ambiguous dynamics. The new, transient,
diffuse, cortical postcontrast abnormalities on MRI in
Patients 1 and 3 preceded episodes of headaches, drowsiness, confusion/hallucinations, stroke-like symptoms,
and complex seizures for several months. By contrast,
Patient 2 suffered from post-stroke neurological impairment without prodromal MRI abnormalities. Due to the
clinical severity of their status, Patients 1 and 2 required
hospital admission. Initial MRI changes mimicked some
aspects of GBM progression, with edema and gadolinium-

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Jun; 166(2):236-241.

Fig. 1a. Axial T1-weighted MRI scan, showing contrast-enhanced lesion in the periventricular region of the right temporal lobe.

Fig. 1b. Diffusion-weighted MRI showing local hyperintensity.

Fig. 1c. PET FLT scan showing no radiotracer uptake in brain
tissue.

Fig. 1d. Axial T1-weighted MRI scan showing effacement of
the contrast-enhanced lesion in the right periventricular region.

Fig. 1e. Axial T1-weighted MRI scan showing multiloculated
contrast-enhanced lesions around the original resection cavity
in the right parietal lobe and a blurred contrast-enhanced region
in the right temporal lobe.

Fig. 1f. Diffusion-weighted MRI scan showing multilocal hyperintensity.

enhancing foci, including the cortex. However, although
standard T1 postcontrast, diffusion imaging and PET FLT
scans showed uncommon or elusive GBM features, the
MRI abnormalities were limited in brain tissues near or
not far from the resection cavity. Results of CSF analysis (cell count, protein transfer, total proteins, glucose,

PCR-based examination of CSF for viral infection) were
unremarkable for all patients. EEG recordings during
the acute phase showed diffuse slow abnormalities in all
patients. To avoid burdensome diagnostic and therapeutic procedures, an intensive wait-and-scan strategy was
adopted. There is no causal treatment, so symptomatic
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Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Jun; 166(2):236-241.

Fig. 1g. CT angiograph confirming a radiation-related basilar
tip aneurysm that was managed with endovascular coil embolization (1h).

Fig. 1h. Endovascular coil embolization.

Fig. 1i. Axial T1-weighted MRI scan showing disappearance of
the multiloculated contrast-enhanced lesions.

Fig. 1j. Axial diffusion-weighted MRI scan showing reduction
in multilocal hyperintensity.

Fig. 2a. Axial T1-weighted MRI scan showing no contrastenhanced lesion.

Fig. 2b. Diffusion-weighted MRI scan showing hypersignal zone
in the frontal periphery of the resection cavity.

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therapy was administered including high-dose corticosteroids and antiepileptics. However, given their uncertain
efficacy, antiplatelet (acetylsalicylic acid, clopidogrel) and
vasodilatory (calcium channel blockers – propranolol,
nimodipine; ß-adrenoceptor blockers – verapamil) agents
were added.
Based on a careful clinical status assessment, the initial high-dose corticotherapy administered to our patients
(16–24 mg of dexamethasone per day) was gradually tapered. At the time of writing, patients 1 and 2 receive no
corticotherapy, and patient 3 remains on a low maintenance dose of 2 mg dexamethasone per day. All patients
were initially administered antiplatelet therapy (acetylsalicylic acid: 100–200 mg per day), and patients 1 and 2
continue to receive it. Patient 1 was originally seizure-free
on carbamazepine, but after a stroke-like attack, lacosamide was added. At the patient’s request, lacosamide was
withdrawn after stabilization of his clinical status. New
antiepileptics (clonazepam, levetiracetam) were added to
patient 3’s chronic medication of valproic acid. As anxiolytic therapy, citalopram was administered in combination
with bromazepam and alprazolam to Patients 1 and 2,
respectively.
Patients 2 and 3 recovered completely. A SMART episode led to permanent worsening of neurological deficits
in Patient 1, and a further complication was the radiationrelated basilar tip aneurysm, which was treated with endovascular coil embolization.

Fig. 3a. Axial T1-weighted MRI scan showing contrast-enhanced lesion around the original resection cavity in the right
parietal lobe.

CONCLUSION

Fig. 3b. Diffusion-weighted MRI scan showing multilocal hypersignal rim encompassing the resection cavity shown in 3a.

Fig. 3c. Axial T1-weighted MRI scan showing disappearance of
the multiloculated contrast-enhanced lesions.

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Stroke-like syndrome is a rare, delayed complication
of brain oncotherapy. More than 100 cases have been
published globally, but only cases with more favorable
brain cancer diagnoses with a longer life expectancy have
been reported3,6. For the first time, our case series presents three long-term survivors of GBM with stroke-like
syndrome. A 5-year survival rate of 17% for GBM patients
under 50 years old was recorded in a randomized phase
III study7, but only a 5-year overall relative survival rate of
6.8% in real clinical practice8. Originally, all our patients
underwent tumor resection and chemoradiotherapy. All
of them had acute MRI alterations, but two had imaging
abnormalities before clinical manifestation. They presented with varied signs and symptoms (focal deficits,
encephalopathy, seizures, and headache) (ref.3,9). Strokelike syndromes developed within 2-5 days but resolved in
2-6 weeks. Diffusion-weighted MR and T2 brain perfusion abnormalities were detected in all patients, with focal
MRI contrast enhancement due to blood-brain barrier
disruption. Only Patient 1 had obscure thick gyriform
cortical enhancement characteristic of SMART. Besides
tumor recurrence, classic stroke, encephalitis, metabolic
and mitochondrial disorders, and post-seizure swelling
should be excluded9. The imaging indicated intensive
MRI scanning and symptomatic medication (steroids, for
their inflammatory and anti-edemic effects, supplemented
by antiepileptics, vasoactive agents, etc.) for judicious

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 Jun; 166(2):236-241.

management. It must be kept in mind that no imaging
technique has 100% specificity and sensitivity, and both
surgery and oncotherapy affect EEG and MRI results.
Regarding the course, invasive procedures such as biopsy
and tumor re-resection were still considered options.
The pathophysiology of stroke-like syndrome remains
unclear, but a set of plausible causes has already been accepted. Compromised brain perfusion has been acknowledged in the literature as a process underlying syndrome
progression10. Cranial irradiation alters neurogenesis, neuron morphology, and mitochondrial disorders, as well as
causing endothelial damage, mainly to small vessels. In
the following period, vascular dysfunction results in hypoxia of brain cells with impaired autoregulatory parameters and activates cerebral hyperexcitability. Conversely,
seizure activity affects the previously injured brain microenvironment and potentiates inflammatory endothelial
damage.
All stroke-like syndromes are diagnoses of exclusion.
To avoid misinterpretation of imaging findings as GBM
recurrence, and avert recall oncotherapy or redundant
interventions, better understanding of delayed complications of brain tumor therapy is crucial. An antecedent
event for the sudden onset of brain tissue destruction has
not been elucidated. Close cooperation of neuro-oncology
team members is essential, but neurological recovery is
not always completed, and the recovery range of strokelike syndromes still remains unpredictable. To date, no
knowledge of the possible parallel effects of surgery and
systemic chemotherapy (temozolomide) on these syndromes’ development has been acquired. Brain tissue
reaction to cranial irradiation evolves in an individual
pattern and without predictive markers. As no effective
GBM treatment that spares normal brain tissue has been
identified to date, cranial irradiation will continue to be
the standard part of GBM treatment, and we will continue
to encounter sequelae (such as stroke-like syndrome) for
the foreseeable future. Hence, there are clear needs to
characterize the sequelae, and identify ways to minimize
both their frequency and severity.
ABBREVIATIONS
ALERT, Acute late-onset encephalopathy after radiotherapy; CNS, Central nervous system; CSF, Cerebrospinal
fluid; FLT, 3'-deoxy-3'-[18 F]fluorothymidine; GBM,
Glioblastoma; IDH, Isocitrate dehydrogenase; MGMT,
Methyl O6-methylguanine-DNA-methyltransferase; PET,
Positron emission tomography; PCR, Polymerase chain
reaction; PIPG, Peri-ictal pseudoprogression; SMART,
Stroke-like migraine attacks after radiotherapy.
Authors contributions: OK: patient management, literature
review, analysis of the radiologic data, initial draft manuscript preparation, concept and design of the study, analysis of the radiologic data, final approval of the version to
be published; LH: conception and design of the study,
final approval of the submitted version; MH, PK, DF, YK,
MD: literature review, patient management; EC: analysis
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of the radiological data; ZS: literature review, evaluation
and provision laboratory data, final approval of the submitted version of the manuscript; JD, MH, LT: literature
review, initial draft manuscript preparation, evaluation
and provision of laboratory and pathological data; OK,
ZS: contributed equally to the work; All authors have read
and approved manuscript.
Conflict of interest statement: The authors state that there
are no conflicts of interest regarding the publication of
this article.
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