Imaging Spectrum of Post Therapy
Related Disorders: A primer for the
Neuroradiologist
PETER FATA MD, SUSAN SOTARDI MD, SHALINI MUKHI MD,
JACQUELINE A. BELLO MD, CHRISTIE M. LINCOLN MD
Disclosure
Nothing to disclose.
Introduction
 A wide range of treatment-related effects result in specific
neurologic symptoms and signs with typical neuroimaging
features.
 Even to the most seasoned neuroradiologist, elucidating therapyrelated side effects distinct from disease and common mimics can
be challenging.
 Our goal is to provide a pictorial survey of common medication
induced and therapy related neuroimaging manifestations, discuss
their pathophysiology and common pitfalls in imaging and
diagnosis.
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthridites and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Tissue Plasminogen Activator Induced
Hemorrhagic Transformation in Stroke
 Hemorrhagic transformation (HT) is a well known complication of stroke
particularly in the setting of tissue plasminogen activator (tPA) with reperfusion
injury as the underlying mechanism.
 tPA promotes fibrinolysis in the acute clot which restores vascular flow,
preserving the penumbra before it becomes non-viable infarcted tissue
 As time progresses, the benefits of giving tPA decrease while risk of HT
increases.
 Specific CT imaging features of acute ischemia may suggest an increased risk
of HT:
 Obvious area of hypodensity
 Large volume of infarct
Case of
Hemorrhagic
Transformation
and IV tPA
Noncontrast head CT
in 45 year-old male
inmate who
complained of right
sided weakness.
T2
Case of
Hemorrhagic
Transformation
and IV tPA
45 year-old male inmate
became obtunded within 5
hours after IV tPA and MRI
and CT were done
showing new area of
hemorrhage in the acute
right middle cerebral artery
territory infarct with new
regional mass effect and
mild rightward midline
shift.
DWI
GRE
Another Case of
Hemorrhagic
Transformation
and IV tPA
55 year old female
before (upper row) IV
tPA and 3.5 hours
after treatment
(bottom row) with
areas of hemorrhage
(arrows).
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral or CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Contrast leakage with conventional
Cerebral or CT Angiography
 Several hypotheses:
1. Hypertonic solutions draw water out of the endothelial cells of brain vessels,
causing the cells to shrink and separating the tight junctions
2. Blood brain barrier break down on the basis of microvascular sludging and possibly
arterial spasm.
 Angiography and CT contrast is a great mimicker of hematoma and a major pitfall.
 There have been reported cases where active contrast extravasation into a preexisting idiopathic intraparenchymal hematoma during CT angiography increased
hematoma expansion and mortality.
 Dual energy CT is a modality which could help in differentiating hemorrhage from
contrast.
Case of
Endovascular
Treatment
Cerebral
Angiography
Noncontrast head CT in
53 year-old male
immediately after a
cerebral angiogram. The
hyperdensity seen in the
left lentiform nucleus
cleared on follow up CT
the next day.
Intraparenchymal hemorrhage, such as hypertensive hemorrhage, should be
considered in cases where history doesn’t support diagnosis of contrast
leakage or hyperdensity doesn’t clear on subsequent scan.
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral or CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Cerebellar Atrophy with Phenytoin Use in
Seizure
 Well known anti-epileptic medication, no longer considered first line.
 Mechanism: Inhibits neuronal action thereby stabilizing hyperexcitability and prevents
high frequency action potentials.
 Dose dependent cerebellar atrophy: Can result in predominant white matter loss and
widespread loss of Purkinje cells and granule cells.
 Common symptoms of cerebellar atrophy: nystagmus and ataxia.
 Cessation of medication results in clinical improvement though imaging findings are
irreversible.
 Other side effects:
 Skull Thickening
 Gingival Hyperplasia
Case of
Cerebellar
Atrophy
Noncontrast head CT in
35 year-old female who
had been on phenytoin
since childhood with
cerebellar atrophy (left
image) and parietooccipital calvarial
thickening (right image).
Consider other etiologies of atrophy as differential: aging brain,
alcohol encephalopathy, lithium intoxication, radiation changes,
hereditary, and multisystem atrophy.
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTL4 antibody therapy in cancer
Posterior Reversible Encephalopathy
Syndrome
 Also referred to as posterior leukoencephalopathy syndrome.
 It is a neurotoxic process due to autoregulatory dysfunction resulting in seizures,
altered mentation, headache, and/ or cortical based visual disturbances.
 Theories exist as to mechanism.
Two controversial and opposing hypotheses are commonly cited:
1. The current more popular theory suggests that severe hypertension exceeds
the limits of autoregulation, leading to breakthrough brain edema.
2. The earlier original theory suggests that hypertension leads to cerebral
autoregulatory vasoconstriction, ischemia, and subsequent brain edema.
Posterior Reversible Encephalopathy
Syndrome
 Most commonly caused by hypertension.
 Numerous other etiologies exist and include autoimmune disease (e.g.
SLE), high dose chemotherapy, post transplantation, infection/
sepsis/shock, and toxemia of pregnancy.
 The syndrome is not necessarily reversible nor is it only limited to the
white matter.
PRES Imaging
 Typically symmetric vasogenic edema in the cortical and subcortical
regions typically in the parietooccipital lobes.
 Can also involve basal ganglia, pons, and cerebellum.
 Can be asymmetric.
 Variable contrast enhancement.
 Imaging improvement lags behind clinical improvement when
offending agent is removed.
Case of
Cisplatin
Induced PRES
60 year old female
with leukemia
undergoing
chemotherapy
presents with acute
change in vision.
FLAIR imaging at two different levels show signal abnormality in
the bilateral parieto-occipital region and centrum semiovale.
Major mimickers with parietooccipital distribution are venous
infarct, infectious encephalitis, and seizures, and if unilateral, acute
infarct.
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTL4 antibody therapy in cancer
Epidural Lipomatosis and Exogenous Steroids
 Not a rare condition.
 Radiographic diagnosis.
 Excess deposition of normal adipose tissue in the epidural space.
 Severe compression of the thecal sac can result in a ‘Y’ shape.
 Patients can be symptomatic ranging from low back pain to lower
extremity numbness to intermittent claudication.
Case of
Epidural
Lipomatosis
from Steroid
19 year old male who was
put on chronic steroid
treatment for his dural
based, pathology proven
histiocytosis from Rosai
Dorfman’s (right image)
with imaging of his lower
lumbar spine showing
steroid induced fat
deposition and Y shaped
configuration of the thecal
sac (left image).
T2
Post T1
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Immune Reconstitution Inflammatory
Syndrome (IRIS) with HAART in HIV patient
 Knowledge of IRIS is important particularly when HIV patients have
been initiated on HAART due to impact on morbidity and mortality.
 It can occur in any organ in the body, i.e. lymph node, lung, or liver but
involves the CNS with a 0.9 to 1.5% incident.
 IRIS has been associated with multiple sclerosis patients on immune
therapy.
Pathogenesis of IRIS
 Not very well understood.
 Occurs as a response to dead or dying organism from opportunistic
infection, untreated or nonresponsive infection or self antigen.
 Innumerable risk factors.
 Once patients have been put on HAART, a more powerful immune
response is triggered, which may not be a normal immune system that
is reconstituted with increase in CD4 count and decrease in HIV-1 RNA
levels.
 This reconstitution leads to a paradoxical worsening of patient’s
symptoms or onset of new symptoms.
 Time interval: Weeks to months; rarely years.
Diagnosis of CNS-IRIS
Though this is a diagnosis of exclusion, there are some
clues.
Imaging findings:
New area(s) of signal abnormality
Contrast enhancement and restricted diffusion.
Imaging features that are not the same as the offending
opportunistic infection
Can be PML, TB, meningitis
Laboratory test showing nonviable organism
Case of
CNS-IRIS
37 year old female with
AIDS (CD4 count 28
and viral load <20)
admitted for altered
mental status with
toxoplasmosis and
possible CMV
encephalitis was started
on HAART therapy.
Pre HAART
MRI a year
before with
toxoplasmosis
lesion in left
superior
parietal
lobule.
FLAIR
MRI after
HAART initiated
shows new
areas of signal
abnormality with
subtle
enhancement
(not shown).
Case of
CNS-IRIS
37 year old female
with AIDS (CD4 count
28 and viral load <20)
admitted for altered
mental status, where
clinical picture and
imaging confirmed
diagnosis of IRIS.
MRI after
HAART showing
new areas of
FLAIR signal
abnormality with
subtle
enhancement
(not shown).
.
MRI after
cessation of
HAART with
improvement in
areas of FLAIR
signal
abnormality,
which
confirmed the
diagnosis.
FLAIR
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Progressive Multifocal Leukoencephalopathy
due to Natalizumab in Multiple Sclerosis
 Current disease modifying therapies in multiple sclerosis (MS) are focused on
modulating and suppressing the immune system.
 Natalizumab is the first monoclonal antibody against alpha-4-integrin used in
relapsing MS.
 A well known side effect which occurred during phase III trials of the drug is
progressive multifocal leukoencephalopathy (PML).
 PML due to Natalizumab therapy is an opportunistic infection of the CNS with
reactivation and replication of the John Cunningham virus (JCV).
 Though PML not from Natalizumab can also be caused by BK or SV40 viruses.
 A risk-benefit stratification is used to place patients on the drug.
 Patient’s serum anti JCV antibody titers are followed closely before initiation and
during treatment.
Diagnosis of Natalizumab associated
Progressive Multifocal Leukoencephalopathy
 Diagnosis of PML:
 Clinical
 Imaging
 Detection of the virus in CSF using PCR
Imaging:
Large T1 hypointense and T2/FLAIR signal abnormality without mass effect in the
subcortical and juxtacortical white matter early on with progressive involvement of
the cortical gray matter.
Involves frontal and parietooccipital lobes more commonly.
Gray matter structures such as basal ganglia can be involved.
Contrast enhancement--punctate.
DWI hyperintensity—either true restriction or shine through.
FLAIR
T1 Post
Case of
Nataluzimab
associated
PML
40 year old female with
multiple sclerosis on
Nataluzimab presents to
ED with sudden onset
headaches and altered
mentation.
FLAIR signal abnormality in the left temporal cortical,
juxtacortical and subcortical white matter (left image) and
punctate enhancement (right image). DWI (not shown) was
hyperintense from T2 shine through. Final diagnosis was
made with CSF PCR for JC virus.
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Antitumor Necrosis Factor Therapy
 Used in inflammatory bowel disease and arthritides.
 Binds soluble or transmembrane TNFα leading to decreased inflammation.
 Most common side effect: Development or exacerbation of CNS demyelination or multiple
sclerosis.
 Demyelinating peripheral neuropathies
 Guillain-Barre syndrome
 Miller Fisher syndrome
 Chronic inflammatory demyelinating polyradiculoneuritis-like neuropathy
 Multifocal motor neuropathy
 Lewis-Sumner syndrome.
 Small fiber sensory neuropathy
Case of
Adalimumab
Induced
Demyelinating
Disease
66 year-old female with
Crohn's disease
complains of new onset of
headaches while on
Adalimumab for Crohn’srelated symptoms;
MRI ordered for evaluation
of demyelinating process.
Top row: Signal
abnormality (left
image) and
enhancing lesion
(right image) in the
left anterior
thalamus. The
homogenous
enhancement and
lack of restricted
diffusion excluded
acute infarct as a
possible differential.
Bottom row: Repeat
MRI 3 months after
cessation of
Adalimumab with
resolution of
enhancement and
residual T2 lesion in
the left anterior
thalamus.
FLAIR
T1 Post
T2
T1 Post
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in in cancer
Pseudoprogression with Radiation Therapy of
Glioblastoma Multiforme (GBM)
Pseudoprogression: Subacute treatment related local tissue reaction with
or without clinical deterioration.
 This phenomenon influences management of the patients, i.e. to keep
patients going on adjuvant chemotherapy or to change to a second line
therapy for recurrence.
 Imaging:
New or increased areas of enhancement induced by pronounced local
tissue reaction with an inflammatory component, edema, and abnormal
vessel permeability.
Advanced imaging can help in diagnosis.
Case of
Pseudoprogression
from Radiation
Therapy
45 year-old male with
pathology proven right
temporal glioblastoma
multiforme with
resection in December
2011 and
chemoradiation from
January to March 2012.
Top left : Surgical
resection cavity with
peripheral
enhancement.
Top right: Increased
peripheral
enhancement with
nodular
enhancement in the
right hippocampal
region.
Bottom left:
Decreasing size of
the area of
peripheral
enhancement.
Bottom right:
Further decrease in
size of the resection
cavity and
associated
enhancement.
December 2011
May 2012
September 2012
January 2013
Pseudoresponse with Bevacizumab in
GBM
 Bevacizumab, a monoclonal immunoglobulin G which binds to vascular
endothelial growth factor of tumor and prevents proliferation of endothelial
cells and formation of new blood vessels.
Changes to the abnormal morphology and organization of tumor
vasculature results in decrease tumor interstitial pressure and efficient
transport of oxygen and therapeutic drugs to the tumor.
 On imaging Bevacizumab results in:
Decreased enhancement
With a small percentage of patients show enlargement of the
nonenhancing T2/ FLAIR region
Case of
Pseudoresponse
from
Bevacizumab
45 year-old male with pathology
proven right frontal glioblastoma
multiforme with partial resection in
April 2013 and chemoradiation
from May to July 2013. Imaging in
August 2014 (top row) showing
areas of abnormal enhancement
and corresponding FLAIR and DWI
signal abnormality. December
2014 (bottom row) demonstrates
decreased enhancement with
increased signal abnormality on
FLAIR and DWI.
Post T1
FLAIR
DWI
Post therapy related disorders
I.
Tissue plasminogen activator in stroke treatment
II.
Cerebral and CT angiography contrast
III. Phenytoin and seizure treatment
IV. Posterior reversible encephalopathy syndrome
V.
Long term corticosteroid use
VI. Highly active antiretroviral therapy in AIDS/ HIV
VII. Natalizumab in treatment of multiple sclerosis
VIII. Anti tumor necrosis factor therapy in arthritides and inflammatory bowel disease
IX. Radiation and chemotherapy in glioblastoma multiforme
X.
Anti-CTLA4 antibody therapy in cancer
Anti-CTLA4 Antibody Therapy in Cancer
 Main aim of many antitumor agents is to enhance antitumor immune
responses and to overcome tumor tolerance.
 Monoclonal antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) has
proven to improve care.
 Approved for use in metastatic melanoma.
 Adverse effects of the medication are related to the enhanced immune
response with patients manifesting clinical signs and with very few patients
also demonstrating affects on imaging.
 Most common side effect are dermatitis (47-68%) followed by colitis (44%).
 Less commonly: uveitis, hepatitis, thyroiditis and hypophisitis (1-6%).
Imaging findings of CTLA-4 Induced
Hypophisitis
 Similar to sporadic lymphocytic hypophisitis, which occurs primarily in
women during late pregnancy and postpartum period.
 On MRI there is marked enlargement and ill defined areas of internal
hypoenhancement.
 In patients who manifest both clinically and radiographically, the
clinical improvement lags far behind imaging improvement with
treatment of hypophisitis.
 Radiologists need to be aware of these imaging findings as patients
may not manifest clinical symptoms/signs.
Case of AntiCTLA-4
induced
hypophisitis
57 year old male with
prostate carcinoma being
treated with one dose of
leuprorelin and two doses of
ipilimumab followed by
prostatectomy. He developed
panyhypopituitarism and was
placed on hormone
replacement therapy.
Top row: After
antiCLA-4
/ipilimumab
therapy where
the pituitary
gland and
infundibulum
are enlarged
and
hetergenous.
Post T1
Bottom row:
MRI one year
later with
resolution of
imaging
findings. No
recovery of
pituitary adrenal
axis with
continued
secondary
hypothyroidism.
Case courtesy of Dr. Linda Chi
Conclusion
A working knowledge of both the clinical management of the patient and
treatment induced imaging abnormalities is essential in the accurate
interpretation and diagnosis from the most routine to most challenging of
clinical situations.
We provide a template for the general radiologist and subspecialist to
employ in order to provide value to our clinical colleagues and more
importantly, patients.
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