Imaging Spectrum of Post Therapy Related Disorders: A primer for the Neuroradiologist PETER FATA MD,...

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 therapy-related 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 disordersI. 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








VIII. Anti tumor necrosis factor therapy in arthridites and inflammatory bowel disease



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.

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.

T2 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).


II. Cerebral or CT angiography contrast









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 pre-existing 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.


II. Cerebral or CT angiography contrast









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 parieto-occipital calvarial

thickening (right image). Consider other etiologies of atrophy as differential: aging brain, alcohol encephalopathy, lithium intoxication, radiation changes, hereditary, and multisystem atrophy.










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.

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.

Posterior Reversible Encephalopathy Syndrome

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

PRES60 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.










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 Steroid19 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

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 IRISNot 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-IRISThough this is a diagnosis of exclusion, there are some clues.Imaging findings: New area(s) of signal abnormalityContrast enhancement and restricted diffusion.Imaging features that are not the same as the offending opportunistic infection

Can be PML, TB, meningitisLaboratory 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.

MRI after HAART initiated shows new areas of signal abnormality with subtle enhancement (not shown).

FLAIR

Case of CNS-IRIS37 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

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.

Case of Nataluzimab associated

PML40 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.

FLAIR T1 Post

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’s-

related 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.

T2

FLAIR T1 Post

T1 Post










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 enhancementWith 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

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 Anti-CTLA-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.

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

Post T1

ConclusionA 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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Imaging Spectrum of Post Therapy Related Disorders: A primer for the Neuroradiologist PETER FATA MD,...

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Transcript of Imaging Spectrum of Post Therapy Related Disorders: A primer for the Neuroradiologist PETER FATA MD,...