Download 1. unintended adverse effects of therapeutic agents

eEdE-04
This is your brain, on drugs.
Path
T1
T2 FLAIR
T2 fat sat
Justin Brucker, MD ([email protected])
Tabassum Kennedy, MD
Aaron Field, MD
University of Wisconsin, Madison
3D
INTRODUCTION: “There’s more than one way to fry an egg.”
In keeping with modern medical practices, there is an increasing trend to rely heavily
upon neuroimaging as the primary diagnostic tool -- especially when clinicians are faced
with a patient that is either medically complex, or presenting with nonspecific
neurologic findings (e.g. “altered mental status”).
Many of these patients have a history of long term pharmaceutical and/or nonpharmaceutical drug use, which may further complicate interpretation of their scans.
This purpose of this exhibit is to showcase the wide range
neuroradiologic manifestations that arise from the use of various
chemical agents, with emphasis on salient imaging and clinical features.
We divide our cases into 3 general categories:
1. Unintended adverse effects of therapeutic agents (over-dosage and regular use)
2. Known side effects of chemotoxic agents (i.e. chemotherapy)
3. Known consequences of non-pharmaceutical agents (illicit drugs and poisons)
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1. UNINTENDED ADVERSE EFFECTS OF THERAPEUTIC AGENTS
Propofol
Gadolinium
Levetiracetam
Hyperoxygenation
Hypervitaminosis
Osmotic Myelinolysis
Hyperinsulinemia
Metronidazole
IRIS
Temozolomide
Phenytoin
Bevacizumab
2. CHEMOTHERAPEUTIC SIDE EFFECTS
Ipilimumab
Pazopanib
Methotrexate
Cyclosporin
Cyclophosphamide
Capecitabine
Tacrolimus
3. ILLICIT/RECREATIONAL DRUGS & POISONS
Cocaine
Heroin
Oxycontin
Benzodiazepine
Delayed Reversible Hypoxic Leukoencephalopathy
Marchifava-Bignami Disease
Ethylene Glycol
Carbon Monoxide
1. UNINTENDED ADVERSE EFFECTS OF THERAPEUTIC AGENTS
In this section, we visit the imaging findings associated with
the use of various pharmaceutical agents.
In some cases, imaging abnormalities are secondary to
overutilization or overdosage, although signal abnormalities
can also be encountered with normal intended use.
These findings have to potential to mimic or mask pathologic
conditions, or to denote true drug-related CNS toxicity.
Propofol
T2 FLAIR
Presentation
There is loss of CSF nullification on T2
FLAIR-weighted imaging is noted along the
cerebral sulci (), interpeduncular cistern
(), and cisterna magna ().
Bottom Images:
These findings have resolved on the shortterm interval follow-up study.
T2 FLAIR
1 week later
Top Images: Imaging obtained with
patient on a propofol drip.
The therapeutic and imaging mechanisms of
propofol are not completely understood, but
may involve potentiation of GABAergic
chloride channels and blockage of voltagegated sodium channels.
It is a lipophilic anesthetic/hypnotic agent
that can cross the blood-brain barrier, often
used as a sedative for short-term procedures.
Intrinsically fast longitudinal (T1) recovery,
increased membrane permeability, increased
cerebral vascularity, and protein interactions
have all been proposed as possible causes of
propofol-related CSF signal changes on T2
FLAIR weighted imaging.
Retained Gadolinium
History: Noncontrast head MRI performed 1-day after contrast-enhanced cardiac MRI in an elderly
patient with chronic renal insufficiency.
T2 FLAIR
Confluent areas of marked T2 FLAIR enhancement of the CSF along the cerebral convexities ().
Subtle foci of T1-hyperintensity are noted along the leptomeningeal margins (), compatible with retained gadolinium-based contrast.
Gadolinium-based contrast agents (GBCAs) are paramagnetic; gadolinium has 7 unpaired electrons, which induce a
relatively large magnetic moment that is several hundred times stronger than a proton’s, when exposed to a strong
magnetic field (B0).
GBCAs shorten the T1 and T2 relaxivities of surrounding protons via electron-dipole interactions, thereby hastening
spin-lattice and spin-spin energy exchanges.
Shorter T1 relaxation times means faster longitudinal relaxation (T1 hyperintensity), as well as faster inversion
recovery; CSF will not appear nullified on T2 FLAIR imaging that is obtained with a standard inversion time (TI).
T1
Hyperoxygenation
T2 FLAIR
case courtesy of Mark Tierney
Stippled and linear areas of T2 FLAIR signal intensity is noted along the cerebral convexities (), denoting impaired CSF nullification.
Exuberant administration of supplemental oxygen (as with this patient who inadvertently received 100% FiO2)
results in a larger percentage of soluble molecular O2 within the blood pool, as opposed to hemoglobin-bound.
Molecular O2 is paramagnetic and therefore results in T1 and T2 shortening effects -- similar to gadolinium and
[theoretically] propofol – however, stippled hyperintensity that stays close to the pial margins is more typical for
hyperoxygenation effects on T2 FLAIR. The differential includes leptomeningeal carcinomatosis and infection.
Long term effects of prolonged hyperoxygenation (FiO2 > 50%) include direct cytotoxic injury to neurons, retina,
and alveoli, secondary to the presence of oxygen reactive species and free radical cascades.
Central Pontine Osmotic Myelinolysis
History: 50-year-old intoxicated male who initially presented with hyponatremia, now with spastic
quadriparesis and poor neurologic response, status post administration of intravenous fluids.
T2 FLAIR
T2
DWI
ADC
Confluent areas of T2 and T2 FLAIR hyperintensity with associated restricted diffusion throughout the central pons (), with relative
sparing of the peripheral fibers and pyramidal tracts ().
Osmotic myelinolysis is a dreaded consequence of overly rapid correction of low serum sodium levels.
In patients who has adjusted to a chronically hyponatremic state, introduction of relatively hypertonic extracellular
environment creates a severe intracellular-extracellular osmotic gradient. Water is forcibly pulled out of the cells
(oligodendrocytes are preferentially affected), resulting in membrane lysis, vacuolization, and demyelination.
Extrapontine osmotic myelinolysis can also accur, sparing the pons, but affecting the basal ganglia, corpus callosum
and descending corticoscpinal tracts.
Hyperinsulinemia/Hypoglycemia
T1
case courtesy of Howard Rowley
T2 FLAIR
Multiplanar, multisequence images demonstrated areas of intrinsic T1
and T2 FLAIR hyperintensity throughout the basal ganglia (),
retrolenticular internal capsules (), subthalamic nuclei (), and
hippocampal formations ().
Profound hypoglycemia can be encountered in the setting of
overadministration of exogenous insulin and sulfonylureas
(Metformin), or occasionally in the setting of insulinoma.
Although marked T2 hyperintensity of the basal ganglia is wellassociated with hypoglycemia, this is an unusual case with
associated T1 hyperintensity, possibly reflecting superimposed
anoxic injury and/or early necrosis.
Hypervitaminosis
T2*
T2
T2*
DWI
2015
2011
T2
Susceptiility-related hypointensity noted
throughout the lentiform nuclei (top images;
), in this patient taking large quantities of
multivitamin with mineral supplement. After
cessation of multivitamin use, the findings have
intervally normalized (bottom images).
Multivitamins and other nutritional
supplements often contain larger-thanneeded quantities of fat soluble
vitamins (A, D, E, & K) and minerals,
which have a tendency to accumulate
within the body over time with heavy
usage.
Eat vegetables, instead.
Metronidazole Induced Encephalopathy (1/3)
History: New onset encephalopathy in patient being treated for Clostridium difficile colitis.
T2 FLAIR
DWI
ADC
T2 FLAIR
splenium
Focal T2 FLAIR hyperintensity is noted within
the dentate nuclei, inferior colliculi, and
splenium (as labeled).
inferior colliculi
dentate nuclei
Of note, there is restricted diffusion within the
splenial lesion, which raises concern of an
additional component of cytotoxic edema.
Metronidazole Induced Encephalopathy (2/3)
T2 FLAIR
centromedian thalamic nuclei
red nuclei
History: Encephalopathy and
seizures in a patient being treated
for severe acute bacterial sinusitis.
Left Side and Top Right Images:
Although the splenium is spared, there
is notable involvement of the
centromedian thalamic nuclei (), red
nuclei (), inferior colliculi (), and
dentate nuclei ().
These findings were resolved after
cessation of metronidazole, and
supplemtation of thiramine and folate
(Bottom Right Image).
inferior colliculi
T2 FLAIR
Before
Metronidazole (Flagyl) is a mainstay
antibiotic for the treatment of
obligate anaerobic bacterial
infections.
These microbes reduce the
metronidazole into its active form via
the pyruvate:ferredoxin oxioreductase
pathway.
dentate nuclei
This active form then covalently binds
to the microbial DNA and
subsequently inhibits DNA synthesis.
After (1 month)
Metronidazole Induced Encephalopathy (3/3)
The pathophysiology of Flagyl-related neurotoxicity are not completely
understood.
The Guillan-Mollaret Triangle
However, multiple mechanisms have been proposed, such as: binding
of nucleic acid moeities, axonal and Purkinje cell swelling, and
interference of GABA-receptor binding.
These effects are typically reversible upon cessation of the drug and
supplementation with thiamine and folate.
Wernicke’s encephalopathy can be a radiologic and clinical mimic of
metronidazole induced encephalopathy, especially when one considers
that the toxic effects of metronidazole are potentiated by liver disease
and alcohol consumption.
red
nucleus
1.
inferior
olive
2.
The Guillain-Mollaret Triangle can be affected by metronidazole toxicity:
Also known as the dentato-rubro-olivary triangle, it is comprised of a set of efferent
pathways connecting the:
1. Dentate nucleus  contralateral red nucleus, via superior cerebellar peduncle
fibers.
3.
2. Red nucleus  ipsilateral inferior olive, via the central tegmental tract.
3. Inferior olive  contralateral dentate nucleus, via inferior cerebellar peduncle
fibers.
Involvement of the first 2 arms of the triangle can lead to hypertrophic olivary
degeneration, with symptoms including ataxia and palatal myoclonus.
Levetiracetam Toxicity
History: Altered mental status in an inpatient being treated with Keppra for worsening seizures.
T2 FLAIR
DWI
ADC
Small irregular focus of T2 FLAIR hyperintensity within the splenium of the corpus callosum (), with subtle restricted diffusion ().
Signal abnormalities within the splenium of the corpus callosum is encountered in a wide variety of toxic, metabolic,
and other inflammatory CNS conditions.
The differential includes metronidazole toxicity, antiepileptic drug overdose, extrapontine myelinolysis, viral
infections, multiple sclerosis and ADEM, Marchifava-Bignami disease, and hypoglycemia.
Phenytoin
T1
T2 FLAIR
case courtesy of Lindell Gentry
CT
Multiplanar, multisequence demonstrate marked diffuse atrophy of the cerebellar hemispheres and
vermis ().
There is also marked hyperostosis of the calvarium evident on T1 weighted and CT imaging ().
Phenytoin (Dilantin) mediates blockage of voltage-gated sodium channels.
Even at therapeutic doses, chronic usage is associated with cerebellar atrophy, as well as
a wide range of other systemic manifestations (hyperostosis and osteopenia, gingival
hypertrophy, hypertrichosis, anemia, and drug-induced lupus.
Immune Reconstitution Inflammatory Syndrome
History: 49-year-old female with history of HIV.
T2 FLAIR
T1+C
Multiplanar T2 FLAIR weighted images demonstrate asymmetric confluent areas of hyperintense signal change throughout the
bifrontal white amtter ().
There is an associated cavitary lesion within the left frontal lobe, with small amount of peripheral nodular enhancement ().
• T cell mediated encephalitis occurs in the setting of HIV/autoimmune disease
• Occurs when restored immunity causes an exaggerated immune response to infectious/non infectious antigens
• Low CD4 count (<50 cells/μL) is a risk factor
Unmasking IRIS:
• Antiretrovirals Rx unmask a subclinical undiagnosed opportunistic infection. Tissue damage by pathogen
and immune response.
Paradoxical IRIS:
• Patient deteriorates despite successful treatment of opportunistic infection. Tissue damage by immune
response to antigens
Temozolomide & Glioma Pseudoprogression
History of high-grade glioma, status post chemoradiation therapy.
T2 FLAIR
T1+C
CBV
case courtesy of Howard Rowley
There is a large area of confluent T2 FLAIR hyperintensity throughout the right frontal white matter (), surrounding a T2
hypointense mass lesion () that demonstrates marked peripheral enhancement (). These findings were noted to be
increased from prior imaging (not shown) and therefore initially concerning for tumor progression. However, corresponding
cerebral blood volume (CBV) map demonstrates the lesion to be non-hyperemic ().
Temozolomide is a purine-methylating agent, which adds a methyl group to guanine and adenine derived bases,
thereby inhibiting DNA synthesis. Its action is counteracted by the enzyme methylguanine methyltransferase (MGMT),
but this enzyme can in turn be inhibited by methylation (“MGMT-methylated tumor status”).
Pseudoprogression mimics apparent increased size and enhancement of the tumor bed, but can actually denote a
more favorable prognosis. It is more common in MGMT-methylated tumors, usually 1-3 months after chemoradiation
therapy that utilizes temozolomide. Decreased CBV is an important distinguishing feature of pseudoprogression.
Bevacizumab and Pseudoresponse vs. Pseudoinfarction
Baseline
History of high-grade glioma, with recent evidence of progression
Initial baseline images
demonstrate enhancing tumor
within the posterior right
subinsular white matter (),
although with intermediate
diffusion characteristics on
DWI/ADC ().
T1+C
DWI
ADC
case courtesy of Howard Rowley
After Treatment
T1+C
DWI
On follow-up imaging – after
initiation of Avastin -- there
appears to be decreased
enhancement (), but there is
markedly increased restricted
diffusion in the tumor bed ().
Bevacizumab (Avastin) is an
anti-VEGF-A (vascular
endothelial growth factor A)
monoclonal antibody that
intercepts the protein before it
can bind to the VEGF-receptor.
ADC
This results in decreased
angiogenesis and vascularity,
which can reduce the
apparent size and
enhancement of a tumor.
Avastin Related Hypoenhancement
History: 40-year-old female with widely metastatic ovarian cancer.
T2
T2 FLAIR
T1+C
Large metastatic mass lesion centered in the left basal ganglia with intermediate T2 () and T2 FLAIR signal intensity (). There is
notable absence of perilesional vasogenic edema, as well as little to no postcontrast enhancement (), which are considered out of
proportion to the size of the mass.
Bevacizumab is utilized in the treatment of various malignancies, including ovarian cancer, lung cancer, renal cancer,
breast cancer, and colorectal cancer.
Poor tumoral enhancement while on Avastin should be interpreted with caution, as actual progression can be masked.
2. CHEMOTHERAPEUTIC SIDE EFFECTS
Chemopharmaceuticals are often toxic by nature, intended to
inhibit cellular growth and division in highly proliferative
tissues, or significantly alter the patient’s immune system.
Although side effects related to chemotherapy are not
intended, they are not unexpected.
The CNS imaging features of various chemotoxic agents often
overlap, although several medications are associated with
more specific radiologic findings.
Ipilimumab Hypophysitis
History: 65-year-old female with history of metastatic melanoma.
At presentation
2 months later
T1
T1+C
T2 FLAIR
Top images: Mass-like enlargement and peripheral enhancement of the pituitary gland and stalk () are noted at presentation.
Bottom Images: Findings show marked improvement (), 2 months after cessation of ipilimumab.
Ipilimumab is a monoclonal antibody that binds to cytotoxic T-lymphocyte antigen 4 (CTLA-4), thereby inhibiting the
immunosuppressive effects of CTLA-4 . Unfortunately, CTLA-4 is also present in normal pituitary tissue, allowing for
immune-mediated cross-reactivity.
The imaging and clinical features can mimic pituitary apoplexy, metastatic disease, or other forms of hypophysitis.
Treatment often involves hormonal replacement and cessation of Ipilimumab.
Methotrexate Toxicity (Case #1)
DWI
T2 FLAIR
ADC
Multifocal areas of patchy T2 FLAIR hyperintensity and restricted diffusion are scattered throughout the periatrial and
biparietal white matter () as well as the splenium of the corpus callosum ().
Methotrexate is a competitive inhibitor of dihydrofolate reductase, effectively blocking the pathway for
conversion of folate into nucleic acid precursors. It is often used in the treatment of lymphoma and leukemia.
Methotrexate Toxicity (Case #2)
An example of intrathecal
methotrexate use for the
treatment of acute
lymphoblastic leukemia.
T2
DWI
ADC
Focal T2 hyperintense signal changes and restricted diffusion are noted within the lateral
margin of the right centum semiovale () and splenium of the corpus callosum ().
Signal abnormalities within the
centrum semiovale and
splenium are often reported,
and can be rather transitory and
migratory; short term interval
follow-up often demonstrates
interval resolution or
redistribution of signal
abnormalities to different
portions of the cerebral white
matter.
Methotrexate Toxicity (Case #3)
T2 FLAIR
Large, symmetric, confluent T2 FLAIR hyperintense signal changes are seen throughout the majority of the cerebral white
matter (), with relative sparing of the subcortical U-fibers, and notable involvement of the internal capsules.
More extensive white matter toxicity related to methotrexate use have been reported with an intrathecal
route of delivery, younger age at the time of therapy, and combination with radiation therapy.
The neurotoxicity effects can have delayed onset, as with this patient who presented with confusion and
seizures several weeks after treatment.
Cyclophosphamide
History: Long-term followup in a patient previously
treated for lymphoma.
Multiplanar T2 FLAIR images
demonstrate symmetric patchy areas
of hyperintense signal change within
the bilateral periatrial white matter
(), with indistinct borders that spare
the subcortical U-fibers.
T2 FLAIR
Cyclophosphamide is an alkylating
agent that specifically alkylates
guanine, thereby interference with
DNA synthesis.
It is used in the treatment of
various malignancies, including
lymphoma, leukemia, and several
primary CNS neoplasms.
Capecitabine
T2 FLAIR
T1+C
Diffuse smooth pachymeningeal thickening is noted throughout the dural convexities on T2 FLAIR () and
postcontrast T1-weighted () imaging, in this patient with confusion and lethargy, being treated for intestinal cancer.
Capecitabine is the oral prodrug of 5-fluorouracil (5FU), which undergoes a 3-step enzymatic conversion to its active
form. The third step is catalyzed by thymidine phosphorylase, which is present in tumoral tissues and normal
hepatocytes. Detoxification of 5FU is mediated by dihydropyrimidine dehydrogenase, which is absent in 2-4% of the
patient population; the toxic effects of capecitabine are therefore potentiated in these individuals.
In addition to white matter T2 FLAIR changes similar to methotrexate toxicity, idiopathic intracranial hypotension
with associated dural thickening has been reported with capecitabine toxicity.
Pazopanib -- Posterior Reversible Encephalopathy Syndrome
History: Altered mental status in a patient being treated for renal cell carcinoma.
Top Images: Multifocal areas
of cortical and subcortical T2
FLAIR hyperintensity (),
scattered along the posterior
cerebral margins.
Presentation
Bottom Images: Findings
have resolved on short-term
interval follow-up, after
cessation of pazopanib
T2 FLAIR
Pazopanib is a tyrosine
kinase inhibitor that
has multiple molecular
targets (including
VEGF-R), resulting in
inhibition of tumor
growth and
angiogenesis.
1 month later
It is used in the
treatment of renal cell
carcinoma and various
sarcomas.
T2 FLAIR
Cyclosporine Induced PRES
History: Status post renal transplant, now with seizures and confusion
T2
T2 FLAIR
Asymmetric areas of slightly expansile T2 and T2 FLAIR hyperintensity coursing along the parieto-occipital
white matter and cortical ribbon (), consistent with PRES.
Cyclosporine is a cyclic peptide that inhibits T-cell growth and interleukin-2 transcription via a complex set of
interactions with the calcineurin-mediated signaling pathway. It is used as an immunosuppressive agent in the
setting of organ transplantation. It has been reported with wide variety of systemic side effects, including PRES,
presumably by disrupted autoregulation of cerebrovascular tone.
Tacrolimus Induced PRES (Case #1)
1 month later
Presentation
T2 FLAIR
T2 FLAIR
Asymmetric areas of slightly expansile T2 and T2 FLAIR hyperintensity coursing along the parieto-occipital white matter and cortical
ribbon (), that resolved on follow-up imaging (right most image), consistent with PRES.
Tacrolimus (Prograf) is a macrolide lactone inhibitor of the calcineruin signaling pathway in T-cell
lymphocytes, resulting in decreased IL-2 transcription and lowered T-cell activity.
It has been associated with PRES, electrolyte/metabolic derangement, hypertension, nephrotoxicity, liver
disease, skin disorders, and non-Hodgkins lymphoma.
In immunosuppressed patients, the differential includes viral infection, progressive multifocal
leukoencephalopathy, and acute disseminated encephalomyelitis.
Tacrolimus Induced PRES (Case #2)
Before
T2
After
T2
Patchy areas of T2 hyperintense signal are noted throughout the central pontine belly and pontine tegmentum
(), which resolves on follow-up imaging (right image) after correction of hypertension was achieved.
Posterior reversible encephalopathy syndrome (a.k.a. reversible posterior leukoencephalopathy
syndrome) has a predilection for the posterior cerebral white matter, but can also involve the
cortical ribbon, basal nuclei, and brainstem. Patchy postcontrast enhancement can also be an
associated finding.
3. ILLICIT/RECREATIONAL DRUGS & POISONS
In our last section, we will visit the imaging findings associated
with recreational drug use, alcohol consumption, and
exposure to non-pharmacologic toxins.
Unfortunately, many of these uncontrolled substances are
highly addictive, inconsistently prepared, and/or contain toxic
additives – this can worsen clinical outcomes and confound
the radiologic presentation.
Cocaine Induced PRES
Symmetric areas of expansile confluent
T2 hyperintensity are noted throughout
the bilateral peri-Rolandic white matter
().
There is associated T2 FLAIR
hyperintensity that involves the
overlying cortical ribbon (), as well as
robust postcontrast enhancement ().
T2
Cocaine is a highly addictive
tropane alkyloid derived from the
coca plant.
T2 FLAIR
T1+C
In the CNS, it acts primarily as a
potent sympathomimetic, by
inhibiting reuptake of synaptic
serotonin, dopamine, and
catecholamines.
It can lead to severe hypertension
and tachycardia, as well as
vasospasm and prothrombotic
effects throughout the
cerebrovascular system.
More Cocaine, with Hemorrhage and Aneurysm
CT
Spontaneous intraparenchymal hematoma
with peri-hemorrhagic edema (), in this
patient with cocaine induced hypertension.
TOF MRA
3D time-of-flight MRA acquisition demonstrates a large
aneurysm projecting posterolaterally off of the proximal
left cavernous internal carotid artery ().
Consequences of cocaine intake include intracranial hemorrhage, stroke, aneurysm formation,
moyamoya, vasculitis, and chronic cerebral atrophy.
Inhalational Heroin Leukoencephalopathy
History: Found down, after “chasing the dragon.”
T2 FLAIR
T2
DWI
Patchy, symmetric areas of T2 hyperintensity and restricted diffusion
are noted within the posterior centrum semiovale () and splenium
of the corpus callosum ().
Heroin is an extremely addictive recreational opiate, which
exerts its effect by binding μ-opioid receptors throughout
the CNS and cerebrovascular system.
It is usually either injected intravenously, or the vapors are
inhaled as the heroin is heated over metal foil; the heated
heroin adopts a flowing serpiginous appearance, hence
referred to “chasing the dragon.”
ADC
More “Chasing the Dragon”
CT
T2
DWI
ADC
Large areas of confluent expansile edema replacing the near-entirety of the centrum semiovale, with associated restricted diffusion
and relative sparing of the subcortical U-fibers ().
Consequences of heroin use include stroke and cytotoxic edema, secondary to a combination of: vasospasm,
vasculitis, suppressed central respiratory drive, and decreased cardiovascular tone.
Inhalation of heated heroin vapor is suspected to confer additional toxic effect, possibly secondary to the presence
of lipophilic additives and impurities, which may either be used to cut the heroin or the product of the heating
process.
Oxycontin Overdose
T2
CT
T2*
T1
Necrosis of the globus pallidi that is marginated by edema () and postcontrast enhancement
(), with additional edema tracking along the left posterior limb internal capsule ().
Pallidal necrosis is a relatively common consequence of overdose related
brain injury, particularly in cases that are associated with periods of anoxia.
T1+C
Delayed Reversible Hypoxic Leukoencephalopathy
History: Spastic quadriparesis and decreased neurologic response, following
benzodiazepine overdose complicated by episode of PEA arrest several days before.
T2 FLAIR
DWI
ADC
Indistinct, symmetric areas of T2 FLAIR hyperintensity are noted within the periatrial white matter and retrolenticular internal
capsular regions (), with associated restricted diffusion ().
Delayed reversible hypoxic leukoencephalopathy is a clinical entity that is sometimes encountered in cases of
hypoxia/anoxia that is secondary to overdose or other toxic exposure. These patients develop slow-onset clinical
deterioration that is associated with signal abnormalities in the deep white matter tracts, although sparing the cortical
ribbon. These findings can be near-completely reversible over the course of several weeks to months of rehabilitation.
Benzodiazepine and Hypoxia
History: Found down several days after intentional overdose.
T2
T2 FLAIR
DWI
Symmetric areas of cytotoxic edema
are seen throughout the bilateral
globus pallidi (), bifrontal white
matter (), periatrial white matter
(), splenium, and centrum
semiovale ().
ADC
CT
Carbon Monoxide Poisoning
History: Hunter found down in shed next to running propane heater
CT
T2 FLAIR
DWI
case courtesy of Dick Latchaw
Focal necrosis of the globus pallidi () and demyelination of the bilateral periatrial white matter ().
Carbon monoxide covalently binds to hemoglobiin with an affinity that is several hundred times stronger the
oxygen. Saturation of hemoglobin with carbon monoxide therefore leads to severe hypoxic brain injury.
Ethylene Glycol Toxicity
History: Auto mechanic found down in garage.
T2
T2 FLAIR
DWI
ADC
Extensive cerebral edema is noted
throughout the basal ganglia (),
thalami (), brainstem (), and
temporal lobes ().
Ethylene glycol is metabolized by
alcohol dehydrogenase into glycolic
acid, which is subsequently converted
to oxalic acid. This leads to an anion
gap acidosis that results in cerebral
edema and nephrotoxicity.
Alcohol Related Callosal Demyelination
“Marchifava-Bignami disease” is a
demyelinating disorder initially
described in patients who consumed
large quantities of red wine in Italy.
It is associated with chronic
alcoholism.
Acute demyelination of the corpus
callosum is characteristic of the
disease, which may show restricted
diffusion
Up to half of the cases occur in
combination with Wernicke’s
encephalopathy
The treatment is alcohol cessation
and supplementation with thiamine
and folate.
T2 FLAIR
Focal T2 FLAIR hyperintense lesion centered within the splenium of the
corpus callosum (), in this patient with known alcohol abuse.
At Presentation
Marchiafava-Bignami Disease
ADC
T2 FLAIR
T2
After Treatment
DWI
Top Row: Images demonstrate focal restricted diffusion within the splenium of the corpus callosum (), also known as
“the boomerang sign”.
Bottom row: Residual T2-shine through is seen throughout the splenium after initation of treatment (), associated with
improving neurologic findings.
Another Case of Marchiafava-Bignami
At Presentation
T2 FLAIR
DWI
3 weeks later
T2 FLAIR
T1
ADC
Top Row:
Images demonstrate focal
edema within the splenium
(), with associated restricted
diffusion ().
Bottom row:
Interval follow-up
demonstrates central
cavitation of the lesion (),
compatible with necrosis and
peripheral gliotic changes
IN SUMMARY
• CNS imaging abnormalities are associated with the toxic
and therapeutic effects of both pharmaceutical and nonpharmacologic agents.
• The clinical and imaging features of drug toxicity can share
a high degree of overlap.
• In many cases, the imaging and clinical features of CNS
drug toxicity may be reversible if recognized early enough.
REFERENCES
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12.
13.
14.
15.
16.
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20.
21.
22.
Asaithambi G, et al. Posterior Reversible Encephalopathy Syndrome Induced by Pazopanib for Renal Cell Carcinoma. Journal Clinical
Pharmacology and Therapeutics; 28: 175-176, 2013.
Arbelaez A, et al. Acute Marchiafava-Bignami Disease: MR Findings in Two Patients. AJNR Am J Neuroradiol; 24: 1955-1957, Nov/Dec 2003.
Beppu T, et al. Fractional anisotropy in the centrum semiovale as a quantitative indicator of cerebral white matter damage in the subacute phase
in patients with carbon monoxide poisoning: correlation with the concentration of myelin basic protein in cerebrospinal fluid. J Neurol; 259:
1698-1705, 2012.
Bouz P, et al. The Pathophysiological Basis for Hypertrophic Olivary Degeneration (HOD) Following Brainstem Insult. JSM Neurosurg Spine; 1(1):
1004, 2003.
Bozgetik Z, et al. Age-related metabolic changes in the corpus callosum: assessment with MR spectroscopy. Diagn Interv Radiol; 14: 173-176,
2008.
Carpenter KJ, et al. Ipilimumab-Induced Hypophysitis: MR Imaging Findings. AJNR Am J Neuroradiol; 30: 1751-1753, Oct 2009.
Chelis L, et al. Reversible Posterior Leukoencephalopathy Syndrome Induced by Pazopanib. BMC Cancer; 12: 289, 2012.
Fisher MJ, et al. Diffusion-Weighted MR Imaging of Early Methotrexate-Related Neurotoxicity in Children. AJNR Am J Neuroradiol; 26: 16861689, Aug 2005.
Geibprasert S. Addictive Illegal Drugs: Structural Neuroimaging. AJNR Am J Neuroradiol; 31: 803-808, May 2010.
Goyal M, et al. Hypertrophic Olivary Degeneration: Metaanalysis of the Temporal Evolution of MR Findings. AJNR Am J Neuroradiol; 21: 10731077, June/July 2000.
Hygino da Cruz LC, Pseudoprogression and Pseudoresponse: Imaging Challenges in the Assessment of Posttreatment Glioma. AJNR Am J
Neuroradiol; 32 (11): 1978-85, Dec 2011.
Keogh CF, et al. Neuroimaging Features of Heroin Inhalation Toxicity: “Chasing the Dragon.” AJR; 180: 847-850, Mar 2003.
Kim E, et al. MR Imaging of Metronizaole-Induced Encephalopathy: Lesion Distribution and Diffusion-Weighted Imaging Findings. AJNR Am J
Neuroradiol; 28: 1652-1658, Oct 2007.
Kim J, et al. Delayed Encephalopathy of Acute Carbon Monozide Intoxication: Diffusivity of Cerebral White Matter Lesions. AJNR Am J
Neuroradiol; 24: 1592-1597, Sep 2003.
Kim SS, et al. Focal Lesion in the Splenium of the Corpus Callosum in Epileptic Patients: Antiepileptic Drug Toxicity? AJNR Am J Neuroradiol; 20:
125-129, Jan 1999.
Lyros E, et al. Subacute reversible toxic encephalopathy related to treatment with capecitabine: A case report with literature review and
discussion of pathophysiology. NeuroTox; 42: 8-11, 2014.
Molloy S, et al. Reversible Delayed Posthypoxic Leukoencephalopathy. AJNR Am J Neuroradiol; 27: 1763-1765, Sep 2006.
Park MK, et al. Lesions in the splenium of the corpus callosum: Clinical and radiological implications. Neurology Asia; 19(1): 89-88, 2014.
Poen Tan T, et al. Toxic Leukoencephalopathy after Inhalation of Poisoned Heroin: MR Findings. AJNR Am J Neuroradiol; 15: 175-178, Jan 1994.
Storen EC, et al. Moyamoya-like Vasculopathy from Cocaine Dependency. AJNR Am J Neuroradiol; 21: 1008-1010, June/July 2000.
Walko CM, et al. Capecitabine: A Review. J Clin Thera; 27(1): 23-44, Jan 2005.
Yoo SY, et al. White matter abnormalities in drug-naïve patients with obsessive-compulsive disorder: a Diffusion Tensor Study before and after
citalopram treatment. Acta Psychiatr Sand; 116: 211-219, 2007.