Stroke Differential Diagnosis and Mimics
Introduction
An estimated 9% to 30% of patients with suspected stroke and 2.8% to 17% of patients treated with IV-tPA
have stroke mimics. The majority of stroke mimics are due to seizures, migraines, tumors and toxicmetabolic disturbances. Imaging usually facilitates diagnosis, as stroke has typical imaging features at
different stages and follows typical topographic patterns. However, most of these features, even restricted
diffusion (Table 1), are not unique to stroke. In this article we present stroke and its mimics based on 7
main patterns of topographic distribution (Figure 1). Although overlap exists, these patterns are helpful in
narrowing the differential diagnosis.
Figure 1.
Six main patterns of imaging findings in stroke and its mimics. (*) denotes ischemic causes.
Table 1. Causes of decreased diffusion
Failure of Na/K-ATPase
Hypoglycemia, hyperglycemia, ketosis, seizures, transient global amnesia, drug-
(Ischemic and/or excitotoxic induced encephalopathies like metronidazole, methotrexate or vigabatrin,
injury)
necrotizing infections like HSV, Wernicke's encephalopathy
Tissue vacuolization or
Creutzfeldt-Jakob disease, heroin leukoencephalopathy, demyelination and
spongiform changes
dysmyelination, diffuse axonal injury
High protein concentration
or increased viscosity
Dense cell packing
Pyogenic infection, hemorrhage, extracellular methomoglobin, oxyhemoglobin
Neoplasms such as high-grade glioma, lymphoma, small-cell lung cancer
metastases
Imaging Features of Ischemic Stroke at Different Stages
Acute (Less Than 24 Hours)
Computed tomography findings are initially subtle and include a hyperdense vessel, decreased gray-white
matter differentiation, and sulcal effacement. Diffusion weighted imaging is highly accurate and can detect
stroke as early as 15 minutes after onset. The T2/FLAIR hyperintensity takes hours to become apparent.
Subacute (24 Hours to 2 Months)
The CT hypodensity becomes more apparent and ADC values gradually increase and pseudo-normalize
at 4 to 10 days. Gyriform enhancement appears at 6 days and persists for as long as 2–3 months. Edema
peaks in 3–4 days and decreases after 7 days. Hemorrhagic transformation usually occurs 2 to 7 days after
ictus.
Chronic (More Than 2 Months)
This phase is characterized by volume loss, cavitation and gliosis. The gliosis surrounding the cavitation is
hypodense on CT and hyperintense on T2WI and FLAIR. DWI shows variable signal, typically with
increased ADC values.
Distribution Patterns of Ischemic Stroke and Its Mimics
Regional Gray and White Matter
Single Vascular Distribution Stroke
Ischemic infarctions in a single vascular distribution are most often a consequence of emboli arising from
atherosclerotic plaques or dissection of the large craniocervical arteries, most commonly the carotid
bifurcation. These emboli most frequently occlude the middle cerebral arteries or internal carotid terminus,
followed by posterior cerebral arteries, vertebrobasilar system and the anterior cerebral arteries and results
in regional cortical and subcortical pattern of involvement.
Seizures
One-third of stroke mimics are due to seizures or postictal deficits. Sometimes, seizure may cause restricted
diffusion (Figure 2).The distinguishing features are nonvascular distribution, earlier edema and gyral
enhancement, normal or elevated perfusion, absence of vascular occlusion, and sometimes simultaneous
restricted cortical and elevated subcortical diffusion.
Figure 2.
A 66-year-old man with seizures who presented with altered mental status, acute onset aphasia and right
gaze deviation and received IV-tPA for presumed stroke. The right gaze deviation in the setting of a left
sided lesion is suggestive of seizure. His admission MRI showed restricted diffusion (A and B) and edema
(C) in the left parieto-occipital cortex and subcortical white matter. His symptoms and imaging findings (not
shown) were completely resolved by the time of discharge.
Migraine
Migrainous aura and hemiplegic migraine are the cause of 5–10% of stroke mimics and may show restricted
diffusion.The distinguishing factors are a long history of migraines, involvement of multiple arterial territories
and absence of vascular occlusion. Perfusion decreases in acute-onset aura and is normal or elevated in
prolonged episodes.The lesions are usually reversible, but 15% of strokes in patients younger than 45
years of age are due to migraine.
Brain Tumors
A primary brain neoplasm may present with acute neurologic deficits. Occasionally a low-grade glial tumor
with mild mass effect and cortical involvement may be confused with a subacute infarction (Figure 3). It
can, however, be easily differentiated based on nonvascular distribution and lack of significant restricted
diffusion or gyral enhancement. Nevertheless, both subacute infarcts with hemorrhage and high-grade
hemorrhagic gliomas can show areas of restricted diffusion, heterogeneous enhancement and mass effect
that can be indistinguishable.
Figure 3.
A 49-year-old female woke up suddenly and started gurgling. The CT was initially interpreted as an
infarction with left MCA territory hypodensity and a hyperdense left MCA (A), MRI showed a nonenhancing
(B), T2-FLAIR hyperintense (C) expansile lesion with elevated diffusion (D, DWI and E, ADC map). The
biopsy showed an anaplastic oligoastrocytoma.
Herpes Simplex Encephalitis
Herpes simplex is the most common cause of viral encephalitis and presents with a combination of fever,
headache, confusion, seizures and neurologic deficits. It has a predilection for the limbic system (medial
temporal and inferior frontal lobes, insula and cingulate gyri) (Figure 4). DWI is superior to other sequences
for detection and usually shows concurrent areas with decreased and increased diffusivity. Restricted
diffusion is observed in early stages and leads to irreversible neuronal damage. The glutamate excitotoxic
pathway is believed to be the cause of restricted diffusion. Lesions are typically also hyperintense on FLAIR
images and frequently undergo hemorrhagic transformation.
Figure 4.
A 72-year-old man with altered mental status, focal motor status epilepticus in the right tower extremity,
and fever with productive cough. The patient was initially diagnosed with bilateral ACA and MCA infarctions.
Ultimately, he was diagnosed with HSV encephalitis, MRI showed asymmetric multifocal regions of
restricted diffusion (A-D, DWI) associated with T2/FLAIR hyperintensity (not shown) in the bilateral temporal
lobes, frontal lobes, insula, cingulate gyri and thalami.
Hypoglycemia
Hypoglycemia can present with focal neurologic deficits. Restricted diffusion may be seen in the cerebral
cortex (particularly the occipital lobes), corona radiata and centrum semiovale. Involvement of the basal
ganglia, hippocampi, internal capsules and splenium has also been reported. The cerebellum, brain stem
and hypothalamus are usually spared due to more active glucose transport mechanisms. The cause of
diffusion restriction is thought to be energy failure due to lack of glucose, excitotoxic edema, and/or
asymmetric cerebral blood flow.
Transient Global Amnesia (TGA)
TGA is diagnosed by sudden onset of transient antegrade memory loss. The pathogenesis is unclear, but
ischemia, seizures, and migraine have been considered.It typically appears as punctate foci of restricted
diffusion in the hippocampus (Figure 5). In one report, the frequency of positive DWI findings increased
from 5% to 85% when ictus-to-imaging time increased from 8 hours to 48 hours.
Figure 5.
A 51-year-old female presented with confusion, slurred speech and no recall of recent events. The diffusionweighted imaging 4 days after the ictus showed punctate foci of restricted diffusion in bilateral hippocampi
(A & B, DWI and C & D, ADC map). Follow up MRI showed complete resolution of these lesions (not
shown).
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Events)
MELAS presents with nausea, vomiting, seizures, muscle weakness and abrupt neurological deficits,
usually by age 40.MRI shows T2 hyperintensity, swelling and restricted diffusion in the cortex and
subcortical white matter.The distinguishing factors are multifocal lesions in various stages of evolution,
simultaneous areas of restricted and elevated diffusion in acute lesions, nonvascular distribution and a
predilection for the posterior parietal and occipital lobes (Figure 6).
Figure 6.
A 48-year-otd male with two episodes of recent "left PCA territory" infarctions presented with worsening of
prior neurological deficits, new cognitive impairment and confusion. He was found to have MELAS, FLAIR
imaging showed nonvascular distribution of cortical swelling (A, FLAIR) in the left posterior parietotemporal-occipital region with areas of both restricted and increased diffusion (B, DWI and C, ADC map).
Venous Infarctions
Venous thrombosis is uncommon and accounts for 1% of all strokes. It may show normal parenchyma,
lesions characterized by vasogenic edema with elevated diffusion, lesions characterized by cytotoxic
edema with restricted diffusion and/or hemorrhagic lesions, all in a non-arterial distribution. Restricted
diffusion may be reversible, particularly when it is associated with seizures. Dural venous sinus thrombosis
has a cortical and subcortical pattern and thrombosis of the internal veins and straight sinus causes bilateral
thalamic involvement.
Cortical and Deep Gray Matter
Hypoxic-ischemic Encephalopathy
HIE is the result of global hypoxia. The most common causes are cardiac arrest, respiratory failure and
shock. In severe cases, the cortex and deep gray nuclei are affected (Figure 7). In mild cases, a border
zone infarction pattern may be seen. Rarely, a pure white matter pattern may be seen as global ischemia
may induce demyelination. The cerebellum is usually spared.
Figure 7.
A 31-year-old man with a history of heroin and cocaine abuse suffered PEA arrest. MRI demonstrated
diffuse restricted diffusion (A, DWI and B, ADC map) with associated T2-FLAIR hyperintensity (C, FLAIR)
in the bilateral parieto-occipital and frontal lobes as well as the bilateral thalami, most consistent with global
hypoxic injury.
Wernicke's Encephalopathy
Wernicke's encephalopathy occurs in alcoholics and other malnourished patients with thiamine deficiency.
Patients present with altered mental status, memory impairment, ophthalmoplegia or ataxia. Typically, MRI
shows symmetric T2/FLAIR hyperintensity in the mammillary bodies, hypothalami, medial thalami, tectal
plate and periaqueductal area, but the cerebral cortex may also be involved. In early stages, restricted
diffusion can be seen due to cytotoxic edema (Figure 8).
Figure 8.
A 62-year-old woman with 3 months of diplopia and a few days of hearing loss was admitted for dizziness,
nausea, vomiting, nystagmus and anorexia. She was found to have Wernicke's disease due to malnutrition
with a thiamine level of 35 nmol/L (normal 70–180). MRI showed variable diffusion (A, DWI and B, ADC
map) with FLAIR hyperintensity (C) in quadrigeminal plate, periaqueductal gray matter, hypothalamus and
bilateral superior colliculi.
Hepatic Encephalopathy
The typical imaging finding in milder cases is symmetric T1 hyperintensity in globus pallidus. In more severe
cases, MRI may show T2 hyperintensity and restricted diffusion in the cortex (especially the cingulate gyri
and insula), and basal ganglia (Figure 9).The thalami, periventricular white matter and brainstem may also
be involved. Diffuse cortical involvement can be reversible, but is associated with an increased risk of
permanent neurologic sequela. The decrease in ADC values is attributed to the excitotoxic injury and
osmotic disturbance in astrocytes due to ammonia.
Figure 9.
A 53-year-old woman with alcoholic cirrhosis who initially presented to the ED with abdominal pain, nausea,
and hematemesis. A few days later she became unresponsive with absent brainstem reflexes and an
ammonia level of 360. She was diagnosed with hepatic encephalopathy, MRI showed mildly restricted
diffusion (A, DWI and B, ADC map) with FLAIR hyperintensity (C) In the bilateral frontal and insular cortex
and thalami. There was also mild T1 hyperintensity (D) in the lentiform nuclei.
Creutzfeldt-Jakob Disease
Patients present with a rapidly progressive, transmissible and fatal neurodegenerative disease caused by
a misfolded prion protein. DWI is more sensitive than FLAIR or T2WI and is associated with decreased
ADC. In CJD there is symmetric involvement of the basal ganglia and either symmetrical or asymmetrical
involved of the cortex (Figure 10).
Figure 10.
A 48-year-old woman presented with a one-year history of change in mental status, subacute decline in
memory associated with gait disturbance and, more recently, changes in personality. MRI showed restricted
diffusion (A, DWI and B, ADC map) and T2-FLAIR (C) hyper-intensity in the bilateral basal ganglia, thalami
and cortex. The patient was diagnosed with CJD.
Eastern Equine Encephalitis
The agent is a mosquito-borne arbovirus, and presentation ranges from flu-like symptoms, confusion and
somnolence to neurological deficits, seizures and coma. Approximately 5% of infections lead to
encephalitis, 1/3 of patients die, and the survivors are left with significant morbidity. The lesions typically
appear as T2-FLAIR hyperintense lesions in the basal ganglia, thalami and brainstem (Figure 11).Less
commonly cortex and the periventricular white matter are involved.
Figure 11.
A 43-year-old man presented with 2 days of fever, headache and altered mental status that started 2 days
after camping. Admission MRI showed T2 hyperintensity on FLAIR (A) in the bilateral basal gaglia, thalami
and insula and slightly decreased diffusion (B, DWI and C, ADC map), left worse than right. MRI a few days
later showed a more extensive pattern of involvement of basal ganglia and insular cortices (D, FLAIR).
Deep Gray Matter Diffusion Abnormality
Small Vessel Stroke/Penetrating Vessel Stroke
Small vessel strokes comprise 20–25% of all strokes and are located in the distribution of small penetrating
arteries, including the lenticulostriate, anterior choroidal, thalamoperforator, and paramedian basilar artery
branches. These strokes are usually caused by arteriolosclerosis due to hypertension and are typically less
than 15 mm, but a subset are caused by thrombi at the site of arterial occlusion or embolismand cause
infarction in multiple adjacent deep penetrating artery territories.
Carbon Monoxide Poisoning
In mild cases, there is a predilection for symmetric restriction diffusion and T2 hyperintensity in the bilateral
globus pallidi (Figure 12). In more severe cases the remainder of the basal ganglia, thalami, hippocampi,
supratentorial white matter, corpus callosum, and less often the cerebral cortex may be involved. Following
a period of transient clinical improvement, a delayed encephalopathy may occur with bilateral confluent
periventricular white matter T2 hyperintensity and areas of restricted diffusion. Restricted diffusion in the
acute phase is likely secondary to cytotoxic edema. In the delayed phase, it may be related to
demyelination.
Figure 12.
A 49-year-old man who fell asleep in a camper next to a charcoal fire and was found next morning, awake,
staring, and foaming at the mouth, with a respiratory rate of 6/min and a carboxyhemoglobin level of 22.9.
MRl demonstrates symmetric restricted diffusion (A, DWI and B; ADC map) and T2-FLAIR hyperintensity
(C, T2WI and D, FLAIR) in the bilateral globus pallidi.
Osmotic Myelinolysis
Osmotic myelinolysis is most often due to rapid correction of hyponatremia, but it can be seen with
malnourishment, chronic alcoholism, hyperosmolar conditions, such as hyperglycemia, and in liver
transplant patients. Patients typically present with pseudobulbar palsy and spastic quadriplegia. It can
present with central pontine and/or extrapontine myelinolysis (Figure 13). The pontine lesion is centrally
located and spares the corticospinal tracts. The extrapontine lesions are symmetric and involve the
thalamus, basal ganglia and lateral geniculate body and cerebellar white matter. The T2 hyperintensity may
lag up to 2 weeks, but restricted diffusion appears within the first 24 hours and may persist up to 3
weeks. The pathogenesis of diffusion restriction in is not fully elucidated, but it may be related to the shift
of the extracellular water into the cells or intramyelin splitting, vacuolization, and rupture of myelin sheaths
due to osmotic effects.
Figure 13.
A 46-year-old alcoholic man with severe hyponatremia who developed seizures and poor swallowing after
correction of hyponatremia. MRI demonstrates T2 hyperintensity within the central pons, sparing the
periphery and corticospinal tracts, and bilateral putamen, caudate nuclei, thalami external capsules and
central pons (A and B, FLAIR). Findings are consistent with both central pontine and extrapontine
myelinolysis.
Vigabatrin Toxicity
Vigabatrin is used for treatment of infantile spasms and refractory complex partial epilepsy and is
associated with asymptomatic transient MRI abnormalities (Figure 14) especially in younger ages. Toxicity
is characterized by symmetric T2 hyperintensity and restricted diffusion in the basal ganglia, thalami,
anterior commissure, corpus callosum and midbrain. The MRI abnormalities typically resolve even without
cessation of treatment. The cause for the T2 and diffusion abnormalities is unclear, although it is suggested
that it may be related to intramyelin edema.
Figure 14.
A 10-month-old boy with tuberous sclerosis and intractable epilepsy, MRl demonstrates stigmata of
tuberous sclerosis with reduced diffusion (A, DWI and B, ADC map) and T2 hyperintensity (C, T2WI)
involving the bilateral thalami, inferior globus pallidi, hypothalamus, red nuclei, superior cerebellar
peduncles and dorsal brainstem, suggesting Vigabatrin toxicity, The restricted diffusion resolved
spontaneously.
Nonketotic Hyperglycemia
Nonketotic hyperglycemia occurs in patients with diabetes mellitus type 2 and is associated with new-onset
chorea, seizures and focal neurologic deficits. The findings on imaging studies can be either unilateral or
bilateral and maybe mistaken for a lenticulostriate ischemic stroke (Figure 15). On CT, the basal ganglia
appear dense. The MRI findings are T1 hyperintensity, T2 hypointensity, and restricted diffusion with no
associated susceptibility effect. The T1 hyperintensity may be related to manganese in reactive
astrocytes. The pathophysiologic mechanisms for restricted diffusion remain controversial and include
protein desiccation, myelin breakdown, hyperviscosity, microcalcification, and microhemorrhage.
Figure 15.
A 62-year-old woman with DM presented with subjective feeling of right upper extremity weakness and
increased movement of her right foot, found to have nonketotic hyperglycemia. MRI revealed restricted
diffusion (A, DWI and B, ADC map) and T1 hyperintensity (C) within the left lentiform nucleus. CT shows
hyperdensity of the left lentiform nucleus and caudate head (D).
Conclusion
Stroke mimics are common in the emergency department and some of these patients may be treated with
intravenous tPA. Despite many clinical and imaging overlaps, a pattern-based approach provides a
reasonably accurate method to diagnose of many of these conditions and facilitate appropriate and timely
management.