Intracerebral haemorrhage
Intracerebral haemorrhages account for 15% of strokes [9] and may be revealed by a sudden neurological deficit. Elderly people are the most affected population [10]. At this age, high blood pressure is the main cause of spontaneous brain haematomas, which are mainly located in the basal ganglia and the internal capsules. Other sites of hypertensive haemorrhaging are the pons and the cerebellum. Lobar haemorrhages are more often associated with cerebral amyloid angiopathy in the elderly. In the younger population, the presence of aneurysms or arteriovenous malformation (AVM) ruptures, tumours, infections or coagulopathies must be verified.
The appearance of the haematoma on MRI depends on its age and size. In hyperacute haemorrhages (intracellular oxyhaemoglobin), DWI shows hyperintensity with corresponding ADC restriction, thus mimicking ischaemic stroke. The heterogeneity of the signal intensity and other MRI sequences are used to rectify the diagnosis.
Hyperacute haemorrhages are also isointense on T1-WI, iso- or hyperintense on T2-WI and demonstrate characteristic peripheral hypointensity on T2-GRE or SWI (Fig. 2). Areas of gadolinium leakage within acute haematomas, as observed on post-contrast T1-WI, also called the ‘spot sign’, are correlated with an increased risk of haematoma expansion [11].
Cerebral venous thrombosis
Cerebral venous thrombosis is an important life-threatening neurological condition. It is more common in women, who represent approximately 75% of adult cases [12]. The diagnosis may be challenging in view of the range of clinical symptoms and the variability of the imaging findings, both potentially mimicking AIS.
When suspecting cerebral venous thrombosis, radiologists have a key role and must fulfil three goals: (1) confirm the diagnosis by showing direct signs of occlusion of the venous structure by a thrombus, (2) look for signs of venous infarction in the brain parenchyma and, finally, (3) try to find an origin or a pathology related to this thrombosis [13]. Venous ischaemia begins with a vasogenic oedema that can be accompanied by cytotoxic oedema [14]. Thus, DWI shows variable signal abnormalities within the same parenchymal lesion of venous ischaemia. The topography of such parenchymal changes lacks arterial distribution and depends on where the thrombus lies within the cerebral venous system. Restricted diffusion of venous ischaemia has no prognostic value [15]. These lesions appear hyperintense on T2-WI and FLAIR. T2-GRE may highlight frequent haemorrhagic components. Cerebral venous thrombosis may rarely present as isolated subarachnoid haemorrhage that is in the vicinity of the thrombus [16]. The signal intensity of the clot depends on its age.
In the acute phase, during the very first days, the clot is barely visible on spin echo sequences and can be missed as it appears isointense to the brain parenchyma on T1-WI and hypointense on T2-WI and FLAIR [17], similarly to normal circulating veins. T2-GRE is the key sequence, because, due to the susceptibility artefact, it shows abnormal hypointensity of the thrombus blooming and enlarging the occluded venous structure (Fig. 3).
In the subacute phase (day 5 to day 15), the clot contains extracellular methaemoglobin and appears hyperintense on all sequences, i.e. T1-WI, T2-WI, FLAIR, but also T2-GRE and DWI [17].
In the chronic phase (after 15 days), the thrombus signal depends on the degree of organisation of the thrombus, but is typically isointense on T1-WI, iso- or hyperintense on T2-WI and hypointense on T2-GRE. The clot may enhance after a gadolinium injection. A clue to easily depict the thrombus in a dural sinus is to know that normal venous flow shows opposite signal intensity on FLAIR and T2-GRE. Therefore, in the case of cerebral venous thrombosis, occluded venous structures abnormally appear with identical signal intensities on these sequences, whatever the stage or the age of the thrombosis [18]. Venous occlusion should be visualised by magnetic resonance venography. Contrast-enhanced sequences are recommended to avoid flow artefacts. They show a filling defect of the occluded venous structure, showing the classic empty delta sign. This should not be confused with Paccioni granulations, which are typically focal, regular, well-defined and preferentially located along the superior sagittal sinus and close to the junction between the transverse and sigmoid sinus. Additional CT angiography should be performed in case of residual doubt, as this works remarkably well to demonstrate venous sinus thrombosis. Isolated cortical vein thrombosis is best seen with T2-GRE or, even better, SWI [19].
Finally, the radiologist needs to look for associated magnetic resonance features of an origin or a pathology related to this thrombosis, such as local infection, trauma, systemic diseases like Behcet’s disease, tumours or even intracranial hypotension.
Epilepsy
Epilepsy is one of the most frequent stroke mimics. Some symptoms, such as headaches, involuntary movements, incontinence or postictal confusion, may be helpful pointers against stroke. However, seizures with partial features may be difficult to distinguish from real AIS, especially in the case of ‘negative’ symptoms, such as Todd’s paresis or postictal aphasia/dysphasia.
In the case of a simple epileptic seizure, MRI changes can be focal, multifocal, hemispheric or diffuse [20], but there may also be no changes at all. In status epilepticus, which corresponds to a prolonged series of seizures of at least 20–30 min, during which the patient does not completely regain consciousness or does not exhibit normalisation of his/her EEG, MRI often shows cortical abnormal signal intensities, sometimes associated with pulvinar [21] and hippocampal lesions (Fig. 4). Epileptic activity may be responsible for regional vasogenic and cytotoxic oedema, reflecting haemodynamic and metabolic changes, respectively. This is why the lesions are usually hyperintense on DWI, with no arterial distribution and with variable ADC values. Similarly, they are associated with high signal intensity on FLAIR and T2-WI, low signal intensity on T1-WI and additional cortical swelling. TOF-MRA can reveal prominent arteries facing cortical lesions. PWI may, therefore, show mild hyperperfusion in the epileptic region [22] or be normal. Gyral and leptomeningeal contrast enhancement [23], certainly related to alteration of the leptomeningeal blood–brain barrier, is observed on contrast-enhanced T1-WI. Typically, all these changes lack arterial distribution and are topographically compatible with a clinical seizure or EEG findings because they are on the same side of the periodic discharges. Radiologists must strive to look for an origin of the epilepsy on MRI, such as a tumour or a stroke sequel. Signal changes are usually reversible, but the MRI follow-up may highlight irreversible changes, such as brain atrophy, cortical laminar necrosis and mesial temporal sclerosis, especially in generalised convulsive status epilepticus [24].
Hypoglycaemia
Hypoglycaemia, defined by a plasma glucose < 2.5 mmol/L (45 mg/dl), can manifest with various neurologic deficits, such as drowsiness, mood swings, seizures, confusion and coma, but also acute focal deficits, such as hemiplegia, that can be difficult to differentiate from ischaemic stroke. The main cause of hypoglycaemia is the accidental or deliberate overuse of hypoglycaemic agents in a known diabetic patient. Hypoglycaemia may also be induced by severe sepsis, renal or hepatic failure, Addison’s disease or insulin-secreting tumours. MRI may be normal or may show extensive, bilateral and symmetrical, white and grey matter lesions. They then predominate in the white matter (corona radiata, internal capsule and splenium of corpus callosum), and the grey matter areas most often affected are the occipital and temporal lobes, basal ganglia and hippocampi (Fig. 5). The thalamus, hypothalamus, brain stem and cerebellum are generally spared.
DWI is the most sensitive sequence for detecting such lesions by showing decreased ADC, before T2 and FLAIR hyperintensities become visible. The outcome of hypoglycaemic encephalopathy depends on the severity and duration of the hypoglycaemia, but also on the extent and location of brain lesions observed on DWI [25]. Two patterns of lesions exist on DWI [25]: on the one hand, lesions located anywhere along the corticospinal tracts, including the motor cortex, corona radiate, posterior limb of the internal capsule, pyramidal tracts, splenium of the corpus callosum or middle cerebellar peduncles, which are associated with a good clinical outcome, and on the other hand, lesions involving the cerebral cortex away from the motor cortex, basal ganglia or hippocampus, which are associated with a poor prognosis. The prognosis is usually also poor if the lesions do not regress on follow-up [26]. It is important to note that these hyperintense lesions on DWI also appear hyperintense on T2-WI or FLAIR images, even during the acute phase, and are not associated with abnormal findings on PWI. They may demonstrate enhancement on post-gadolinium T1-WI. Magnetic resonance spectroscopy reveals unspecific mildly reduced N-acetylaspartate and no lactate peak in this metabolic disorder.
MELAS
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS) is a rare, multisystem disorder affecting a young population. It belongs to a group of mitochondrial metabolic diseases [27]. This syndrome is caused by an absence or deficit of subunits of the respiratory chain protein complex due to a mutation in mitochondrial DNA [28] and leads to the impaired function of cells or even death. The clinical diagnosis is based on the following features: stroke-like episodes occurring before the age of 40 years, encephalopathy with seizures and/or dementia, the presence of lactic acidosis, ragged red muscle fibres, as well as additional criteria, such as recurrent headaches and recurrent vomiting [27].
The most characteristic neurological features of MELAS are the stroke-like episodes, such as hemiparesis, hemianopsia or cortical blindness. Their pathophysiology is still controversial. Various hypotheses have been proposed: (1) ischaemic vascular mechanism, (2) generalised cytopathic mechanism and (3) non-ischaemic neurovascular cellular mechanism. Because neurological episodes in MELAS mimic ischaemic stroke clinically, MRI is particularly helpful to distinguish them.
The locations of stroke-like lesions are correlated with focal neurological symptoms. Such lesions involve the cortex and appear with DWI hyperintensity, as is the case for real ischaemic lesions. Interestingly, the ADC is variable, with a possible mix of increase and decrease [29]. Increased-ADC lesions will regress at follow-up, whereas decreased-ADC portions will persist. Furthermore, the distribution of stroke-like lesions does not follow vascular territories (Fig. 6) and often shows a slow, progressive spread. FLAIR or T2-WI shows cortex swelling and areas of abnormally high signal with loss of cortico-subcortical differentiation. Abnormal cortical veins appearing hyperintense on FLAIR can be seen and may be a reflection of cortical venous stenosis, congestion and venous ischaemia [30]. Contrary to ischaemic stroke, TOF-MRA and PWI can reveal arterial vasodilatation and hyperperfusion in the stroke-like lesions of MELAS. Magnetic resonance spectroscopy may aid in the diagnosis, revealing a significantly elevated lactate peak at 1.3 ppm and decreased NAA, in stroke-like lesions as well as in the normal-appearing brain parenchyma [31].
Finally, stroke-like episodes may recur, but then lesions tend to appear in different cerebral locations.
PRES
Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological syndrome characterised by a variable combination of impaired consciousness, seizure activity, headaches, visual abnormalities, nausea/vomiting and focal neurological signs [32]. Prompt diagnosis and the empirical modification of all identifiable risk factors are the determinants of the outcome of patients. The causes are numerous, the most common of which are hypertension, eclampsia and immunosuppressant. The mechanism of PRES is not known. Two opposing hypotheses are commonly cited: (1) the older theory suggests that severe hypertension exceeds the limits of autoregulation, resulting in a brain oedema; (2) the earlier theory suggests that systemic toxicity leads to endothelial dysfunction with subsequent vasoconstriction or leukocyte trafficking, or both [33].
PRES lesions affect the cortex and subcortical white matter, are hyperintense on T2 and FLAIR, and have a predilection for posterior regions with a suggestive symmetric distribution (Fig. 7). Focal areas of vasogenic oedema may also be seen in the brain stem [34], the basal ganglia and deep white matter (external/internal capsule) [35]. However, focal areas of cytotoxic oedema with restricted diffusion can be seen and mixed patterns on DWI are not uncommon [36]; cytotoxic oedema may be associated with a poor outcome [37]. T2-GRE or SWI can detect subarachnoid haemorrhaging at the convexity or intraparenchymal haematoma. Contrast-enhanced T1-WI can show enhancement of lesions, which is seen more commonly in children than in the adults [38]. TOF-MRA may show features resembling vasculopathy, with focal vasoconstriction/vasodilatation or diffuse vasoconstriction.
Brain tumour
Patients with brain tumours may initially present with acute focal neurologic symptoms and may mimic a stroke [39]. It is important to distinguish brain tumours from strokes early, to avoid improper treatment such as thrombolytic therapy with a risk of haemorrhage, and not to delay correct management of the brain tumour.
MRI plays a crucial role in the initial diagnosis of brain tumours, treatment planning and in their monitoring.
Conventional T1-WI pre- and post-contrast, T2-WI and FLAIR sequences are usually straightforward and easily distinguish brain neoplasm from AIS by showing a round or ovoid enhancing lesion (Fig. 8) surrounded by vasogenic oedema, which are features not encountered in the first few hours following stroke onset. However, brain tumours may not harbour all these signs and display as a stroke mimic on the initial MRI. This can happen especially if tumours are small, included in an arterial territory and involve the cortex.
DWI shows variable signal intensities for primary and secondary tumours. The ADC is inversely proportional to cellular density. Therefore, the ADC value of high-grade gliomas is classically lower than that of low-grade gliomas [40]. In the same way, lymphoma tends to have low ADC due to its high cellularity. The tumour may, therefore, appear with high DWI signal intensity. PWI may then be helpful because solid tumours do not show areas of low relative cerebral blood volume (rCBV) as a stroke would. On the contrary, rCBV tends to increase with neoplasm grade [41]. Magnetic resonance spectroscopy may be useful too, as the typical pattern of an intra-axial tumour includes an elevated peak of choline and reduced NAA, the former not being present in an acute stroke. In cases where the diagnosis remains uncertain, follow-up will confirm or deny the presence of a brain tumour.
Demyelinating diseases
Multiple sclerosis is the leading cause of non-traumatic neurological disability in young adults. In 85% of patients, multiple sclerosis follows a relapsing–remitting course and is associated with acute demyelinating lesions [42].
On DWI, these acute demyelinating lesions sometimes demonstrate hyperintensity, generally associated with an increased ADC. However, acute demyelinating lesions have also been described with a decreased ADC [43], which raises the issue of differential diagnosis with ischaemic stroke, especially if no contrast-enhanced MRI is performed. It is important to note that most acute demyelinating lesions only involve cerebral white matter and do not demonstrate cortico-subcortical arterial distribution. T2-WI or FLAIR shows multiple white matter lesions, which might be disseminated in space and time according to the McDonald criteria [44], to be diagnosed as multiple sclerosis. Dissemination of lesions in space is demonstrated by at least one T2 lesion in at least two of the four following areas of the central nervous system: (1) periventricular, (2) juxtacortical, (3) infratentorial and (4) spinal cord. The European collaborative research network that studies MRI in MS (MAGNIMS) proposed new MRI criteria to be applied in multiple sclerosis, adding optic nerve lesions as an additional area to the dissemination in space, increasing the number of DIS locations from 4 to 5 [45]. Note that this area may not be conserved in the future McDonald criteria.
Additionally, contrast-enhanced T1-WI may highlight gadolinium uptake in acute lesions (Fig. 9), a feature not encountered in the first few hours following stroke onset. Furthermore, the simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions on a single MRI now proves dissemination of lesions in time based on the McDonald criteria. PWI is not really helpful because both mildly increased [46] and decreased [47] perfusions have been reported. Magnetic resonance spectroscopy may instead help diagnose acute demyelinating lesions as it shows a reduction of the N-acetylaspartate peak while choline is typically increased [58], and a negative doublet corresponding to lactate is abnormally visible on long TE [49].
Susac’s syndrome
Susac’s syndrome is a form of retinocochleocerebral arteriopathy. There is a strong predilection in women between the ages of 20 and 40 years. Susac’s syndrome is probably caused by the obstruction of pre-capillary arterioles of the brain, retina and inner ear, secondary to lesions from anti-endothelial cell antibodies [50]. The physiopathology of the selective tissue distribution is still not clearly understood; this could be explained by a common embryologic origin of the brain [51]. Symptoms include visual and hearing disturbances, as well as neurological deficits, the latter mimicking stroke or transient ischaemic attacks. Susac’s syndrome needs to be treated early, aggressively and durably to prevent relapses. Although the obstruction of arterioles is responsible for microinfarcts, treatment is not covered by thrombolysis but by immunosuppressant drugs [52], based on the hypothesis of being an autoimmune disease.
On MRI, acute lesions appear as small multifocal lesions of 3–7 mm spread in both white matter and basal ganglia, typically demonstrating DWI and FLAIR high signal intensity. A more specific pattern is described on DWI that shows restrictive lesions in the centre of the corpus callosum, described as ‘snowballs’, and in the posterior limb of internal capsule appearing as a ‘string of pearls’ (Fig. 10). The central location of the lesions of the corpus callosum is important to differentiate Susac’s syndrome from multiple sclerosis, in which lesions are more readily at the under-surface and at the septal interface of the corpus callosum. The combination of typical central callosal lesions and a ‘string of pearls’ in the internal capsule is considered pathognomonic for Susac’s syndrome [53]. Contrast-enhanced T1-WI can highlight suggestive leptomeningeal contrast enhancement [54]. Three-dimensional TOF is usually normal because Susac’s syndrome affects only the precapillary arterioles, which are below the resolution of magnetic resonance angiography.
Herpes simplex encephalitis
Herpes simplex virus (HSV) encephalitis is the most common cause of fatal sporadic fulminant necrotising viral encephalitis, usually due to HSV-1 in most patients and HSV-2 in the remainder. HSV encephalitis manifests as a bilateral asymmetrical involvement of the limbic system, medial temporal lobes, insular cortices and inferolateral frontal lobes. The basal ganglia are typically spared, helping to distinguish it from a middle cerebral artery stroke. DWI is known to be more sensitive than T2-weighted images to highlight the parenchymal lesions and shows restricted diffusion due to cytotoxic oedema at the acute phase. A lesion involving only a single medial temporal lobe could be mistaken for a middle cerebral artery stroke; in that case, the anterior aspect of the parahippocampal gyrus, called the uncus, is spared, this small area being supplied by the anterior choroidal artery (Fig. 11). The lesions are hyperintense on T2-WI and FLAIR. T2-GRE or SWI may demonstrate blooming if the HSV encephalitis is haemorrhagic. Additionally, contrast-enhanced T1-WI may highlight gadolinium uptake with gyral enhancement due to the breakdown of the blood–brain barrier or with leptomeningeal enhancement related to the associated meningitis.
