Ischemic stroke is a medical emergency because the proportion of patients who benefit from intravenous thrombolysis (IVT) and mechanical thrombectomy, decreases rapidly over time [1,2]. Hemorrhagic stroke is also an emergency because it is recommended to lower blood pressure rapidly, to treat coagulation disorders, and, in rare cases, to perform surgery . Therefore, efforts should be made to have an accurate diagnosis within a very short period, based on an interview with the patient or relatives, focused clinical examination, and either a brain MRI or a computed tomographic (CT) scan. Time constraints increase risks of misdiagnoses. Brain imaging helps diagnosing properly stroke but it may be negative, or may even not be performed if the clinical hypothesis was not a brain disorder.
The typical clinical presentation of a stroke consists of a sudden onset of a focal neurological deficit of maximum intensity at onset. Other disorders may also be associated with a similar clinical presentation: these ‘false positives’ are called ‘stroke mimics’ [4▪]. It may also happen that a stroke has an unusual clinical presentation, when the onset of symptoms is not sudden, the clinical presentation is not explained by a single lesion, and symptoms are ‘positive’ such as paresthesia, movement disorder, or seizures, rather than negative such as hemiplegia, aphasia, or hemianopia. These ‘false negatives’ are called ‘stroke chameleons’ because the clinical presentation suggests another disorder [4▪]. Table 1 summarizes what these false and true negative and positive mean in practice.
The objective of this review is to identify the most frequent clinical situations associated with stroke mimics and chameleons and the consequences for the patient.
The proportion of patients with stroke mimics depends on who evaluates the patient, when the patient is examined, and how brain imaging is performed. MRI with diffusion-weighted imaging (DWI) is a sensitive and specific tool for the diagnosis of ischemic stroke, but it may be normal in patients with transient ischemic attacks (TIA) and its accuracy decreases over time . The overall frequency of mimics in the emergency room ranges between 15 and 25% [4▪,6,7].
Types of mimics
A postictal motor deficit may follow an undiagnosed focal seizure of short duration. The diagnosis may be difficult when a seizure is the first manifestation of stroke, or when the cause is a previous stroke. MRI with DWI and ADC (apparent diffusion coefficient) sequences is crucial to differentiate old and recent ischemic strokes. DWI hyperintensities have been described mainly in patients with status epilepticus or repeated seizures, and in up to 3% of patients with single focal seizure [8▪].
An aura may be misinterpreted as a focal deficit suggesting a stroke or TIA. Auras can be isolated and occur without headache in patients with migraine, and headache is present in more than 25% of patients with ischemic stroke . In migraine, most auras are sensitive or visual. The most difficult situation is in presence of a first episode of transient sensory or aphasic symptoms, in patients without the criteria for migraine. A rapidly progressive extension of the symptoms over a few minutes suggests an aura, but the diagnosis may remain uncertain in a few patients.
Hemiplegic auras are very rare, except in familial hemiplegic migraine, in which the family history is usually clear, the disorder being of autosomal dominant transmission with a high penetrance. The first episodes start usually before 20 years of age, and tend to be less frequent but of longer duration with age [10▪▪]. Most patients have the four usual types of aura (visual, sensory, aphasic, and motor) and all patients have at least two of them during attacks [10▪▪]. Therefore, in present of isolated motor symptoms the diagnosis of familial hemiplegic migraine is unlikely.
Headache associated with acute neurological deficits and lymphocytosis
Headache associated with acute neurological deficits and lymphocytosis is difficult to differentiate from a stroke: patients often report recurrent neurological deficits and headache with lymphocytosis [11▪▪]. The neurological deficit usually lasts several hours. During attacks brain imaging is normal except sometimes in perfusion sequences . Between attacks there is no symptom, and the condition spontaneously improves within 3 months.
A focal neurological deficit is frequent in hypoglycemia. The diagnosis is usually easy in diabetic patients treated by insulin or sulphonylureas, in acute alcohol consumption, and in Addison's disease. It may be difficult in case of insulinoma. The focal deficit is often associated with autonomic symptoms, agitation, or delirium. Two traps should be known to prevent misdiagnoses: first, blood glucose measurements may remain within normal limits because of food absorption, drug metabolism, or hypersecretion of corticosteroids induced by hypoglycemia; and second, a transient area of higher hyperintensity on DWI with moderate decreased ADC is possible . If the rule of measuring blood glucose concentration in emergency in strokes is respected, the diagnosis is easy.
Functional disorders may be revealed by an acute motor or sensory deficit mimicking a stroke. Clinical symptoms are often preceded by a trigger, such as an emotional event .
The most appropriate way to diagnose functional disorders is not to exclude an organic disease with a negative MRI, but to find positive features [14▪▪] such as inconsistency in the extent of weakness, for example, a patient who cannot move his leg but can walk, or incongruities, for example, a dense hemiplegia sparing face, or sensory disturbances of nonanatomical distribution, or a positive Hoover's sign which is specific of a functional disorder, but not sensitive [15▪▪]: it consists of an extension of the ‘paralyzed’ leg when flexing the contralateral leg against resistance.
A tumor, usually malignant, may be revealed by an acute neurological deficit: it may be due to a postictal deficit, an intratumoral hemorrhage, or an extrinsic compression of surrounding vessels . The diagnosis is usually easy with MRI.
Consequences of mimics
Delayed diagnosis of the underlying disease is usually not the major problem. Blood glucose dosage at – or before – admission will easily detect hypoglycemia, and brain imaging detects tumors. Migraine, isolated seizures, and functional disorders may be more difficult to diagnose at admission, but a small delay in diagnosis is not harmful.
Inappropriate use of available facilities because of an inappropriate diagnosis of stroke does not harm patients, because most investigations needed in stroke patients are not dangerous. They can however lead to extra costs and inappropriate use of stroke facilities.
Finally, the most serious consequence of over diagnosing stroke is that patients receive unnecessary treatments, especially IVT. The risk of treating a mimic with IVT is smaller in patients who undergo MRI at baseline. In a multicenter European study [17▪▪], of 5581 consecutive patients who received IVT, 100 (1.8%) had stroke mimics: they were younger, more often women, with fewer vascular risk factors, except smoking and history of stroke or TIA [17▪▪]. The rate of symptomatic intracranial hemorrhage was 1%, that is, much lower than that observed in other patients (7.9%). In the Norwegian Tenecteplase Stroke trial, tenecteplase was as safe as alteplase in stroke mimics . In difficult cases there is probably more risk to delay IVT to exclude stroke mimics with certainty, than to treat with IVT stroke mimics [17▪▪].
Stroke chameleons occur when the clinical presentation includes an unusual time-course, for example, a progressive or stepwise evolution of symptoms, or positive symptoms such as involuntary movements or seizures, contrasting with negative symptoms such as hemiplegia, aphasia, or hemianopia. Two population-based studies found rates of chameleons around 13% [18,19], whereas other studies found huge variations from 2 to 26% in emergency departments (EDs) [20–22]. It is quite impossible to know exactly how frequent chameleons are, because we know only those who were finally identified as strokes.
Types of chameleons
Dizziness and vertigo
Depending on cultures and languages, the term ‘dizziness’ may include vertigo, imbalance or just ‘not feeling well’. This is a very frequent reason for admission in an ED. Although most causes of dizziness are benign, it may be the warning symptom of a disabling stroke . In a population-based study, 0.7% of patients with isolated dizziness had a stroke, but in presence of additional symptoms, the probability to have a stroke was four to five-fold higher . One of the main difficulties is to differentiate a peripheral from a central cause of vertigo (Table 2). The duration of vertigo, associated symptom and possible triggers as well as medical history should be assessed. The association of headache, neurological symptoms, or unilateral hearing loss tend to exclude vestibular neuritis . The Dix–Hallpike maneuver and the head-impulse test can be useful to demonstrate the peripheral origin of the vertigo. Patients with a missed diagnosis of stroke are more likely to have a stroke located in the posterior circulation [20,26]. These types of strokes may require a more comprehensive neurological examination than a cursory test . Although one-sixth of vertebrobasilar infarcts are preceded by brainstem TIA (isolated vertigo, diplopia, dysarthria), less than 10% of these symptoms meet the definition of TIA . Indeed, most transient neurologic attacks with brainstem symptoms, such as vertigo, dysarthria, dizziness, or wooziness should not be diagnosed as TIA . Nausea and vomiting are frequent in patients with vertigo: they should be even more considered if they occur without other gastrointestinal symptoms [26–29]. Another important pitfall is the reinsurance of clinicians by a negative brain CT scan in patients with vertigo because of the low sensitivity of CT scan for vertebrobasilar infarcts, especially at the acute stage [29,30].
Less than 5% of all strokes are revealed by an isolated monoparesis that can be misdiagnosed for peripheral nerve palsy . Most of these strokes are due to subcortical lesions, but 30% are caused by cortical lesions . Most monoparetic strokes involve the arm and are due to a lesion in the territory of the middle cerebral artery. Monoparesis of the leg or face are associated with lesions located in the territory of the anterior cerebral artery.
Altered mental status
An isolated decreased level of consciousness has been identified as the leading type of chameleons [18,22]. This clinical presentation is frequent but usually transient in patients with bilateral thalamic strokes  (Fig. 1) or, less frequently, in brainstem strokes. These chameleons are often initially diagnosed as metabolic, toxic, or infectious disorders. Focal neurological deficits such as aphasia, mild limb weakness, or gaze palsy may remain unidentified . Altered mental status is frequently attributed to other neurologic diseases such as seizures or central nervous system infections .
When stroke affects the nondominant hemisphere, especially in the temporoparietal area, a clinical presentation of delirium may lead to a wrong diagnosis. Indeed, although verbal fluency remains preserved, right hemisphere symptoms may cause attention deficits, lack of usual expression of emotion or empathy with others and inability to cope with nonverbal communication suggesting a psychiatric disorder . An additional challenge is that delirium or altered mental status may prevent from achieving a good quality brain imaging.
Movement disorders associated with stroke set against usual ‘negative’ symptoms seen in typical presentations. Hemichorea, hemidystonia, or hemiballismus occur in lesions involving the basal ganglia . Rhythmic tonic movements may occasionally reveal brainstem ischemia [37,38]. These movements may be seizure-like rhythmic jerking, sometimes with prolonged tonic muscle contractions. Although the pathophysiology is not known, these warning signals should be recognized as symptoms of basilar artery occlusion .
Limb shaking TIA are rhythmic, involuntary jerky limbs movements due to severe carotid or middle cerebral artery stenosis . This hemodynamic TIA can be triggered by a reduced cerebral blood flow [40▪] such as postural change or physical exercise and be mistaken for focal motor seizures [41,42].
Patients with acute stroke frequently have concomitant headache . Given the frequency of benign headache, it is not discriminating to expect a stroke in patients with headache of moderate severity. Thunderclap headache is the only exception of a new severe nontraumatic headache frequently associated with cerebrovascular disorders  such as subarachnoid hemorrhage, reversible vasoconstriction syndrome, cerebral venous thrombosis, or dissection.
Consequences of chameleons
Missed diagnoses of stroke may result in delayed admissions and lower chance to receive IVT or to undergo mechanical thrombectomy. These factors are also associated with risk factors for worse outcomes after stroke . Patients with chameleons are also less likely to be properly investigated, and consequently to receive an appropriate secondary prevention, leading to higher rates of disability and mortality at 12 months . These considerations highlight the need to raise awareness to identify properly stroke patients with unusual symptoms . Stroke chameleons may be substantially reduced with the use of MRI, at least when the clinical presentation is that of a central nervous system disorder. However, improvement in imaging techniques with higher resolution brain imaging leads to a risk of finding ‘incidentalomas’ which are not relevant and may also negatively impact the management . Education of the population, and health providers is crucial to improve identification of chameleons.
Stroke mimics are not major issues in practice. We need to go fast and therefore, to accept the risk of treating a few mimics. Being 15 min slower in all patients to improve diagnostic accuracy will probably harm 99% of patients and will perhaps allow the identification of the 1% of patients who will receive unneeded IVT and will usually tolerate it. Neurologists should not blame emergency services for alerting for stroke mimics: those who never do probably miss many strokes. The problem with mimics is not that the diagnosis is wrong but that inappropriate treatments are given, and facilities are not properly used. There is – usually – no consequence for the patient. The problem with stroke chameleons is more serious because stroke is not identified, and patients are not properly treated at the acute stage and afterwards. Education of all health providers to identify unusual presentations of stroke is crucial.
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Conflicts of interest
There are no conflicts of interest.
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Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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