Diagnosing stroke is not always straightforward. Stroke mimics such as Todd's paresis or hemiplegic migraine account for between a fifth and a quarter of suspected strokes (depending on the setting in which they are assessed). Stroke chameleons can arise when the tempo of symptom onset is not apoplectic or if the loss of function is not clearly consistent with a deficit within an arterial territory. Thrombolysis and secondary prevention have much to offer patients with stroke chameleons, though those with stroke mimics may be harmed by these treatments and have more to gain from other therapies.
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The clinical presentation of stroke varies. It is common to mistake other diseases for strokes (stroke mimics) and strokes for other diseases (stroke chameleons).
Stroke is common: there is a high prior probability that a sudden onset neurological deficit is due to a stroke. Rare presentations of stroke are probably more likely than common presentations of rarer conditions: ‘when you hear hoof beats behind you, don't expect to see a zebra’.
Assessment of stroke mimics or chameleons depends on the context—an ambulance crew will use tools such as the FAST score,1 an emergency department doctor may use the Recognition of Stroke in the Emergency Room scale,2 while a stroke or neurology registrar will put greater emphasis on the history. Because of these different approaches to assessment by people with different diagnostic skills, as well as the occasional difficulty distinguishing stroke from its mimics very soon after onset, the context may affect the proportion of suspected stroke patients with an eventual diagnosis of stroke (figure 1).
Rapid recognition of stroke is important: the sooner ischaemic stroke patients receive thrombolysis3 or are investigated and given secondary prevention to avoid further vaso-occlusive events,4 the better the outcome. The correct diagnosis for patients without stroke leads to appropriate treatment and avoids the potentially harmful effects of secondary stroke prevention therapies.
Like many neurological conditions, stroke lacks a perfect diagnostic test and a robust reference standard. It is a rare transient ischaemic attack (TIA) clinic or stroke unit ward round—at least for these authors—where one is certain of the diagnosis for every patient. Challenges include late presentations of stroke, when intracerebral haemorrhage may be impossible to distinguish from infarction on a CT scan, or where there is no diffusion restriction due to infarction on MR scanning. Other problems are the difficulty in obtaining advanced imaging soon after stroke onset,5 assessment of patients whose presentations are mild or with purely sensory symptoms6 and patients who are too unwell or agitated to obtain interpretable brain imaging.
Rather than labouring these everyday challenges, we will present a few cases where we were able to ascertain the eventual diagnosis but where the initial presentation was misleading.
Stroke mimics account for 20–25% of suspected stroke presentations, depending on the context (figure 1). There is a diverse array of mimics (figure 2), and we will deal with a small selection of them.
Unfortunately, brain imaging is not the simple answer to distinguishing stroke from its mimics. Although brain MRI with diffusion-weighted imaging (DWI) is sensitive and specific for the diagnosis of acute haemorrhagic or ischaemic stroke, this may decline with time after stroke onset.7 Similarly, the higher attenuation of intracerebral haemorrhage is usually evident on brain CT performed within the first week of stroke symptom onset, but CT's sensitivity for haemorrhage also declines with time.8 Therefore, the reference standard for the diagnosis of stroke can only be clinical history and examination, supported by brain imaging (which may be normal).
A 65-year-old right-handed man complained of difficulty speaking and visual disturbance on the right side, lasting for less than an hour. Neurological examination in hospital showed a right homonymous hemianopia, right-sided inattention and right-sided weakness. Before the onset of symptoms, there had been a 5-min episode of muscle twitching affecting his right face and body, after which his symptoms worsened before fully resolving over the next 24 h. His past history included a metallic mitral valve replacement and a left hemisphere cortical ischaemic stroke 2 years previously. Brain MRI showed old left hemisphere cortical and lacunar infarctions (figure 3). We made a diagnosis of Todd's paresis.
Postictal Todd's paresis can be difficult to differentiate from stroke and accounts for almost 20% of stroke mimics (figure 2). The diagnosis is more readily apparent if patients have recurrent focal motor seizures (which can be subtle). There may be a history of epilepsy, although this may not necessarily have been diagnosed before admission. The substrate for the seizure is often an old ischaemic or haemorrhagic stroke, easily mistaken for an acute stroke when brain imaging is reviewed. The use of MRI with DWI and apparent diffusion coefficient sequences can help differentiate remote stroke (indicating seizure as the cause of paresis) from recent ischaemic stroke. Most episodes of Todd's paresis in specialised epilepsy practice are brief: a video-telemetry study9 found a median deficit of 173 s, although patients with tonic-clonic seizures may have longer deficits.
Seizures are a relative contraindication to thrombolysis because a neurological deficit may be attributable to Todd's paresis rather than acute stroke. There are few data available on the frequency of seizures at the onset of stroke, although the ‘Seizures after Stroke’ study10 showed that 8.6% of patients experienced seizures soon after stroke onset (3.4% in the first 24 h).
A 75-year-old right-handed man woke with severe left-sided hemiparesis. Capillary blood sugar in the ambulance was 1.8 mmol/l, successfully treated with intravenous dextrose. Neurological examination was normal by the time of arrival in the emergency unit, as was brain CT. Full blood count showed an elevated mean corpuscular volume. The patient did not take any hypoglycaemic agents but did admit to alcohol excess, including a heavy intake of gin the evening before presentation. We diagnosed hypoglycaemic hemiparesis and the patient was counselled over his alcohol intake.
Hypoglycaemia normally presents with autonomic symptoms but can present with focal neurological symptoms and signs alone. The most common causes for hypoglycaemia are insulin or sulphonylureas; others include alcohol, Addison's disease or insulinoma. There may be episodes of focal neurological disturbance at the same time each day, associated with diabetic medication. Although blood glucose measurement at the time of onset of neurological deficit can help, it may be normal at the time of assessment (due to metabolism of food or medications) and brain MRI may show transient DWI high signal in the context of hypoglycaemia.11 The ‘airway, breathing, circulation, don't ever forget glucose’ (ABC-DEFG) approach is important: blood sugar should always be measured before thrombolysis is given.
Sepsis accounts for 12% of stroke mimics (figure 2), so a thorough systemic examination is always necessary. This, together with a septic screen, may identify a focus of infection. Raised inflammatory markers and fever support a diagnosis of sepsis, although sepsis may itself be a risk factor for stroke: the risk from mycotic emboli is well established and severe sepsis can induce a hypercoagulable state.12 Differentiating sepsis and stroke is difficult when patients have both conditions simultaneously, for example, aspiration pneumonia secondary to stroke. A systemic upset may also exacerbate the neurological deficits of a previous stroke. Establishing a clear history of previous strokes and residual neurological deficits, a full drug history and a history of symptoms of sepsis is crucial but often difficult in the acutely unwell patient. Collateral histories from relatives or the general practitioner may help to distinguish exacerbation of an old deficit from new stroke.
Migraine and other headache disorders
Headache is a common feature of acute ischaemic stroke: 27% of patients experience a headache at stroke onset.13 A migraine aura with positive, spreading, mild symptoms may be readily diagnosed, but less obvious presentations can create confusion: primary headache disorders are responsible for 10% of stroke mimics (figure 2). Severe neurological deficits associated with headache—including familial hemiplegic migraine (box 3) and headache with associated neurological deficits and lymphocytosis (box 4)—are difficult to disentangle from strokes.
International Headache Society diagnostic criteria for familial hemiplegic migraine
At least two attacks fulfilling B and C
Aura consisting of fully reversible motor weakness and at least one of the following:
Fully reversible visual symptoms including positive and/or negative features
Fully reversible sensory symptoms including positive and/or negative features
Fully reversible dysphasic speech disturbance
At least two of following:
At least one aura symptom developing gradually over ≥5 min and/or different aura symptoms occur in succession over ≥5 min
Each aura symptom lasts ≥5 min and <24 h
Headache fulfilling criteria for migraine without aura begins during aura or within 60 min of onset of aura
International Headache Society diagnostic criteria for syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis
Episodes of moderate or severe headache lasting hours before resolving fully and fulfilling criteria C and D
Cerebrospinal fluid (CSF) pleocytosis with lymphocytic predominance (>15 cells/µl) and normal neuroimaging, CSF culture and other tests for aetiology
Episodes of headache are accompanied by or shortly follow transient neurological deficits and commence in close temporal relation to the development of CSF pleocytosis
Episodes of headache and neurological deficits recur over <3 months
A family history may help to identify cases of familial hemiplegic migraine, which is an autosomal dominant disorder with high penetrance. Patients with this condition are typically young (average age of onset 17 years), female (70%) and tend to have fewer attacks as they age.14
Patients with headache with associated neurological deficits and lymphocytosis (HaNDL) report recurrent neurological deficits and headache, and have cerebrospinal fluid abnormalities (lymphocytosis, elevated protein and high opening pressures).15 The neurological deficits typically last for hours and may include dysphasia, focal weakness or confusion. CT and MRI are normal, although perfusion imaging may show focal deficits.16 Patients have no deficits between attacks and the condition spontaneously remits within 3 months. Making these diagnoses can be difficult on first presentation, and may require investigation of several attacks before a confident verdict can be reached.
Functional disorders often manifest as acute weakness or sensory disturbance, mimicking stroke. There is frequently a trigger, such as a panic attack or dissociative episode.17 When diagnosing functional disorders, the positive features of functional disease are more important than the absence of features of organic disease—for example, a positive Hoover's sign is more important than a normal brain CT. The key finding in the examination of functional weakness is inconsistency. Inconsistency in the extent of impairment is illustrated by task-dependent weakness—the patient who walks into the room but cannot move their leg at all when examined on the couch. Hoover's sign is another example and is very specific and moderately sensitive for functional weakness,18 although hip pain or neglect may give a false positive result. Inconsistency in the nature of impairment manifests as incongruities such as dense hemiparesis with complete facial sparing. Other indicators of functional disease include the presence of Hoover's sign in the upper limbs, collapsing or ‘give-way’ weakness, waxy flexibility, non-anatomical sensory disturbance and other tests of varying utility.19
Brain tumour mimic
A 92-year-old man woke at 06:30 with fluctuating right hand weakness and word-finding difficulty. At 11:00 he found he was dribbling saliva from the right side of his mouth, and presented to medical attention. Neurological examination showed right facial weakness and mild hemiparesis of the right arm and leg. Brain MRI showed a left cortical meningioma with oedema (figures 4 and 5).
Tumours typically cause slowly progressive deficits but 5% of tumours have a stroke-like presentation.20 Acute deficits are commonly due to haemorrhage into the lesion but may also be secondary to extrinsic compression of vascular structures by oedema, obstructive hydrocephalus or Todd's paresis. The presence of very early mass effect suggests a tumour, as large artery strokes usually take 24–48 h to develop cerebral oedema.21
Stroke chameleons imitate other diseases due to their tempo of onset (eg, gradual progression or stuttering) or have symptoms that do not necessarily implicate an arterial territory.22 It is uncommon to consider these patients for thrombolysis, but their recognition enables patients to benefit from secondary prevention. Here, we discuss a selection of case studies; table 1 gives some further examples.
A 75-year-old woman presented to the emergency unit with a 1-day history of dizziness, vertigo and vomiting. She had a history of sick sinus syndrome with permanent pacemaker and also of Ménière's disease. On examination, she had atrial fibrillation, an ataxic gait, nystagmus (fast phase to the left) and marked unsteadiness. The initial diagnosis was recurrent Ménière's disease and she was prescribed prochlorperazine. However, the symptoms, signs and lack of improvement with vestibular suppressants prompted a neurologist to organise a brain CT, which showed a subacute left cerebellar hemisphere infarction.
A 70-year-old woman had an episode of right leg weakness of sudden onset, fully resolving within an hour. The right leg weakness recurred the next day, prompting admission to hospital. She had a history of rheumatoid arthritis. On examination, there was weakness of the right leg. The initial diagnosis was of a myelopathy. Brain MRI showed acute ischaemia in the territory of the left anterior cerebral artery (figures 6 and 7).
A 79-year-old man went for his usual local walk. On his way home he could not recognise his house, despite his wife standing at the window waving. He was brought to the hospital where he was very talkative and would frequently get lost in the ward. There were no other symptoms and no focal neurological deficit. He had a past history of paroxysmal atrial fibrillation and hypertension. Brain CT showed a right frontal infarction. (figure 8).
Cauda equina syndrome chameleon
A 75-year-old woman presented at midnight with bilateral leg weakness and numbness. She had a history of hypertension and of type 2 diabetes mellitus. One month previously she had an episode of haematuria. Her symptoms had started at midday with back pain radiating down both calves. By 14:30 she had pain, numbness and paraesthesia affecting both legs, and difficulty walking. Her general practitioner assessed her at 18:00, at which point she could only move her toes. There was reduced tone strength and reflexes in both legs. In the emergency unit, she had a flaccid paraplegia, areflexia, sensory level at T11 and painless urinary retention. She was admitted under the neurosurgical team with a diagnosis of cauda equina syndrome. Urgent MR scan of the spine showed a cord infarction from T9 to the conus (figures 9 and 10), with an additional left renal cell carcinoma.
Stroke is rarely the cause of dizziness: only 3% of patients presenting with dizziness and additional symptoms have had a stroke or TIA, diminishing to less than 1% of those presenting with isolated dizziness.23
Differentiating peripheral from central causes of vertigo can be difficult, particularly with the patient who is reluctant to participate fully with an examination that exacerbates their symptoms. The presence of new—or worsened—unilateral hearing loss, headache, tinnitus or neurological symptoms is uncommon in isolated vestibular neuronitis.24 Lateral medullary, lateral pontine and inferior cerebellar patterns of infarction may mimic the clinical features of vestibular neuronitis.25 In peripheral lesions, symptoms of vertigo may be ameliorated by visual fixation on a stationary object; this effect is less pronounced in central lesions. The Dix–Hallpike manoeuvre distinguishes central from peripheral lesions that induce nystagmus (table 2), as does the head-impulse test.26 Nystagmus in acute cerebellar stroke has the fast phase towards the side of the lesion.
Acute isolated monoparesis has a limited differential diagnosis, usually being caused by cerebral or spinal ischaemia, injury to the brachial or sacral plexus, multiple sclerosis, or, rarely nowadays, poliomyelitis.
Isolated monoparesis is a rare presentation of stroke, comprising fewer than 5% of all strokes.27 Monoparetic stroke most commonly affects the arm, where the causative lesion is often a middle cerebral artery stroke. However, monoparesis of the face and leg can also occur, where the likely vascular territories affected are subcortical arteries (causing facial weakness) and the anterior cerebral artery (causing leg weakness). Most strokes presenting with monoparesis are subcortical or deeper, although about 30% are caused by cortical lesions.28
Non-dominant anterior circulation strokes affecting the temporoparietal region may cause visual agnosia, prosopagnosia, loss of spatial orientation and disinhibition of speech. The excessive speech production and difficulty in path finding often lead to a diagnosis of delirium, with a search for an underlying infective or metabolic cause. Patients with non-dominant hemisphere deficits may have problems with attention, lack of usual expression of emotion, lack of empathy with others, lack of prosody of speech, lack of judgement of time and inability to comprehend non-verbal communication or to recognise familiar sounds.29 ,30
Cauda equina syndrome
The differential diagnosis of acute flaccid paraparesis includes spinal stroke, cauda equina syndrome and Guillain–Barré syndrome. A spinal stroke is suggested by the presence of vascular risk factors and rapid onset of symptoms: patients usually develop symptoms within a few minutes, although progression may occur over a few hours.31 The syndrome usually involves the anterior cord predominantly, so preserved posterior column sensation with a sensory level for pin prick and temperature (reflecting spinothalamic loss) provides a further clue.
The definitive test is an MR scan of the whole spine; if suspecting Guillain–Barré syndrome then it is helpful to look for cerebrospinal fluid protein–cellular dissociation. Further imaging may be required to exclude an aortic dissection as the cause of spinal stroke. Cord ischaemia and infarction may follow surgical repair of aortic aneurysms and various interventions may help in this context.32
The diagnosis of stroke remains a clinical one, supported by imaging. Emergency departments and medical admission units need neurological expertise to help accomplish this.33
Diagnostic accuracy in stroke has been increased by improvement in imaging techniques. However, higher resolution brain imaging means that there is a greater risk of finding ‘incidentalomas’, not relevant to the presenting complaint.34 It is therefore essential to relate the clinical picture to the radiographic images. For example, a radiographic lacune may create confusion in a stroke mimic unless it is shown that the location of the lacune is clearly anatomically irrelevant to the neurological deficit, or that the lacune is chronic rather than from an acute lacunar infarction. A thorough review of the imaging with a neuroradiologist will help sort the wheat of real findings from the chaff of incidental findings.
It is also important to consider the pretest probability of the patient having cerebrovascular disease. An elderly male smoker with hypertension and diabetes is more likely to have had a stroke than a young woman with no risk factors, despite identical presenting complaints. This should not be taken as an infallible rule but applying probabilities (of diagnosis and greater absolute benefit from treatment) may help to resolve the uncertainty.
Thrombolysis is potentially harmful, and this causes concern about the risks of thrombolysing stroke mimics. However, the available evidence suggests that thrombolysis in stroke mimics is generally of low risk.35 ,36 Conversely, a patient with a stroke chameleon could miss out on the beneficial effects of thrombolysis,37 acute stroke unit care38 and/or secondary prevention measures.39 Ultimately, false negatives (stroke chameleons) may be of greater immediate concern than false positives (stroke mimics).
Contributors All authors were involved with conception/design of the review, critically revising the article for important intellectual content, and giving final approval for the version to be published. The guarantor of the overall content is PMF.
Funding WNW: MRC Clinician Scientist fellowship. RASS: MRC Senior Clinical fellowship.
Competing interests None declared.
Provenance and Peer Review Commissioned; externally peer reviewed. This paper was reviewed by Tom Hughes, Cardiff, UK.
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