Stroke Mimics: A Comprehensive Review for the Practicing Internist

Dr Neeraj Manikath , claude.ai

Abstract

Stroke mimics account for approximately 15-30% of acute stroke code activations, creating diagnostic challenges that can lead to inappropriate thrombolytic therapy or missed alternative diagnoses. This review synthesizes current evidence on the most clinically relevant stroke mimics, their distinguishing features, and practical diagnostic approaches. Understanding these conditions is essential for emergency physicians, neurologists, and internists managing patients with suspected acute stroke.

Introduction

The rapid evaluation and treatment of acute ischemic stroke has revolutionized outcomes, with thrombolysis and thrombectomy offering significant benefits within critical time windows. However, this urgency creates a paradox: the pressure to treat quickly may lead to misdiagnosis of stroke mimics. Studies demonstrate that 15-30% of patients receiving thrombolysis ultimately have non-stroke diagnoses, though serious complications from inappropriate treatment remain relatively rare at 0.5-1%.

The differential diagnosis of stroke mimics spans metabolic, infectious, structural, functional, and toxic etiologies. Recognizing these conditions requires systematic clinical reasoning that balances the imperative for rapid stroke treatment against the risk of misdiagnosis.

Epidemiology and Clinical Impact

Stroke mimics are more common in certain populations. Younger patients (under 50 years), those with seizures at onset, absence of vascular risk factors, and presentation with isolated sensory symptoms or decreased level of consciousness show higher rates of stroke mimicry. The most commonly misdiagnosed conditions include seizures (18-23%), systemic infections with delirium (12-15%), functional neurological disorders (10-12%), and metabolic encephalopathies (8-10%).

Pearl: The "FABS" mnemonic (Fever, Absence of vascular risk factors, Bilateral symptoms, Seizure) can raise suspicion for stroke mimics, though these features have limited sensitivity and should not delay imaging.

Major Stroke Mimic Categories

Seizures and Postictal States

Todd's paralysis represents transient postictal weakness lasting minutes to 48 hours, mimicking acute stroke. Historical features including witnessed convulsive activity, tongue biting, incontinence, or prolonged confusion favor seizure. However, focal seizures without obvious convulsive activity pose diagnostic challenges.

Distinguishing features:

Positive neurological phenomena (jerking, sensory symptoms) at onset favor seizure
Gradual improvement over minutes to hours is characteristic
EEG showing lateralized periodic discharges or focal slowing supports recent seizure
MRI with restricted diffusion in cortical distribution following gyral pattern suggests seizure
Hyperperfusion on CT or MRI perfusion (opposite to ischemic stroke) may be present

Oyster: Stroke can trigger seizures (estimated 2-4% acutely), creating dual pathology. When uncertainty exists, treat the stroke acutely and address seizure management subsequently.

Hemiplegic Migraine

Hemiplegic migraine presents with transient unilateral motor weakness accompanied by typical migraine features. Familial hemiplegic migraine involves genetic mutations (CACNA1A, ATP1A2, SCN1A), while sporadic cases lack family history.

Key differentiators:

Gradual onset with progressive "march" of symptoms over 5-60 minutes (versus sudden stroke onset)
Complete reversibility, though symptoms may last hours
Accompanying headache (though may be absent or delayed)
History of similar episodes
Age typically under 50 years
Normal vascular imaging

Hack: In recurrent cases, obtaining genetic testing during workup (not acutely) can provide diagnostic certainty and guide family counseling.

Functional Neurological Disorder

Functional neurological disorders (conversion disorders) present with neurological symptoms incompatible with known neuroanatomical patterns. These represent approximately 10-12% of stroke mimics, particularly in younger patients without vascular risk factors.

Clinical clues:

Inconsistency on examination (varying weakness with different maneuvers)
Hoover's sign (absence of hip extension when lifting opposite leg)
Splitting of midline on sensory testing
Tubular visual field defects
Dramatic improvement with suggestion or distraction
Normal neuroimaging including diffusion-weighted sequences

Pearl: Approach these patients with empathy and avoid judgmental language. The symptoms are real to the patient, and a positive diagnosis using specific signs is more helpful than diagnosis by exclusion. Early psychiatric/psychology involvement improves outcomes.

Hypoglycemia

Severe hypoglycemia (typically <40 mg/dL or <2.2 mmol/L) can produce focal neurological deficits mimicking stroke. This represents a critical "not-to-miss" diagnosis as treatment is immediately available and curative.

Recognition features:

Point-of-care glucose testing is mandatory in all suspected strokes
Diaphoresis, tachycardia, or altered mental status may accompany focal findings
Patients with diabetes, particularly on insulin or sulfonylureas, are highest risk
Rapid resolution with glucose administration is diagnostic and therapeutic
Rare cases show restricted diffusion on MRI, typically in splenium of corpus callosum

Hack: Always obtain glucose measurement before CT imaging when possible. Even brief delays for imaging can be harmful in severe hypoglycemia.

Intracranial Mass Lesions

Brain tumors, subdural hematomas, and brain abscesses occasionally present with acute neurological deterioration mimicking stroke. These account for 5-8% of stroke mimics.

Distinguishing characteristics:

Subacute progression over days to weeks with acute worsening
Seizures at presentation (40-50% of tumors)
Headache, particularly worse in morning or with Valsalva
Papilledema on fundoscopy (though often absent acutely)
Surrounding vasogenic edema on MRI (versus cytotoxic edema in stroke)
Mass effect with midline shift
Enhancement patterns atypical for stroke

Oyster: Hemorrhagic transformation of brain metastases can closely mimic hemorrhagic stroke. Look for disproportionate edema and consider CT with contrast if hemorrhage seems atypical.

Toxic-Metabolic Encephalopathies

Hepatic encephalopathy, uremia, hyperammonemia, and other metabolic derangements can produce focal neurological findings, particularly in patients with pre-existing anatomical vulnerabilities.

Clinical approach:

Asterixis, though nonspecific, suggests metabolic etiology
Fluctuating level of consciousness is more common than in pure stroke
Bilateral symptoms or multiple vascular territories should raise suspicion
Basic metabolic panel identifies most cases
Consider ammonia level in unexplained encephalopathy

Multiple Sclerosis and Demyelinating Disorders

Acute demyelinating lesions in eloquent locations can mimic stroke, particularly in younger patients.

Differentiating features:

Age typically 20-50 years
Subacute onset over hours (though can be acute)
Prior episodes of neurological dysfunction
Optic neuritis, internuclear ophthalmoplegia, or Lhermitte's sign
MRI shows T2 hyperintense periventricular lesions perpendicular to corpus callosum ("Dawson's fingers")
CSF oligoclonal bands (though not needed for acute management)

Pearl: The presence of multiple age-dissociated lesions on MRI (some with enhancement, others without) strongly suggests demyelinating disease rather than acute stroke.

Central Nervous System Infections

Meningitis, encephalitis, and brain abscesses can present with focal deficits. Herpes simplex encephalitis classically affects temporal lobes, potentially mimicking posterior circulation stroke.

Red flags for infection:

Fever and headache (though both can occur in stroke)
Altered mental status disproportionate to focal findings
Seizures
Meningismus
CSF pleocytosis, elevated protein, reduced glucose
MRI findings in medial temporal lobes with herpes encephalitis

Hack: In patients with fever and stroke symptoms, consider both stroke with concurrent infection and infectious stroke mimics. Don't anchor on a single diagnosis.

Peripheral Neurological Disorders

Bell's palsy and other peripheral nerve lesions occasionally prompt stroke evaluation, particularly when patients or providers focus on facial asymmetry.

Key distinguisher:

Forehead involvement indicates peripheral (Bell's palsy) rather than central (stroke) facial weakness
Hyperacusis, loss of taste, or ear pain suggest Bell's palsy
Absence of other cortical or brainstem signs
Normal brain imaging

Diagnostic Approach and Decision-Making

Clinical Assessment

A systematic examination remains fundamental despite technological advances. Key elements include:

Temporal profile: Stroke produces maximal deficit at onset. Progressive or stuttering symptoms suggest alternatives.
Pattern recognition: Symptoms conforming to single vascular territories favor stroke. Bizarre distributions, multiple territories, or non-anatomical patterns suggest mimics.
Vascular risk factors: Absence in younger patients increases mimic probability (though never excludes stroke).
Associated features: Fever, headache, seizure, or constitutional symptoms broaden the differential.

Neuroimaging

CT imaging remains first-line for rapid hemorrhage exclusion and stroke assessment. CT angiography identifies large vessel occlusions guiding thrombectomy decisions.

MRI with diffusion-weighted imaging provides superior sensitivity for acute ischemia, detecting lesions within minutes of onset. However, approximately 20-25% of strokes show negative DWI in the first 24 hours, particularly small lacunar or brainstem strokes.

Pearl: Negative MRI doesn't exclude stroke but significantly reduces probability. Clinical context remains paramount.

Laboratory Evaluation

Essential testing includes:

Point-of-care glucose (immediate)
Complete blood count (infection, thrombocytopenia)
Metabolic panel (electrolytes, renal function, glucose)
Coagulation studies (particularly if anticoagulation considered)
Troponin (cardiac events can coexist)

Additional testing based on clinical suspicion:

Toxicology screening
Ammonia, liver function tests
Blood cultures
Lumbar puncture (when infection or subarachnoid hemorrhage suspected)

Treatment Implications and Risk Mitigation

Thrombolysis in Uncertain Cases

The decision to administer thrombolysis when stroke mimics are possible requires careful risk-benefit analysis. Current evidence suggests:

Serious hemorrhagic complications in mimics occur in <1% of cases
Delay waiting for absolute certainty may harm true stroke patients
Most mimics receiving thrombolysis suffer no adverse effects

Practical approach:

Use validated scales (NIHSS) to objectify deficits
Document clear deficits that matter to the patient
Involve neurology when available
Consider MRI when time permits and adds diagnostic value
Communicate uncertainty to patients/families during informed consent

Oyster: When doubt exists between stroke and seizure, simultaneous administration of benzodiazepines with thrombolysis is generally safe if both conditions are plausibly present.

Door-to-Needle Time Considerations

While speed remains critical for true strokes, brief additional time for focused evaluation may identify obvious mimics without compromising outcomes. A pragmatic approach includes:

Glucose testing (adds <2 minutes)
Focused history including onset characterization (adds 2-3 minutes)
Brief examination including consistency testing (adds 2-3 minutes)
Review of imaging for alternative diagnoses (no additional time if done during routine review)

This structured approach may prevent some unnecessary treatments without significantly delaying appropriate therapy.

Future Directions

Advances in diagnostic capabilities continue evolving. CT perfusion imaging helps distinguish stroke from mimics through perfusion patterns. Artificial intelligence algorithms show promise in detecting stroke mimics through pattern recognition beyond human capability. Blood biomarkers including GFAP, NfL, and other proteins may eventually provide rapid point-of-care stroke confirmation.

Conclusion

Stroke mimics represent a significant challenge in acute neurological care, requiring clinicians to balance competing priorities of rapid stroke treatment against diagnostic accuracy. A systematic approach incorporating temporal profile assessment, pattern recognition, focused examination, appropriate imaging, and selective laboratory testing enables identification of most mimics without compromising care for true stroke patients. Understanding common mimics, their distinguishing features, and their treatment implications empowers internists and neurologists to provide optimal care in this high-stakes clinical scenario.

Recognition that some diagnostic uncertainty is inherent and acceptable in this setting—coupled with knowledge that thrombolysis complications in mimics are rare—allows clinicians to act decisively when stroke is likely while remaining vigilant for alternative diagnoses that require different management approaches.

Selected References

Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke. 2003;34(1):71-76.
Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke. 2013;44(4):1080-1084.
Giraldo EA, Khalidi NA, Zinkstok SM. Recognizing stroke mimics. Expert Rev Cardiovasc Ther. 2013;11(5):583-595.
Tsivgoulis G, Zand R, Katsanos AH, et al. Safety of intravenous thrombolysis in stroke mimics: prospective 5-year study and comprehensive meta-analysis. Stroke. 2015;46(5):1281-1287.
Dawson A, Cloud GC, Pereira AC, Moynihan BJ. Stroke mimic diagnoses presenting to a hyperacute stroke unit. Clin Med (Lond). 2016;16(5):423-426.
Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology. 2010;74(17):1340-1345.
Ali SF, Viswanathan A, Singhal AB, et al. The Hajj pilgrimage and stroke. Int J Stroke. 2018;13(2):121-130.
Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome. Stroke. 2009;40(4):1522-1525.

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