The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–9, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter
http://dx.doi.org/10.1016/j.jemermed.2014.12.072
Clinical Review STROKE MIMICS AND ACUTE STROKE EVALUATION: CLINICAL DIFFERENTIATION AND COMPLICATIONS AFTER INTRAVENOUS TISSUE PLASMINOGEN ACTIVATOR Peggy L. Nguyen, MD* and Jason J. Chang, MD† *Department of Neurology, University of Southern California, Los Angeles, California and †Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee Reprint Address: Jason J. Chang, MD, Department of Neurology, University of Tennessee Health Science Center, 1325 Eastmoreland, Suite 460, Memphis, TN 38104
, Keywords—stroke mimic; stroke; fibrinolysis; thrombolysis; hemorrhage; hemorrhagic transformation; symptomatic intracranial hemorrhage; safety; tissue plasminogen activator; tPA
, Abstract—Background: Intravenous tissue-plasminogen activator remains the only U.S. Food and Drug Administration-approved treatment for acute ischemic stroke. Timely administration of fibrinolysis is balanced with the need for accurate diagnosis. Stroke mimics represent a heterogeneous group of patients presenting with acute-onset focal neurological deficits. If these patients arrive within the extended time window for acute stroke treatment, these stroke mimics may erroneously receive fibrinolytics. Objective: This review explores the literature and presents strategies for differentiating stroke mimics. Discussion: Clinical outcome in stroke mimics receiving fibrinolytics is overwhelmingly better than their stroke counterparts. However, the risk of symptomatic intracranial hemorrhage remains a real but rare possibility. Certain presenting complaints and epidemiological risk factors may help differentiate strokes from stroke mimics; however, detection of stroke often depends on presence of posterior vs. anterior circulation strokes. Availability of imaging modalities also assists in diagnosing stroke mimics, with magnetic resonance imaging offering the most sensitivity and specificity. Conclusion: Stroke mimics remain a heterogeneous entity that is difficult to identify. All studies in the literature report that stroke mimics treated with intravenous fibrinolysis have better clinical outcome than their stroke counterparts. Although symptomatic intracranial hemorrhage remains a real threat, literature searches have identified only two cases of symptomatic intracranial hemorrhage in stroke mimics treated with fibrinolytics. Ó 2015 Elsevier Inc.
INTRODUCTION Since the landmark National Institute of Neurological Disorders and Stroke (NINDS) study in 1995, intravenous tissue plasminogen activator (IVtPA) remains the only treatment approved by the U.S. Food and Drug Administration for acute ischemic stroke (AIS) within the extended 4.5-h time window (1). Earlier treatment and recanalization is clearly associated with improved mortality and clinical outcome due to prevention of neuronal ischemia (2,3). However, the timely manner in which AIS must be treated can result in patients without AIS erroneously receiving IVtPA. This heterogeneous group, presenting with acuteonset focal neurological deficits that are later found to have nonvascular etiologies, has been termed stroke mimics (MIM). Across all studies, MIM treated with IVtPA have significantly better clinical outcomes than their AIS counterparts. This review highlights four clinical questions pertaining to MIM: 1) defining MIM, 2) diagnosing and identifying MIM, 3) defining MIM etiologies, and 4) management of MIM after imaging confirmation.
RECEIVED: 19 July 2014; FINAL SUBMISSION RECEIVED: 4 December 2014; ACCEPTED: 22 December 2014 1
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DISCUSSION
Table 1. Compilation of Stroke Mimic Etiologies Receiving IVtPA and Complications
Defining Stroke Mimics Stroke mimics: heterogeneous definition and caseload per institution. Rates of MIM treated with IVtPA—ranging from 1.4% to 16.7%—vary widely by institute. Although numerous papers have cited MIM and their characteristics, lack of uniformity in defining AIS and MIM may be one reason for these heterogeneous rates (4–6). MIM classification ranges from purely clinical diagnosis to imaging confirmation with magnetic resonance imaging (MRI). With recent literature questioning the accuracy of diagnosing diffusion weighted imaging (DWI)negative imaging as ‘‘aborted strokes,’’ rates of MIM treated with IVtPA may actually be under-represented (7). Classification of MIM and aborted strokes based on clinical and radiological criteria remains ongoing and will likely shift reported rates of MIM treated with IVtPA. Caseloads of AIS and IVtPA administration also factor into rates of MIM treated with IVtPA. In general, higher MIM rates are found in larger volume stroke centers. Four single-center studies with MIM rates of 14%, 10.4%, 7%, and 6.5% yielded average yearly treatment rates of 102.4 patients/year for 5 years, 89.3 patients/year for 6 years, 81.4 patients/year for 4 years, and 92.6 patients/year for 7 years, respectively (8–11). Conversely, smallervolume centers are associated with lower rates of MIM. An institute’s function as a primary stroke center vs. a tertiary referral center for ‘‘drip-and-ship’’ IVtPA cases can also affect MIM rates. One tertiary center with mostly drip-and-ship IVtPA cases reported a MIM rate of 16.7% (120 patients/year for 1 year) (12). Symptomatic intracranial hemorrhage after IVtPA. As shown in Table 1, although the majority of studies did not report any instances of symptomatic intracranial hemorrhage (SIH), the risk of SIH remains a real and potentially destructive complication of IVtPA (8,9,11–15). A meta-analysis with IVtPA use in myocardial infarction reported an SIH rate of 0.94% (16). However, these early studies with myocardial infarction and IVtPA are difficult to compare due to differences in dosing (with higher amounts of fibrinolytics used in myocardial infarction) and oftentimes more aggressive concomitant use of therapies, such as heparinization and aspirin, which are typically withheld in current guidelines for IVtPA use in stroke (16). In fact, extensive literature searches for SIH in MIM treated with IVtPA yielded only two cases. One case report demonstrated SIH after IVtPA use in a patient with glioblastoma multiforme (17). And finally, a large multicenter study showed SIH rates of 1.0% (one patient with seizure) in MIM treated with IVtPA (18). Despite
Stroke Mimic Diagnosis Seizure (8–15,18) Tumor (9,11,14,17,18) Complicated migraine (8–12,14,15,18) Benign paroxysmal positional vertigo (9,14,15,18) Alcohol intoxication (9,14,18) Psychiatric (depression, anxiety, conversion disorder) (8–14,18) Myocardial infarction (9,14) Drug toxicity (9,14) Bell’s Palsy (9,12,14) Hypoglycemia (9,10,12,14,18) Syncope (8) Sepsis (12) Dementia (11) Spinal cord lesion (epidural abscess, spinal hematoma) (8,18) Meningitis (8) Encephalitis (15,18) Heat stroke (8) Demyelinating disease (9,10,14,15,18) Brachial plexopathy (18) Sinusitis (10,18) Amaurosis fugax (9,14) Rheumatoid arthritis (9,14) Appendicitis (9,14)
Hemorrhagic Conversion Other (Post IVtPA) Complications Yes Yes None
None None None
None
None
None None
None None
None None None None None None None None
None None None None None None None None
None None None None
None None None None
None None None None None
None None None None None
IVtPA = intravenous tissue plasminogen activator.
these low rates, SIH still remains possible, necessitating identification of MIM and avoidance of IVtPA. Diagnosis and Identification of Stroke Mimic Diagnosis. The diagnosis of AIS vs. MIM depends on several factors: presenting complaint, epidemiological factors, onset time of focal neurological deficit, presence of anterior vs. posterior circulation vascular distribution, and available imaging modalities for stroke evaluation. A summary of some of the factors favoring AIS vs. MIM are provided in Table 2. Presenting complaint. Presenting complaint can often indicate whether a clinical syndrome represents AIS or MIM. One study evaluated presenting complaints and found only three could be used to differentiate AIS from MIM: paresthesia (odds ratio [OR] 10) and chest pain (OR 16.7) identified MIM, whereas focal unilateral weakness (OR 4.15) identified AIS. Other presenting complaints—including altered mental status, aphasia, isolated facial droop, dizziness or vertigo, visual field
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Table 2. Factors Favoring Acute Ischemic Stroke (AIS) vs. Stroke Mimic (MIM) Favors AIS
Favors MIM
Inconclusive Gender (6,8,9,11–13,15,18) Age (6,8,9,11–15,18) Hypertension (6,8,9,11–13,18) Hyperlipidemia (6,8,9,11–13,18) Tobacco use (6,8,9,11–13,18) Diabetes (6,8,9,11–14,18) Coronary artery disease (4,8,11–13,18) Atrial fibrillation (8,9,11–15,18) Peripheral vascular disease (4,11) Prior stroke (5,11,18) Malignancy (11) Chronic kidney disease (11) Congestive heart failure (11) Obstructive sleep apnea (11) Alcohol abuse (11) Prior antiplatelet or anticoagulation use (18) Prior statin use (18) Psychiatric disorder (11,12) Paresthesia (4,11,14) Headache (4,11) Disorientation (11,14) Dizziness/vertigo (14) Visual field loss (4,11,14) Aphasia/loss of speech or language (4,11,14) Less severe clinical deficit (i.e., lower admission NIHSS) (6,9,12–14,18) Facial palsy (11,14) Convulsions at onset (4,11,14)
Epidemiology
None
Epilepsy (11,14) Migraine (11,14) Cognitive impairment (4,11)
Presenting complaint
Focal weakness Dysarthria (11) Hemiparesis (11) Horizontal gaze palsy (11) Visuospatial dysfunction/ neglect (4,11) Focal symptoms (4) Eye deviation (4)
Loss of consciousness (4) Global aphasia without hemiparesis (13,18) Chest pain (14)
NIHSS = National Institutes of Health Stroke Scale.
cut, seizure presentation—did not differentiate AIS from MIM (14). A different study found that aphasia (OR 2.55) and convulsions (OR 4.59) identified MIM, whereas dysarthria (OR 0.25), horizontal gaze palsy (OR 0.18), facial palsy (OR 0.22), hemiparesis (OR 0.26), paresthesia (OR 0.50), and visual field neglect (OR 0.15) identified AIS (11). The vast majority of presenting complaints that have been analyzed by more than three separate studies have had contradictory results. For instance, paresthesia, aphasia, and convulsions as presenting complaints were identified as MIM in one study, but as AIS in the other; this may be rectified by linking presenting complaints. Presenting complaints taken in isolation may be random, however, analyses linking certain combinations of presenting complaints may show better correlations with AIS or MIM. For instance, aphasia as an isolated complaint, which usually denotes left middle cerebral artery (MCA) territory infarct, may not confirm stroke. However, aphasia in combination with right-sided upper-extremity weakness, right-lower facial droop, and gaze deviation provides overwhelming clinical evidence of a large left MCA stroke. Simple neuroanatomical knowledge remains essential in stroke diagnosis. Epidemiology.The strongest and most consistent epidemiological variable in predicting MIM has been younger age,
with the only exception being Winkler et al., which found age to be inconclusive (8,9,11–15,18,19). A 10-year study of 8187 consecutive patients evaluated for stroke showed significant differences in metabolic risk factors (hypertension, diabetes, hyperlipidemia, coronary artery disease, and atrial fibrillation) between AIS and MIM (19). However, metabolic risk factors have been inconsistently associated with AIS in smaller studies involving administration of IVtPA to MIM. Atrial fibrillation is largely associated with AIS, with two studies showing inconclusive results (8,9,11–14,18–20). However, only one study showed diabetes as identifying AIS, only two studies showed coronary artery disease identifying AIS, only three studies showed hyperlipidemia identifying AIS, and only two studies showed hypertension identifying AIS (8,9,11,12,14,18). No study showed smoking history as being predictive of AIS. Time of onset. Onset time represents another critical variable in stroke evaluation due to the fluctuating nature of ischemia associated with the acute time period. Imaging studies have characterized this early ischemic fluctuation. In MRI studies, the initial DWI may be negative, only to show DWI positivity in the expected corresponding area when re-imaged at 225 min post ischemia (21). Similarly, a study of 39 patients who did not receive IVtPA due to initial rapidly improving clinical status showed that 4 of
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these patients later developed acute neurological deterioration. Of these 4 patients, 3 presented during an acute time frame (within 3 h of onset), suggesting that earlier time periods are associated with greater unpredictability in ischemia (22). Anterior vs. posterior circulation stroke. Location of the ischemic lesion dramatically influences diagnostic accuracy. An anterior circulation stroke involving the MCA or anterior cerebral artery (ACA) will usually present with clear focal deficits. This will include an upperextremity weakness, possibly aphasia (dependent on dominant hemisphere involvement), or leg weakness. Larger, more devastating strokes will damage the frontal eye fields, resulting in gaze deviation toward the affected hemisphere, resulting in contralateral leg weakness due to internal capsule involvement, and have varying degrees of worsening encephalopathy. Conversely, posterior circulation strokes often present with more amorphous symptoms lacking clear focal deficits. For instance, a cerebellar lesion may present with dizziness or ‘‘feeling drunk.’’ Pontine or lower midbrain lesions may present with an acute ophthalmoplegia or cranial nerve palsy, which, taken in isolation, may be misinterpreted as a peripheral neuropathy. Upper midbrain lesions due to basilar artery stroke may present with altered mental status or loss of consciousness. Finally, posterior cerebral artery strokes presenting with varying degrees of visual field deficits may go unnoticed by the patient and evaluator. One exception would be focal motor weakness due to corticospinal tract injury in a pontinepenetrating artery occlusion. Taken in isolation, each of these deficits is nonspecific, as such presentations can be attributed to metabolic etiologies. Posterior circulation stroke presentations oftentimes will go unnoticed; the most common stroke chameleons as reported by Dupre et al. are altered mental status changes, syncope or loss of consciousness, hypertensive emergency, and systemic infection (7). Imaging modalities for diagnosis. Imaging capacities for institutions for diagnosis of stroke will range from noncontrast computed tomography (CT) of the head—offering the lowest sensitivity and specificity—to MRI of the brain. Large anterior circulation strokes, where clot is thought to be located in a proximal large artery (i.e., proximal M1 occlusion) can usually be diagnosed with fair certainty and minimal imaging modalities (noncontrast CT head). For distal embolic strokes of the anterior circulation where clot is located in a distal artery (i.e., M2 occlusions) with atypical presentations (i.e., isolated aphasia or isolated R-arm weakness without facial involvement), the addition of angiography and perfusion imaging greatly aids the clinician in diagnosis. Finally,
P. L. Nguyen and J. J. Chang
posterior circulation strokes with their variable presentations oftentimes can be successfully diagnosed only with MRI imaging. For institutes with MRI capabilities, identification of AIS is straightforward due to the high sensitivity and specificity of the DWI sequence. Gradient echo imaging can also detect early, clinically asymptomatic hemorrhage and exclude patients who may be susceptible to potential SIH from IVtPA. MRI has been estimated to have a sensitivity of 83% and specificity of 96% irrespective of the practitioner’s clinical experience (23). When comparing a cohort consisting of clinical transient ischemic attacks (symptom duration under 24 h) and minor strokes (National Institutes of Health Stroke Scale < 4), MRI sensitivity of 56% surpasses CT sensitivity of 12% (p < 0.0001) (24). However, MRI is not absolutely sensitive for stroke detection with potential DWI-negative stroke rates of 2.2% (21). When commenting on focal neurological deficits with DWI-negative imaging, Ay et al. (1999) estimated that 63% of these cases would be ischemic strokes (21). The lower rates (approaching 40%) of DWI-negative ischemic strokes appearing in literature on MIM and IVtPA suggest that fibrinolysis of clots will result in lesser probability of permanent ischemia and more ‘‘aborted strokes’’ (8,14). However, these rates of DWI-negative aborted strokes in patients treated with IVtPA have recently been questioned by Freeman et al., who obtained pre- and post-IVtPA treatment MRI studies and found only 0.9% of patients treated with IVtPA had aborted strokes, as demonstrated by reversibility of DWI lesions (25). Centers without access to MRI dedicated for emergent stroke diagnosis can still utilize existing CT technology. Presence of diffuse atherosclerosis on CT angiography (CTA) has an OR of 23.6 for identifying an ischemic stroke (14). Any large-vessel occlusion noted on CTA predicted an increased modified Rankin Score (mRS) (OR 4.76, p = 0.02) that denoted a poorer, more disabled functional outcome (OR 5.07, p = 0.06) (26). Utilization of CT perfusion (CTP) for detection of stroke increased sensitivity to 71% and specificity to 88% over noncontrast CT head (27). Similarly, when looking for small ischemic lesions, evidenced by clinical transient ischemic attacks (duration of symptoms # 24 h), CT head was always negative, CTP identified ischemic lesions in 35% of patients, and MRI identified ischemic lesions in 53% of patients (28). Although IVtPA results in better clinical outcome than placebo in MCA occlusions, the importance of acute intervention in internal carotid artery (ICA) occlusions is debatable. In fact, treatment with IVtPA vs. placebo made no difference in clinical outcome after ICA occlusion (29). No literature exists on the use of endovascular
Stroke Mimics and Acute Stroke Evaluation
intervention exclusively in ICA occlusion. And although the recently published Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN) showed significantly improved clinical outcomes at 90 days for occlusions of the proximal anterior circulation, ICA occlusions were not well represented with only 4 cases total (30). Regardless, CTA, by identifying large-vessel occlusions, can stratify cases requiring further interventional procedures. Finally, noncontrast CT head is largely universally accessible and used to evaluate for absolute contraindications such as hemorrhage, and relative contraindications such as area of hypodensity. However, sensitivities for acute ischemic stroke detection are estimated at only 52.5% (27). Stroke Mimic Etiologies The most frequent stroke mimic etiologies and identifying characteristics are identified below. Complicated migraine. Complicated migraines originated from observations that auras of migraneurs resembled focal neurological deficits present during headaches. These focal deficits include scintillating scotomas, numbness, aphasia, dysarthria, and focal weakness, as can be seen in sporadic or familial hemiplegic migraines. Basilar-type migraines, which may be accompanied by decreased level of consciousness, vertigo, and ataxia, may mimic posterior circulation infarcts (31). Often, no accompanying headache or history of migraines can be elicited from the patient. Seizure. Seizures are one of the most commonly diagnosed stroke mimics in patients presenting to the emergency department (ED) (32–34). Seizures present more commonly in the ictal phase with positive symptoms such as motor stereotypes or paresthesias. However, negative symptoms such as postictal aphasia or paresis have been reported with an incidence up to 40% (35). In one case series involving 325 patients admitted to an epilepsy monitoring unit, 44 patients with a total of 72 recorded seizures had postictal paresis, more commonly after complex partial seizure as opposed to a secondarily generalized tonic-clonic seizure (36). Complicating the presentation is the concurrence of seizures and stroke. Bladin et al. found that seizures occurred in 9% of stroke patients, with 40% of seizures after ischemic stroke occurring in the first 24 h, and 57% of seizures after hemorrhagic stroke occurring in the first 24 h (37). Neoplasm. Acute neurologic presentations from cerebral neoplasms are less common than the progressive symp-
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toms, which usually result from slowly growing masses, yet according to the literature, 5% of patients diagnosed with brain tumors are diagnosed at initial presentation with stroke, and 12% of patients initially diagnosed with stroke were ultimately given the diagnosis of brain tumor (32,38). After seizure and systemic infection, brain tumor was the most common misdiagnosis in a case series of patients presenting through the ED (32). The most common presenting symptom in patients who were misdiagnosed at initial presentation were changes in vision, aphasia, and long tract symptoms, although pure motor hemiparesis has also been reported (32,39). The nature of the presentation likely predicates at least in part on the location of the tumor, which would mimic strokes in the same vascular territory. The exact mechanism of these stroke-like presentations is unclear, but have been suggested to include hemorrhage or tumor apoplexy, compressive acute intracranial pressure changes, and consequently, reduced cerebral blood flow, tumor embolus, and vascular compression or encasement (38,40). Gliomas, including glioblastoma multiforme, and meningiomas are most commonly reported, but additional case reports also exist in the literature with less common lesions represented, including central nervous system lymphoma and anaplastic astrocytoma (38,40–43). Metabolic. Metabolic derangements that may be mistaken for stroke include hypo- or hyperglycemia, electrolyte abnormalities, and hepatic encephalopathy (32,34). Neuroglycopenic symptoms most commonly manifest as confusion, personality change, and autonomic complaints, but can uncommonly present with focal symptoms such as hemiparesis (44). There appears to be a right-sided predominance, possibly attributable to differences in metabolism, although the etiology is unclear, with an average blood glucose level of 1.8 mmol/L, or approximately 32 mg/dL in patients with hypoglycemic hemiparesis. Conversely, hyperosmolar, nonketotic hyperglycemia can uncommonly present with movement disorders such as hemichorea-hemiballismus, which may mimic a basal ganglia infarct (45–47). This phenomenon is well documented in the literature and is seen at higher rates in females and those of East-Asian descent, and corrects with the normalization of serum glucose levels (47). Sepsis. Many case series have shown sepsis accounting for 6–17% of MIM (32–34). Encephalopathy, ranging from delirium to coma, weakness, and speech changes, may accompany sepsis. Some of these changes may be mediated by a combination of neuroinflammatory responses and alteration of the blood–brain barrier allowing the passage of neurotoxic markers, as well as
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P. L. Nguyen and J. J. Chang
Figure 1. Suggested radiological paradigm for evaluating acute-onset focal neurological deficits for thrombolysis. ICA = internal carotid artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; UE = upper extremity; CT = computed tomography; MRI = magnetic resonance imaging.
endothelial dysfunction leading to microcirculatory failure (48). Serum tests for markers of inflammation, including complete blood count with differential, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin can help make a diagnosis. Syncopal episode. In one case series, 13% of patients ultimately diagnosed as MIM presented with a syncopal episode (33). A syncopal episode may be misdiagnosed as a stroke of the vertebrobasilar artery system. Strokes of the vertebrobasilar artery distribution may lead to alteration of consciousness but will usually be accompanied by unilateral cranial nerve deficits leading to diplopia, dysarthria, vertigo, and ataxia. Isolated loss of consciousness, as would be expected in nonneurological syncope, is not the norm. Management Once a MIM is identified, the appropriate care specific to that etiology should be taken. If uncertainty still remains about whether a neurological deficit represents a stroke and advanced neuroimaging such as MRI is unavailable, the practitioner should be aggressive with IVtPA, especially if a posterior circulation stroke—with the lowest
sensitivity rate for imaging confirmation—is suspected. However, the risk of SIH in MIM in should also be acknowledged and discussed with the patient (18). Guidelines. Consensus guidelines do not exist for accuracy of stroke diagnosis. Stroke remains a clinical diagnosis based on the clinician’s experience and knowledge of neuroanatomy. As of 2014, the minimum imaging modality necessary for IVtPA use remains CT of the head, and exclusion criteria for IVtPA usage remains the same as delineated in the NINDS trial. CONCLUSIONS MIM can be erroneously treated with IVtPA. Although most studies show no harmful effects from treating a MIM with IVtPA and all studies report MIM having better clinical outcome than AIS counterparts, SIH still remains a potential adverse reaction. As such, MIM should be identified. However, given time constraints and the necessity to treat AIS quickly, absolute confirmation may not always be feasible or practical. MIM remain a heterogeneous entity that can be difficult to identify. A uniform definition for AIS and MIM does not exist in the literature—definitions range from
Stroke Mimics and Acute Stroke Evaluation
clinical diagnosis to imaging confirmation. MRI remains the most sensitive and specific radiological tool for identifying AIS. Our authors suggest that AIS and MIM diagnosis be stratified by the uncertainty associated with vessel occlusions or emboli affecting the following occluded blood vessels: 1) anterior circulation occlusion of a proximal large vessel, 2) anterior circulation stroke of a distal blood vessel, 3) posterior circulation stroke. As shown in Figure 1, the authors recommend that correspondingly more sensitive imaging modalities may be necessary to identify a MIM (i.e., MRI of the brain for identification of posterior circulation strokes, CT perfusion and angiography for identification of anterior circulation strokes of distal blood vessels, and CT of the head for identification of anterior circulation strokes of proximal large vessels). Regardless of stroke location, CTA is useful for evaluation of proximal occlusions in the ICA, MCA, ACA, or basilar artery to stratify patients that may benefit from endovascular intervention. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–7. 2. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309:2480–8. 3. Saver JL. Time is brain—quantified. Stroke 2006;37:263–6. 4. Hand PJ, Kwan J, Lindley RI, Dennis MS, Wardlaw JM. Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke 2006;37:769–75. 5. Tobin WO, Hentz JG, Bobrow BJ, Demaerschalk BM. Identification of stroke mimics in the emergency department setting. J Brain Dis 2009;1:19–22. 6. Brunser AM, Illanes S, Lavados PM, et al. Exclusion criteria for intravenous thrombolysis in stroke mimics: an observational study. J Stroke Cerebrovasc Dis 2013;22:1140–5. 7. Dupre CM, Libman R, Dupre SI, Katz JM, Rybinnik I, Kwiatkowski T. Stroke chameleons. J Stroke Cerebrovasc Dis 2014;23:374–8. 8. Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010;74:1340–5. 9. Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series. Stroke 2011; 42:1771–4. 10. Sarikaya H, Yilmaz M, Luft AR, Gantenbein AR. Different pattern of clinical deficits in stroke mimics treated with intravenous thrombolysis. Eur Neurol 2012;68:344–9. 11. Forster A, Griebe M, Wolf ME, Szabo K, Hennerici MG, Kern R. How to identify stroke mimics in patients eligible for intravenous thrombolysis? J Neurol 2012;259:1347–53. 12. Mehta S, Vora N, Edgell RC, et al. Stroke mimics under the dripand-ship paradigm. J Stroke Cerebrovasc Dis 2014;23:844–9. 13. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome. Stroke 2009;40: 1522–5. 14. Chang J, Teleb M, Yang JP, et al. A model to prevent fibrinolysis in patients with stroke mimics. J Stroke Cerebrovasc Dis 2012;21: 839–43.
7 15. Artto V, Putaala J, Strbian D, et al. Stroke mimics and intravenous thrombolysis. Ann Emerg Med 2012;59:27–32. 16. Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review. QJM 2003;96:103–13. 17. Grimm SA, DeAngelis LM. Intratumoral hemorrhage after thrombolysis in a patient with glioblastoma multiforme. Neurology 2007;69:936. 18. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke 2013;44:1080–4. 19. Merino JG, Luby M, Benson RT, et al. Predictors of acute stroke mimics in 8187 patients referred to a stroke service. J Stroke Cerebrovasc Dis 2013;22:e397–403. 20. Spokoyny I, Raman R, Ernstrom K, Meyer BC, Hemmen TM. Imaging negative stroke: diagnoses and outcomes in intravenous tissue plasminogen activator-treated patients. J Stroke Cerebrovasc Dis 2014;23:1046–50. 21. Ay H, Buonanno FS, Rordorf G, et al. Normal diffusion-weighted MRI during stroke-like deficits. Neurology 1999;52:1784–92. 22. Rajajee V, Kidwell C, Starkman S, et al. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology 2006;67:980–4. 23. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369:293–8. 24. Moreau F, Asdaghi N, Modi J, Goyal M, Coutts SB. Magnetic resonance imaging versus computed tomography in transient ischemic attack and minor stroke: the more you see the more you know. Cerebrovasc Dis Extra 2013;3:130–6. 25. Freeman JW, Luby M, Merino JG, et al. Negative diffusionweighted imaging after intravenous tissue-type plasminogen activator is rare and unlikely to indicate averted infarction. Stroke 2013;44:1629–34. 26. Poisson SN, Nguyen-Huynh MN, Johnston SC, Furie KL, Lev MH, Smith WS. Intracranial large vessel occlusion as a predictor of decline in functional status after transient ischemic attack. Stroke 2011;42:44–7. 27. Hopyan J, Ciarallo A, Dowlatshahi D, et al. Certainty of stroke diagnosis: incremental benefit with CT perfusion over noncontrast CT and CT angiography. Radiology 2010;255:142–53. 28. Kleinman JT, Mlynash M, Zaharchuk G, et al. Yield of CT perfusion for the evaluation of transient ischaemic attack. Int J Stroke 2012 Dec 11; http://dx.doi.org/10.1111/j.1747-4949.2012.00941.x. [Epub ahead of print]. 29. De Silva DA, Brekenfeld C, Ebinger M, et al. The benefits of intravenous thrombolysis relate to the site of baseline arterial occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Stroke 2010;41:295–9. 30. Berkhemer OA, Fransen PSS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med 2015;372:11–20. 31. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(Suppl 1):9–160. 32. Libman RB, Wirkowski E, Alvir J, Rao TH. Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol 1995;52:1119–22. 33. Kose A, Inal T, Armagan E, Kiyak R, Demir AB. Conditions that mimic stroke in elderly patients admitted to the emergency department. J Stroke Cerebrovasc Dis 2013;22:e522–7. 34. Fernandes PM, Whiteley WN, Hart SR, Al-Shahi Salman R. Strokes: mimics and chameleons. Pract Neurol 2013;13:21–8. 35. Adam C, Adam C, Rouleau I, Saint-Hilaire JM. Postictal aphasia and paresis: a clinical and intracerebral EEG study. Can J Neurol Sci 2000;27:49–54. 36. Gallmetzer P, Leutmezer F, Serles W, Assem-Hilger E, Spatt J, Baumgartner C. Postictal paresis in focal epilepsies—incidence, duration, and causes: a video-EEG monitoring study. Neurology 2004;62:2160–4.
8 37. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57:1617–22. 38. Morgenstern LB, Frankowski RF. Brain tumor masquerading as stroke. J Neurooncol 1999;44:47–52. 39. Fisher M, Recht LD. Brain tumor presenting as an acute pure motor hemiparesis. Stroke 1989;20:288–91. 40. Intracranial tumours that mimic transient cerebral ischaemia: lessons from a large multicentre trial. The UK TIA Study Group. J Neurol Neurosurg Psychiatry 1993;56:563–6. 41. Sumer M, Ozon AO, Bakar B, Cila A, Ruacan S. Intravascular lymphoma masquerading as multiembolic stroke developing after coronary artery by-pass surgery. Neurologist 2009;15:98–101. 42. Streletz LJ, Terzic D, Salem K, Raza A, Deleu DT. CNS lymphoma masquerading as hemorrhagic stroke. Clin Neurol Neurosurg 2012; 114:262–4.
P. L. Nguyen and J. J. Chang 43. Li L, Yin J, Li Y, et al. Anaplastic astrocytoma masquerading as hemorrhagic stroke. J Clin Neurosci 2013;20:1612–4. 44. Yoshino T, Meguro S, Soeda Y, Itoh A, Kawai T, Itoh H. A case of hypoglycemic hemiparesis and literature review. Ups J Med Sci 2012;117:347–51. 45. Cheema H, Federman D, Kam A. Hemichorea-hemiballismus in non-ketotic hyperglycaemia. J Clin Neurosci 2011;18:293–4. 46. Padmanabhan S, Zagami AS, Poynten AM. A case of hemichoreahemiballismus due to nonketotic hyperglycemia. Diabetes Care 2013;36:e55–6. 47. Postuma RB, Lang AE. Hemiballism: revisiting a classic disorder. Lancet Neurol 2003;2:661–8. 48. Adam N, Kandelman S, Mantz J, Chretien F, Sharshar T. Sepsisinduced brain dysfunction. Expert Rev Anti Infect Ther 2013;11: 211–21.
Stroke Mimics and Acute Stroke Evaluation
ARTICLE SUMMARY 1. Why is the topic important? The topic is important to emergency physicians and neurologists because the most impactful acute stroke treatment begins and ends in the emergency department with the use of fibrinolysis. All treatment after the time window for recombinant tissue plasminogen activator (rt-PA) passes by is supportive. 2. What does this review attempt to show? This review attempts to show that rt-PA is largely safe to use in patients without ischemic stroke and that a large amount of uncertainty occurs when diagnosing posterior circulation strokes. 3. What are the key findings? Surveying the literature yields only two cases of symptomatic intracranial hemorrhage in stroke mimics that received intravenous rt-PA: one case of seizure and one case of glioblastoma multiforme. Earlier rates of symptomatic intracranial hemorrhage occurred in patients receiving different doses of intravenous rt-PA for myocardial infarction. 4. How is patient care impacted? Patient care will be impacted because if more eligible patients receive intravenous rt-PA, greater disability can be prevented. Until magnetic resonance imaging becomes more universal as an admission diagnostic tool, some degree of uncertainty—particularly when dealing with posterior circulation strokes—will always exist. This review explores the assertion that the probability of symptomatic intracranial hemorrhage in stroke mimics may actually be less harmful than the uncertainty of not giving treatment to a potential stroke.
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http://dx.doi.org/10.1016/j.jemermed.2014.12.072
Clinical Review STROKE MIMICS AND ACUTE STROKE EVALUATION: CLINICAL DIFFERENTIATION AND COMPLICATIONS AFTER INTRAVENOUS TISSUE PLASMINOGEN ACTIVATOR Peggy L. Nguyen, MD* and Jason J. Chang, MD† *Department of Neurology, University of Southern California, Los Angeles, California and †Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee Reprint Address: Jason J. Chang, MD, Department of Neurology, University of Tennessee Health Science Center, 1325 Eastmoreland, Suite 460, Memphis, TN 38104
, Keywords—stroke mimic; stroke; fibrinolysis; thrombolysis; hemorrhage; hemorrhagic transformation; symptomatic intracranial hemorrhage; safety; tissue plasminogen activator; tPA
, Abstract—Background: Intravenous tissue-plasminogen activator remains the only U.S. Food and Drug Administration-approved treatment for acute ischemic stroke. Timely administration of fibrinolysis is balanced with the need for accurate diagnosis. Stroke mimics represent a heterogeneous group of patients presenting with acute-onset focal neurological deficits. If these patients arrive within the extended time window for acute stroke treatment, these stroke mimics may erroneously receive fibrinolytics. Objective: This review explores the literature and presents strategies for differentiating stroke mimics. Discussion: Clinical outcome in stroke mimics receiving fibrinolytics is overwhelmingly better than their stroke counterparts. However, the risk of symptomatic intracranial hemorrhage remains a real but rare possibility. Certain presenting complaints and epidemiological risk factors may help differentiate strokes from stroke mimics; however, detection of stroke often depends on presence of posterior vs. anterior circulation strokes. Availability of imaging modalities also assists in diagnosing stroke mimics, with magnetic resonance imaging offering the most sensitivity and specificity. Conclusion: Stroke mimics remain a heterogeneous entity that is difficult to identify. All studies in the literature report that stroke mimics treated with intravenous fibrinolysis have better clinical outcome than their stroke counterparts. Although symptomatic intracranial hemorrhage remains a real threat, literature searches have identified only two cases of symptomatic intracranial hemorrhage in stroke mimics treated with fibrinolytics. Ó 2015 Elsevier Inc.
INTRODUCTION Since the landmark National Institute of Neurological Disorders and Stroke (NINDS) study in 1995, intravenous tissue plasminogen activator (IVtPA) remains the only treatment approved by the U.S. Food and Drug Administration for acute ischemic stroke (AIS) within the extended 4.5-h time window (1). Earlier treatment and recanalization is clearly associated with improved mortality and clinical outcome due to prevention of neuronal ischemia (2,3). However, the timely manner in which AIS must be treated can result in patients without AIS erroneously receiving IVtPA. This heterogeneous group, presenting with acuteonset focal neurological deficits that are later found to have nonvascular etiologies, has been termed stroke mimics (MIM). Across all studies, MIM treated with IVtPA have significantly better clinical outcomes than their AIS counterparts. This review highlights four clinical questions pertaining to MIM: 1) defining MIM, 2) diagnosing and identifying MIM, 3) defining MIM etiologies, and 4) management of MIM after imaging confirmation.
RECEIVED: 19 July 2014; FINAL SUBMISSION RECEIVED: 4 December 2014; ACCEPTED: 22 December 2014 1
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DISCUSSION
Table 1. Compilation of Stroke Mimic Etiologies Receiving IVtPA and Complications
Defining Stroke Mimics Stroke mimics: heterogeneous definition and caseload per institution. Rates of MIM treated with IVtPA—ranging from 1.4% to 16.7%—vary widely by institute. Although numerous papers have cited MIM and their characteristics, lack of uniformity in defining AIS and MIM may be one reason for these heterogeneous rates (4–6). MIM classification ranges from purely clinical diagnosis to imaging confirmation with magnetic resonance imaging (MRI). With recent literature questioning the accuracy of diagnosing diffusion weighted imaging (DWI)negative imaging as ‘‘aborted strokes,’’ rates of MIM treated with IVtPA may actually be under-represented (7). Classification of MIM and aborted strokes based on clinical and radiological criteria remains ongoing and will likely shift reported rates of MIM treated with IVtPA. Caseloads of AIS and IVtPA administration also factor into rates of MIM treated with IVtPA. In general, higher MIM rates are found in larger volume stroke centers. Four single-center studies with MIM rates of 14%, 10.4%, 7%, and 6.5% yielded average yearly treatment rates of 102.4 patients/year for 5 years, 89.3 patients/year for 6 years, 81.4 patients/year for 4 years, and 92.6 patients/year for 7 years, respectively (8–11). Conversely, smallervolume centers are associated with lower rates of MIM. An institute’s function as a primary stroke center vs. a tertiary referral center for ‘‘drip-and-ship’’ IVtPA cases can also affect MIM rates. One tertiary center with mostly drip-and-ship IVtPA cases reported a MIM rate of 16.7% (120 patients/year for 1 year) (12). Symptomatic intracranial hemorrhage after IVtPA. As shown in Table 1, although the majority of studies did not report any instances of symptomatic intracranial hemorrhage (SIH), the risk of SIH remains a real and potentially destructive complication of IVtPA (8,9,11–15). A meta-analysis with IVtPA use in myocardial infarction reported an SIH rate of 0.94% (16). However, these early studies with myocardial infarction and IVtPA are difficult to compare due to differences in dosing (with higher amounts of fibrinolytics used in myocardial infarction) and oftentimes more aggressive concomitant use of therapies, such as heparinization and aspirin, which are typically withheld in current guidelines for IVtPA use in stroke (16). In fact, extensive literature searches for SIH in MIM treated with IVtPA yielded only two cases. One case report demonstrated SIH after IVtPA use in a patient with glioblastoma multiforme (17). And finally, a large multicenter study showed SIH rates of 1.0% (one patient with seizure) in MIM treated with IVtPA (18). Despite
Stroke Mimic Diagnosis Seizure (8–15,18) Tumor (9,11,14,17,18) Complicated migraine (8–12,14,15,18) Benign paroxysmal positional vertigo (9,14,15,18) Alcohol intoxication (9,14,18) Psychiatric (depression, anxiety, conversion disorder) (8–14,18) Myocardial infarction (9,14) Drug toxicity (9,14) Bell’s Palsy (9,12,14) Hypoglycemia (9,10,12,14,18) Syncope (8) Sepsis (12) Dementia (11) Spinal cord lesion (epidural abscess, spinal hematoma) (8,18) Meningitis (8) Encephalitis (15,18) Heat stroke (8) Demyelinating disease (9,10,14,15,18) Brachial plexopathy (18) Sinusitis (10,18) Amaurosis fugax (9,14) Rheumatoid arthritis (9,14) Appendicitis (9,14)
Hemorrhagic Conversion Other (Post IVtPA) Complications Yes Yes None
None None None
None
None
None None
None None
None None None None None None None None
None None None None None None None None
None None None None
None None None None
None None None None None
None None None None None
IVtPA = intravenous tissue plasminogen activator.
these low rates, SIH still remains possible, necessitating identification of MIM and avoidance of IVtPA. Diagnosis and Identification of Stroke Mimic Diagnosis. The diagnosis of AIS vs. MIM depends on several factors: presenting complaint, epidemiological factors, onset time of focal neurological deficit, presence of anterior vs. posterior circulation vascular distribution, and available imaging modalities for stroke evaluation. A summary of some of the factors favoring AIS vs. MIM are provided in Table 2. Presenting complaint. Presenting complaint can often indicate whether a clinical syndrome represents AIS or MIM. One study evaluated presenting complaints and found only three could be used to differentiate AIS from MIM: paresthesia (odds ratio [OR] 10) and chest pain (OR 16.7) identified MIM, whereas focal unilateral weakness (OR 4.15) identified AIS. Other presenting complaints—including altered mental status, aphasia, isolated facial droop, dizziness or vertigo, visual field
Stroke Mimics and Acute Stroke Evaluation
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Table 2. Factors Favoring Acute Ischemic Stroke (AIS) vs. Stroke Mimic (MIM) Favors AIS
Favors MIM
Inconclusive Gender (6,8,9,11–13,15,18) Age (6,8,9,11–15,18) Hypertension (6,8,9,11–13,18) Hyperlipidemia (6,8,9,11–13,18) Tobacco use (6,8,9,11–13,18) Diabetes (6,8,9,11–14,18) Coronary artery disease (4,8,11–13,18) Atrial fibrillation (8,9,11–15,18) Peripheral vascular disease (4,11) Prior stroke (5,11,18) Malignancy (11) Chronic kidney disease (11) Congestive heart failure (11) Obstructive sleep apnea (11) Alcohol abuse (11) Prior antiplatelet or anticoagulation use (18) Prior statin use (18) Psychiatric disorder (11,12) Paresthesia (4,11,14) Headache (4,11) Disorientation (11,14) Dizziness/vertigo (14) Visual field loss (4,11,14) Aphasia/loss of speech or language (4,11,14) Less severe clinical deficit (i.e., lower admission NIHSS) (6,9,12–14,18) Facial palsy (11,14) Convulsions at onset (4,11,14)
Epidemiology
None
Epilepsy (11,14) Migraine (11,14) Cognitive impairment (4,11)
Presenting complaint
Focal weakness Dysarthria (11) Hemiparesis (11) Horizontal gaze palsy (11) Visuospatial dysfunction/ neglect (4,11) Focal symptoms (4) Eye deviation (4)
Loss of consciousness (4) Global aphasia without hemiparesis (13,18) Chest pain (14)
NIHSS = National Institutes of Health Stroke Scale.
cut, seizure presentation—did not differentiate AIS from MIM (14). A different study found that aphasia (OR 2.55) and convulsions (OR 4.59) identified MIM, whereas dysarthria (OR 0.25), horizontal gaze palsy (OR 0.18), facial palsy (OR 0.22), hemiparesis (OR 0.26), paresthesia (OR 0.50), and visual field neglect (OR 0.15) identified AIS (11). The vast majority of presenting complaints that have been analyzed by more than three separate studies have had contradictory results. For instance, paresthesia, aphasia, and convulsions as presenting complaints were identified as MIM in one study, but as AIS in the other; this may be rectified by linking presenting complaints. Presenting complaints taken in isolation may be random, however, analyses linking certain combinations of presenting complaints may show better correlations with AIS or MIM. For instance, aphasia as an isolated complaint, which usually denotes left middle cerebral artery (MCA) territory infarct, may not confirm stroke. However, aphasia in combination with right-sided upper-extremity weakness, right-lower facial droop, and gaze deviation provides overwhelming clinical evidence of a large left MCA stroke. Simple neuroanatomical knowledge remains essential in stroke diagnosis. Epidemiology.The strongest and most consistent epidemiological variable in predicting MIM has been younger age,
with the only exception being Winkler et al., which found age to be inconclusive (8,9,11–15,18,19). A 10-year study of 8187 consecutive patients evaluated for stroke showed significant differences in metabolic risk factors (hypertension, diabetes, hyperlipidemia, coronary artery disease, and atrial fibrillation) between AIS and MIM (19). However, metabolic risk factors have been inconsistently associated with AIS in smaller studies involving administration of IVtPA to MIM. Atrial fibrillation is largely associated with AIS, with two studies showing inconclusive results (8,9,11–14,18–20). However, only one study showed diabetes as identifying AIS, only two studies showed coronary artery disease identifying AIS, only three studies showed hyperlipidemia identifying AIS, and only two studies showed hypertension identifying AIS (8,9,11,12,14,18). No study showed smoking history as being predictive of AIS. Time of onset. Onset time represents another critical variable in stroke evaluation due to the fluctuating nature of ischemia associated with the acute time period. Imaging studies have characterized this early ischemic fluctuation. In MRI studies, the initial DWI may be negative, only to show DWI positivity in the expected corresponding area when re-imaged at 225 min post ischemia (21). Similarly, a study of 39 patients who did not receive IVtPA due to initial rapidly improving clinical status showed that 4 of
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these patients later developed acute neurological deterioration. Of these 4 patients, 3 presented during an acute time frame (within 3 h of onset), suggesting that earlier time periods are associated with greater unpredictability in ischemia (22). Anterior vs. posterior circulation stroke. Location of the ischemic lesion dramatically influences diagnostic accuracy. An anterior circulation stroke involving the MCA or anterior cerebral artery (ACA) will usually present with clear focal deficits. This will include an upperextremity weakness, possibly aphasia (dependent on dominant hemisphere involvement), or leg weakness. Larger, more devastating strokes will damage the frontal eye fields, resulting in gaze deviation toward the affected hemisphere, resulting in contralateral leg weakness due to internal capsule involvement, and have varying degrees of worsening encephalopathy. Conversely, posterior circulation strokes often present with more amorphous symptoms lacking clear focal deficits. For instance, a cerebellar lesion may present with dizziness or ‘‘feeling drunk.’’ Pontine or lower midbrain lesions may present with an acute ophthalmoplegia or cranial nerve palsy, which, taken in isolation, may be misinterpreted as a peripheral neuropathy. Upper midbrain lesions due to basilar artery stroke may present with altered mental status or loss of consciousness. Finally, posterior cerebral artery strokes presenting with varying degrees of visual field deficits may go unnoticed by the patient and evaluator. One exception would be focal motor weakness due to corticospinal tract injury in a pontinepenetrating artery occlusion. Taken in isolation, each of these deficits is nonspecific, as such presentations can be attributed to metabolic etiologies. Posterior circulation stroke presentations oftentimes will go unnoticed; the most common stroke chameleons as reported by Dupre et al. are altered mental status changes, syncope or loss of consciousness, hypertensive emergency, and systemic infection (7). Imaging modalities for diagnosis. Imaging capacities for institutions for diagnosis of stroke will range from noncontrast computed tomography (CT) of the head—offering the lowest sensitivity and specificity—to MRI of the brain. Large anterior circulation strokes, where clot is thought to be located in a proximal large artery (i.e., proximal M1 occlusion) can usually be diagnosed with fair certainty and minimal imaging modalities (noncontrast CT head). For distal embolic strokes of the anterior circulation where clot is located in a distal artery (i.e., M2 occlusions) with atypical presentations (i.e., isolated aphasia or isolated R-arm weakness without facial involvement), the addition of angiography and perfusion imaging greatly aids the clinician in diagnosis. Finally,
P. L. Nguyen and J. J. Chang
posterior circulation strokes with their variable presentations oftentimes can be successfully diagnosed only with MRI imaging. For institutes with MRI capabilities, identification of AIS is straightforward due to the high sensitivity and specificity of the DWI sequence. Gradient echo imaging can also detect early, clinically asymptomatic hemorrhage and exclude patients who may be susceptible to potential SIH from IVtPA. MRI has been estimated to have a sensitivity of 83% and specificity of 96% irrespective of the practitioner’s clinical experience (23). When comparing a cohort consisting of clinical transient ischemic attacks (symptom duration under 24 h) and minor strokes (National Institutes of Health Stroke Scale < 4), MRI sensitivity of 56% surpasses CT sensitivity of 12% (p < 0.0001) (24). However, MRI is not absolutely sensitive for stroke detection with potential DWI-negative stroke rates of 2.2% (21). When commenting on focal neurological deficits with DWI-negative imaging, Ay et al. (1999) estimated that 63% of these cases would be ischemic strokes (21). The lower rates (approaching 40%) of DWI-negative ischemic strokes appearing in literature on MIM and IVtPA suggest that fibrinolysis of clots will result in lesser probability of permanent ischemia and more ‘‘aborted strokes’’ (8,14). However, these rates of DWI-negative aborted strokes in patients treated with IVtPA have recently been questioned by Freeman et al., who obtained pre- and post-IVtPA treatment MRI studies and found only 0.9% of patients treated with IVtPA had aborted strokes, as demonstrated by reversibility of DWI lesions (25). Centers without access to MRI dedicated for emergent stroke diagnosis can still utilize existing CT technology. Presence of diffuse atherosclerosis on CT angiography (CTA) has an OR of 23.6 for identifying an ischemic stroke (14). Any large-vessel occlusion noted on CTA predicted an increased modified Rankin Score (mRS) (OR 4.76, p = 0.02) that denoted a poorer, more disabled functional outcome (OR 5.07, p = 0.06) (26). Utilization of CT perfusion (CTP) for detection of stroke increased sensitivity to 71% and specificity to 88% over noncontrast CT head (27). Similarly, when looking for small ischemic lesions, evidenced by clinical transient ischemic attacks (duration of symptoms # 24 h), CT head was always negative, CTP identified ischemic lesions in 35% of patients, and MRI identified ischemic lesions in 53% of patients (28). Although IVtPA results in better clinical outcome than placebo in MCA occlusions, the importance of acute intervention in internal carotid artery (ICA) occlusions is debatable. In fact, treatment with IVtPA vs. placebo made no difference in clinical outcome after ICA occlusion (29). No literature exists on the use of endovascular
Stroke Mimics and Acute Stroke Evaluation
intervention exclusively in ICA occlusion. And although the recently published Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke (MR CLEAN) showed significantly improved clinical outcomes at 90 days for occlusions of the proximal anterior circulation, ICA occlusions were not well represented with only 4 cases total (30). Regardless, CTA, by identifying large-vessel occlusions, can stratify cases requiring further interventional procedures. Finally, noncontrast CT head is largely universally accessible and used to evaluate for absolute contraindications such as hemorrhage, and relative contraindications such as area of hypodensity. However, sensitivities for acute ischemic stroke detection are estimated at only 52.5% (27). Stroke Mimic Etiologies The most frequent stroke mimic etiologies and identifying characteristics are identified below. Complicated migraine. Complicated migraines originated from observations that auras of migraneurs resembled focal neurological deficits present during headaches. These focal deficits include scintillating scotomas, numbness, aphasia, dysarthria, and focal weakness, as can be seen in sporadic or familial hemiplegic migraines. Basilar-type migraines, which may be accompanied by decreased level of consciousness, vertigo, and ataxia, may mimic posterior circulation infarcts (31). Often, no accompanying headache or history of migraines can be elicited from the patient. Seizure. Seizures are one of the most commonly diagnosed stroke mimics in patients presenting to the emergency department (ED) (32–34). Seizures present more commonly in the ictal phase with positive symptoms such as motor stereotypes or paresthesias. However, negative symptoms such as postictal aphasia or paresis have been reported with an incidence up to 40% (35). In one case series involving 325 patients admitted to an epilepsy monitoring unit, 44 patients with a total of 72 recorded seizures had postictal paresis, more commonly after complex partial seizure as opposed to a secondarily generalized tonic-clonic seizure (36). Complicating the presentation is the concurrence of seizures and stroke. Bladin et al. found that seizures occurred in 9% of stroke patients, with 40% of seizures after ischemic stroke occurring in the first 24 h, and 57% of seizures after hemorrhagic stroke occurring in the first 24 h (37). Neoplasm. Acute neurologic presentations from cerebral neoplasms are less common than the progressive symp-
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toms, which usually result from slowly growing masses, yet according to the literature, 5% of patients diagnosed with brain tumors are diagnosed at initial presentation with stroke, and 12% of patients initially diagnosed with stroke were ultimately given the diagnosis of brain tumor (32,38). After seizure and systemic infection, brain tumor was the most common misdiagnosis in a case series of patients presenting through the ED (32). The most common presenting symptom in patients who were misdiagnosed at initial presentation were changes in vision, aphasia, and long tract symptoms, although pure motor hemiparesis has also been reported (32,39). The nature of the presentation likely predicates at least in part on the location of the tumor, which would mimic strokes in the same vascular territory. The exact mechanism of these stroke-like presentations is unclear, but have been suggested to include hemorrhage or tumor apoplexy, compressive acute intracranial pressure changes, and consequently, reduced cerebral blood flow, tumor embolus, and vascular compression or encasement (38,40). Gliomas, including glioblastoma multiforme, and meningiomas are most commonly reported, but additional case reports also exist in the literature with less common lesions represented, including central nervous system lymphoma and anaplastic astrocytoma (38,40–43). Metabolic. Metabolic derangements that may be mistaken for stroke include hypo- or hyperglycemia, electrolyte abnormalities, and hepatic encephalopathy (32,34). Neuroglycopenic symptoms most commonly manifest as confusion, personality change, and autonomic complaints, but can uncommonly present with focal symptoms such as hemiparesis (44). There appears to be a right-sided predominance, possibly attributable to differences in metabolism, although the etiology is unclear, with an average blood glucose level of 1.8 mmol/L, or approximately 32 mg/dL in patients with hypoglycemic hemiparesis. Conversely, hyperosmolar, nonketotic hyperglycemia can uncommonly present with movement disorders such as hemichorea-hemiballismus, which may mimic a basal ganglia infarct (45–47). This phenomenon is well documented in the literature and is seen at higher rates in females and those of East-Asian descent, and corrects with the normalization of serum glucose levels (47). Sepsis. Many case series have shown sepsis accounting for 6–17% of MIM (32–34). Encephalopathy, ranging from delirium to coma, weakness, and speech changes, may accompany sepsis. Some of these changes may be mediated by a combination of neuroinflammatory responses and alteration of the blood–brain barrier allowing the passage of neurotoxic markers, as well as
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P. L. Nguyen and J. J. Chang
Figure 1. Suggested radiological paradigm for evaluating acute-onset focal neurological deficits for thrombolysis. ICA = internal carotid artery; MCA = middle cerebral artery; ACA = anterior cerebral artery; UE = upper extremity; CT = computed tomography; MRI = magnetic resonance imaging.
endothelial dysfunction leading to microcirculatory failure (48). Serum tests for markers of inflammation, including complete blood count with differential, C-reactive protein, erythrocyte sedimentation rate, and procalcitonin can help make a diagnosis. Syncopal episode. In one case series, 13% of patients ultimately diagnosed as MIM presented with a syncopal episode (33). A syncopal episode may be misdiagnosed as a stroke of the vertebrobasilar artery system. Strokes of the vertebrobasilar artery distribution may lead to alteration of consciousness but will usually be accompanied by unilateral cranial nerve deficits leading to diplopia, dysarthria, vertigo, and ataxia. Isolated loss of consciousness, as would be expected in nonneurological syncope, is not the norm. Management Once a MIM is identified, the appropriate care specific to that etiology should be taken. If uncertainty still remains about whether a neurological deficit represents a stroke and advanced neuroimaging such as MRI is unavailable, the practitioner should be aggressive with IVtPA, especially if a posterior circulation stroke—with the lowest
sensitivity rate for imaging confirmation—is suspected. However, the risk of SIH in MIM in should also be acknowledged and discussed with the patient (18). Guidelines. Consensus guidelines do not exist for accuracy of stroke diagnosis. Stroke remains a clinical diagnosis based on the clinician’s experience and knowledge of neuroanatomy. As of 2014, the minimum imaging modality necessary for IVtPA use remains CT of the head, and exclusion criteria for IVtPA usage remains the same as delineated in the NINDS trial. CONCLUSIONS MIM can be erroneously treated with IVtPA. Although most studies show no harmful effects from treating a MIM with IVtPA and all studies report MIM having better clinical outcome than AIS counterparts, SIH still remains a potential adverse reaction. As such, MIM should be identified. However, given time constraints and the necessity to treat AIS quickly, absolute confirmation may not always be feasible or practical. MIM remain a heterogeneous entity that can be difficult to identify. A uniform definition for AIS and MIM does not exist in the literature—definitions range from
Stroke Mimics and Acute Stroke Evaluation
clinical diagnosis to imaging confirmation. MRI remains the most sensitive and specific radiological tool for identifying AIS. Our authors suggest that AIS and MIM diagnosis be stratified by the uncertainty associated with vessel occlusions or emboli affecting the following occluded blood vessels: 1) anterior circulation occlusion of a proximal large vessel, 2) anterior circulation stroke of a distal blood vessel, 3) posterior circulation stroke. As shown in Figure 1, the authors recommend that correspondingly more sensitive imaging modalities may be necessary to identify a MIM (i.e., MRI of the brain for identification of posterior circulation strokes, CT perfusion and angiography for identification of anterior circulation strokes of distal blood vessels, and CT of the head for identification of anterior circulation strokes of proximal large vessels). Regardless of stroke location, CTA is useful for evaluation of proximal occlusions in the ICA, MCA, ACA, or basilar artery to stratify patients that may benefit from endovascular intervention. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–7. 2. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013;309:2480–8. 3. Saver JL. Time is brain—quantified. Stroke 2006;37:263–6. 4. Hand PJ, Kwan J, Lindley RI, Dennis MS, Wardlaw JM. Distinguishing between stroke and mimic at the bedside: the brain attack study. Stroke 2006;37:769–75. 5. Tobin WO, Hentz JG, Bobrow BJ, Demaerschalk BM. Identification of stroke mimics in the emergency department setting. J Brain Dis 2009;1:19–22. 6. Brunser AM, Illanes S, Lavados PM, et al. Exclusion criteria for intravenous thrombolysis in stroke mimics: an observational study. J Stroke Cerebrovasc Dis 2013;22:1140–5. 7. Dupre CM, Libman R, Dupre SI, Katz JM, Rybinnik I, Kwiatkowski T. Stroke chameleons. J Stroke Cerebrovasc Dis 2014;23:374–8. 8. Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010;74:1340–5. 9. Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series. Stroke 2011; 42:1771–4. 10. Sarikaya H, Yilmaz M, Luft AR, Gantenbein AR. Different pattern of clinical deficits in stroke mimics treated with intravenous thrombolysis. Eur Neurol 2012;68:344–9. 11. Forster A, Griebe M, Wolf ME, Szabo K, Hennerici MG, Kern R. How to identify stroke mimics in patients eligible for intravenous thrombolysis? J Neurol 2012;259:1347–53. 12. Mehta S, Vora N, Edgell RC, et al. Stroke mimics under the dripand-ship paradigm. J Stroke Cerebrovasc Dis 2014;23:844–9. 13. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in stroke mimics: frequency, clinical characteristics, and outcome. Stroke 2009;40: 1522–5. 14. Chang J, Teleb M, Yang JP, et al. A model to prevent fibrinolysis in patients with stroke mimics. J Stroke Cerebrovasc Dis 2012;21: 839–43.
7 15. Artto V, Putaala J, Strbian D, et al. Stroke mimics and intravenous thrombolysis. Ann Emerg Med 2012;59:27–32. 16. Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review. QJM 2003;96:103–13. 17. Grimm SA, DeAngelis LM. Intratumoral hemorrhage after thrombolysis in a patient with glioblastoma multiforme. Neurology 2007;69:936. 18. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Stroke 2013;44:1080–4. 19. Merino JG, Luby M, Benson RT, et al. Predictors of acute stroke mimics in 8187 patients referred to a stroke service. J Stroke Cerebrovasc Dis 2013;22:e397–403. 20. Spokoyny I, Raman R, Ernstrom K, Meyer BC, Hemmen TM. Imaging negative stroke: diagnoses and outcomes in intravenous tissue plasminogen activator-treated patients. J Stroke Cerebrovasc Dis 2014;23:1046–50. 21. Ay H, Buonanno FS, Rordorf G, et al. Normal diffusion-weighted MRI during stroke-like deficits. Neurology 1999;52:1784–92. 22. Rajajee V, Kidwell C, Starkman S, et al. Early MRI and outcomes of untreated patients with mild or improving ischemic stroke. Neurology 2006;67:980–4. 23. Chalela JA, Kidwell CS, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet 2007;369:293–8. 24. Moreau F, Asdaghi N, Modi J, Goyal M, Coutts SB. Magnetic resonance imaging versus computed tomography in transient ischemic attack and minor stroke: the more you see the more you know. Cerebrovasc Dis Extra 2013;3:130–6. 25. Freeman JW, Luby M, Merino JG, et al. Negative diffusionweighted imaging after intravenous tissue-type plasminogen activator is rare and unlikely to indicate averted infarction. Stroke 2013;44:1629–34. 26. Poisson SN, Nguyen-Huynh MN, Johnston SC, Furie KL, Lev MH, Smith WS. Intracranial large vessel occlusion as a predictor of decline in functional status after transient ischemic attack. Stroke 2011;42:44–7. 27. Hopyan J, Ciarallo A, Dowlatshahi D, et al. Certainty of stroke diagnosis: incremental benefit with CT perfusion over noncontrast CT and CT angiography. Radiology 2010;255:142–53. 28. Kleinman JT, Mlynash M, Zaharchuk G, et al. Yield of CT perfusion for the evaluation of transient ischaemic attack. Int J Stroke 2012 Dec 11; http://dx.doi.org/10.1111/j.1747-4949.2012.00941.x. [Epub ahead of print]. 29. De Silva DA, Brekenfeld C, Ebinger M, et al. The benefits of intravenous thrombolysis relate to the site of baseline arterial occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). Stroke 2010;41:295–9. 30. Berkhemer OA, Fransen PSS, Beumer D, et al. A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. N Engl J Med 2015;372:11–20. 31. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(Suppl 1):9–160. 32. Libman RB, Wirkowski E, Alvir J, Rao TH. Conditions that mimic stroke in the emergency department. Implications for acute stroke trials. Arch Neurol 1995;52:1119–22. 33. Kose A, Inal T, Armagan E, Kiyak R, Demir AB. Conditions that mimic stroke in elderly patients admitted to the emergency department. J Stroke Cerebrovasc Dis 2013;22:e522–7. 34. Fernandes PM, Whiteley WN, Hart SR, Al-Shahi Salman R. Strokes: mimics and chameleons. Pract Neurol 2013;13:21–8. 35. Adam C, Adam C, Rouleau I, Saint-Hilaire JM. Postictal aphasia and paresis: a clinical and intracerebral EEG study. Can J Neurol Sci 2000;27:49–54. 36. Gallmetzer P, Leutmezer F, Serles W, Assem-Hilger E, Spatt J, Baumgartner C. Postictal paresis in focal epilepsies—incidence, duration, and causes: a video-EEG monitoring study. Neurology 2004;62:2160–4.
8 37. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57:1617–22. 38. Morgenstern LB, Frankowski RF. Brain tumor masquerading as stroke. J Neurooncol 1999;44:47–52. 39. Fisher M, Recht LD. Brain tumor presenting as an acute pure motor hemiparesis. Stroke 1989;20:288–91. 40. Intracranial tumours that mimic transient cerebral ischaemia: lessons from a large multicentre trial. The UK TIA Study Group. J Neurol Neurosurg Psychiatry 1993;56:563–6. 41. Sumer M, Ozon AO, Bakar B, Cila A, Ruacan S. Intravascular lymphoma masquerading as multiembolic stroke developing after coronary artery by-pass surgery. Neurologist 2009;15:98–101. 42. Streletz LJ, Terzic D, Salem K, Raza A, Deleu DT. CNS lymphoma masquerading as hemorrhagic stroke. Clin Neurol Neurosurg 2012; 114:262–4.
P. L. Nguyen and J. J. Chang 43. Li L, Yin J, Li Y, et al. Anaplastic astrocytoma masquerading as hemorrhagic stroke. J Clin Neurosci 2013;20:1612–4. 44. Yoshino T, Meguro S, Soeda Y, Itoh A, Kawai T, Itoh H. A case of hypoglycemic hemiparesis and literature review. Ups J Med Sci 2012;117:347–51. 45. Cheema H, Federman D, Kam A. Hemichorea-hemiballismus in non-ketotic hyperglycaemia. J Clin Neurosci 2011;18:293–4. 46. Padmanabhan S, Zagami AS, Poynten AM. A case of hemichoreahemiballismus due to nonketotic hyperglycemia. Diabetes Care 2013;36:e55–6. 47. Postuma RB, Lang AE. Hemiballism: revisiting a classic disorder. Lancet Neurol 2003;2:661–8. 48. Adam N, Kandelman S, Mantz J, Chretien F, Sharshar T. Sepsisinduced brain dysfunction. Expert Rev Anti Infect Ther 2013;11: 211–21.
Stroke Mimics and Acute Stroke Evaluation
ARTICLE SUMMARY 1. Why is the topic important? The topic is important to emergency physicians and neurologists because the most impactful acute stroke treatment begins and ends in the emergency department with the use of fibrinolysis. All treatment after the time window for recombinant tissue plasminogen activator (rt-PA) passes by is supportive. 2. What does this review attempt to show? This review attempts to show that rt-PA is largely safe to use in patients without ischemic stroke and that a large amount of uncertainty occurs when diagnosing posterior circulation strokes. 3. What are the key findings? Surveying the literature yields only two cases of symptomatic intracranial hemorrhage in stroke mimics that received intravenous rt-PA: one case of seizure and one case of glioblastoma multiforme. Earlier rates of symptomatic intracranial hemorrhage occurred in patients receiving different doses of intravenous rt-PA for myocardial infarction. 4. How is patient care impacted? Patient care will be impacted because if more eligible patients receive intravenous rt-PA, greater disability can be prevented. Until magnetic resonance imaging becomes more universal as an admission diagnostic tool, some degree of uncertainty—particularly when dealing with posterior circulation strokes—will always exist. This review explores the assertion that the probability of symptomatic intracranial hemorrhage in stroke mimics may actually be less harmful than the uncertainty of not giving treatment to a potential stroke.
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