Stroke Mimics: Insights from a Retrospective Neuroimaging Study

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Introduction
Stroke Mimics (SMs) refer to a wide spectrum of nonvascular/non-ischemic conditions characterized by acute, focal neurological de icits at presentation, simulating ischemic stroke symptoms.SMs correspond to patients diagnosed with acute stroke at the admission to the hospital not receiving a de inite diagnosis of stroke during the diagnostic procedures in the acute setting (acute stroke false positives).The main https://doi.org/10.29328/journal.jnnd.1001083 and the prevalence of different SMs aetiologies in the stroke care pathway [4].SMs overall prevalence was 38% and the most frequent SMs diagnosis at discharge resulted headache disorders (18.6%), psychological disorder (16.7%), peripheral vertigo (11.9%) and epilepsy (10.6%) [4].Further studies similarly found that the group of headache disorders and epileptic seizures is the most represented diagnostic category in SMs patients [5].Other common SMs causes include medical conditions such as sepsis/infections and metabolic disorders, mass lesions, transient global amnesia, mononeuropathy or radiculopathy and demyelinating disease [6].In addition, several vascular lesions other than stroke can present with stroke-like symptoms such as subdural hematoma, arteriovenous malformations and Reversible Cerebral Vasoconstriction Syndrome, an increasingly recognized entity in children [7].When clinical scoring system designed for stroke suffers from a lack of speci icity, especially in case of absence of cardiovascular risk factors, female sex and young age, neuroimaging, in particular MRI, helps to recognize real stroke and stroke mimics [8].Neuroimaging, beyond establishing a differential diagnosis between haemorrhagic and ischemic stroke, is able to differentiate cerebrovascular diseases from structural or functional, reversible causes of neurological de icits [9].Actually, it is well established that the identi ication rate of patients with SMs increases with the use of MRI at baseline respect to CT-based protocols [10,11], due to Diffusion Weighted Imaging (DWI) normal indings [4,12] but also to advanced non-contrast perfusion MRI techniques such as ASL [13].The advantages of basic MRI scans and DWI in emergency assessment of SMs have been widely outlined in literature, however to our knowledge the role of perfusion weighted MRI in this setting, being suggested in a number of case reports, has not been systematically evaluated yet.This retrospective study aims to highlight, through the presentation of some clinical cases, the advantage of advanced imaging in the early diagnosis of SMs within the wide range of stroke codes.The systematic and harmless study of cerebral perfusion can indeed help identify physiopathological mechanisms underlying non-purely vascular conditions where ibrinolysis should not be employed.

Methods
A retrospective chart review was conducted on all cases admitted to the Emergency Unit of Siena University Hospital, a hub center in stroke management, with an acute stroke presentation between January 2018 and January 2019.Written informed consent was obtained from all patients before conducting CT and MRI, following the rules of the Ethics Board of the General Hospital "Santa Maria alle Scotte," University of Siena, Italy.The University Hospital database was used, and privacy rules were followed to anonymize the iles of individual patients.
Only subjects presenting with an acute onset of focal neurological de icits were included.The clinical suspicion of ischemic stroke and therefore the stroke code was activated by emergency physician during the irst aid.At emergency department admission, the stroke code was con irmed by neurologist or excluded.The inal diagnosis was pulled out from the administrative database of Department of Emergency, Stroke Unit, Neuroscience and Clinical Departments.Patients under the age of 18 were excluded.These presentations, henceforth referred to as SMs, were tabulated, and then compared with the total number of patients correctly admitted with acute ischemic stroke.Patients discharged with the same diagnosis they had on admission were considered the control group and the positive and negative predictive values of clinical diagnosis of SMs and acute stroke were assessed.The patients were divided in different subgroups such as TIAs (transient ischemic attacks), ischemic strokes, hemorrhagic strokes and SMs.TIA diagnosis was based on regression of the acute focal neurological de icits and concomitant negative imaging (DWI sequence acquired when the clinical assessment was uncertain).All non-vascular pathologies were classi ied as SMs.The retrospective analysis was performed on not-contrastenhanced CT (NCCT) (acquired in all patients), CT Angiography (CTA), CT Perfusion (CTP) and MRI.The neuroimaging protocol was determined by the neuroradiologist and the clinician, based on the clinical scenario.Depending on the situation, the protocol varied.In cases of strong clinical suspicion of acute ischemic stroke, a protocol including CTA and CTP after NCCT was used.Alternatively, if intraparenchymal hemorrhage was detected at NCCT, especially if in an "atypical" location, only CTA was performed.To demonstrate blood-brain permeability alterations, a delayed CT scan after contrast medium administration was performed.If the CT examination proved to be inconclusive or if there was a need to con irm a diagnostic hypothesis, an MRI examination was performed.
The revised MRI examinations were those performed within 21 days from the hospital admission.Susceptibility Weighted Imaging and T1-weighted sequences were revised to assess intracranial haemorrhagic foci and conditions such as cortical hemosiderosis.The irst clinical and instrumental evaluation in the emergency department was compared with retrospective evaluation of all imaging indings [non-contrastenhanced CT, CT Angiography (CTA), CT Perfusion (CTP), MRI] and with the inal discharged diagnosis.

MRI examination
MRI scans were performed on a Siemens (Munich, Germany, Europe) Avanto 1.5T scanner with a 12-channel head-coil.A https://doi.org/10.29328/journal.jnnd.1001083population.Additionally, within 21 days of hospital admission, a total of 125 subjects (24.2% of all patients) underwent MRI examinations, with 40 of those performed within 3 hours from the activation of the stroke code.Advanced MRI sequences such as ASL, MR perfusion, and MR spectroscopy were utilized to reach an accurate diagnosis.Upon admission, all subjects underwent non-contrast-enhanced CT (NCCT) scans (513/513).Out of these, 136 subjects were assessed with NCCT scans only (26.5%).A total of 372 subjects underwent concurrent CTA scans at admission (72.5%), and 223 subjects were evaluated with both CTA and CTP scans (NCCT + CTA + CTP) (43.5%).Four subjects received a delayed scan after the administration of iodine contrast medium (less than 1%).One subject was excluded because deceased before imaging acquisition (less than 1%).

Discussion
The found prevalence of SMs, at 19.29% among all stroke admissions, is slightly lower than what is reported in the literature.Speci ically, our rate of SMs is lower than the 38% value found in a prospective study by Quenardelle, et al. [4] that used MRI screening for stroke code patients, as well as in a retrospective study by Liberman, et al. [3].
Since in our study, only 32% of SM patients underwent MRI scans within the irst 3 hours from the activation of the stroke code, the incidence of SMs might have been higher if MR examinations had been performed for all stroke codes [13].Liberman, et al. [14] also suggested that the high prevalence of SMs could be related to the signi icant reduction in door-toneedle time, which could lead to increased errors due to less time available for diagnostic formulation when is using the CT approach exclusively.
In our case series, the door-to-needle time optimization might contribute to the extremely low (18.5%)diagnostic accuracy, as well as the negative and positive predictive values (respectively 0.35 and 0.23) for the clinical SMs diagnosis, con irming the dif iculty to differentiate clinically an ischemic stroke from other diagnosis in patients presenting with acute neurological de icits.The imperfect accuracy and the small negative predictive value of clinical assessment of SMs in our patient population underline the value of MRI implementation in emergency protocols.standardized protocol was applied using T1-weighted, T2weighted, FLAIR and DWI sequences.Pulsed ASL images were acquired using a PICORE Q2T sequence (TR = 3,100 ms, TE = 22 ms, TI1 = 700 ms, TI2 = 1,800 ms, number of slices = 16, thickness = 6.3 mm, gap = 1.6 mm, imaging matrix = 84 ⇥ 84, lip angle [FA] = 90, and acquisition duration = 4 min 45 s).T1-weighted 3D-MPRAGE sequences (TR = 1,880 ms, TE = 3.38 ms, TI = 1,100 ms, FA = 15, number of slices = 176, thickness = 1 mm, gap = 0 mm, and imaging matrix = 256 ⇥ 256) were used to obtain high-resolution T1-weighted axial images covering the whole brain.

R esults
The initial clinical and instrumental evaluation in the emergency department identi ied 98 cases (19.1%) as SMs and 275 cases (53.6%) as ischemic strokes.The analysis of the inal discharge diagnosis and the retrospective evaluation of CTA, CTP, and MRI examinations revealed 99 cases (19.29%) classi ied as SMs (excluding 59 TIAs), and 355 cases of neurovascular diseases, including 282 con irmed ischemic stroke events (54.9%) and 73 cases of hemorrhagic strokes (20.79%).Among the 282 con irmed ischemic strokes, 146 (51.77%) were classi ied as major stroke events, and 136 (48.22%) were minor strokes (Figure 1, Table 1).Among the 99 SMs, the identi ied pathologies were as follows: 13 cases of infection (sepsis, meningitis, encephalitis) (13.1%), 12 cases of syncope (12.1%), 11 cases of epilepsy (11.1%), 11 cases of haemodynamic conditions (pulmonary embolisms, heart failure, etc.) (11.1%), 10 cases of tumors (glioblastoma, meningioma, metastasis, paraneoplastic syndrome) (10.1%), 9 cases of metabolic disorders (electrolytic and glycemic disorders) (9.1%), 9 cases of dizziness (peripheral vestibular disorders and peripheral neuropathy) (9.1%), 7 cases of migraine (7.1%), 4 cases of exogenous toxins (drugs and/or alcohol) (4%), 3 cases of functional disorders (3%), 3 cases of acute hydrocephalus (3%), 2 cases of multiple sclerosis (2%), 2 cases of arteriovenous malformation (2%), 1 case of spinal cord compression (1%), and 2 cases of unexplained conditions (2%) (Table 2).The diagnostic accuracy of the clinical diagnosis of SMs was 18.5%, with positive and negative predictive values of 0.23 and 0.35, respectively.In terms of ischemic stroke diagnosis, no false negatives were observed, indicating the absence of stroke chameleons in our MRI advantages over CT-based protocols in SMs management are related to better diagnostic accuracy for recent ischemia due to DWI sequences, to improved detectability of posterior fossa lesions, lacunar infarction and brain tumors, as well as in lammatory and metabolic disorders not evident on CT examination.Past prospective studies showed that the 38% -43% SMs incidence at initial clinical and laboratory evaluation declines to 4% -6.5 % with CT scanning at admission [15] and drops to further 0% -1.3% with MRI imaging in addition [11,16].Moreover, an early MRI diagnosis could impact both SMs and acute ischemic strokes management in terms of length of stay and imaging resources within the health service.In this single centre experience, MRI examination was performed when the diagnosis was not really clear (24,6%) with a mean delayed diagnosis time of 4,6 days.Knowing that the waste of time is harmful in all patients, actually the main concern is that if patients are not correctly identi ied, therefore they cannot be properly treated.CT, CTA, CTP and standard MRI acquisitions could not be able to improve the diagnostic accuracy of SM.Quantitative technique such as MR ASL perfusion offers the possibility to evaluate functional, hemodynamic parameters not explored by conventional imaging.Cerebral Blood Flow (CBF) map, beyond demonstrating ischemic penumbra in stroke, displays typical patterns with peculiar features respect to real stroke (especially when coupled with DWI) in different SM such as epileptic seizures, in particular post-ictal paresis [17][18][19] (Figures 1,2), brain tumors [20,21] (Figure 3) arteriovenous malformations or istulas (Figure 4) migraine with aura, other primary headache disorders [22,23], in lammatory or infectious conditions like multiple sclerosis (Figure 5) or encephalitis (Figure 6), metabolic disorder like hypoglycaemic hemiparesis [24,25], or other unusual causes (Figure 7).ASL perfusion, a contrast medium-free MRI perfusion technique, appears more suitable than bolus methods in an emergency care setting where creatinine blood level may not be readily available or contrast medium may be contraindicated [26].In this technique blood acts as an "endogenous tracer" and is able to quantify the CBF [27,28].The latter propriety is unique in comparison with other imaging acquisition.Moreover, CTP, is usually acquired on a limited section of brain tissue after bolus administration of contrast medium, while perfusion weighted MRI by using ASL sequences brings the bene its of whole brain acquisition besides the opportunity to avoid contrast medium administration.It's well known that non-contrast CT and CTA negativity does not exclude stroke and only few MRI sequences as diffusion restriction highly sensitive for acute ischemia cannot help in cases of diagnostic uncertainty and increase the incidence of SMs.Multimodal MRI applied in the stroke care pathway as the irst line imaging could increase the diagnostic accuracy of acute neurological de icit without     loss of time and lead to correct patient management.The main limitation of the present study consists of its retrospective nature; however, this analysis can help to adjust the current diagnostic approach and to draw the way of future prospective studies regarding the best SMs management.

Conclusion
Appropriate management of ischemic stroke is provided by standard MRI.In fact, DWI and FLAIR sequences are able to assess TIA versus ischemic lesions, to suggest the timing of the ischemic lesion and to de ine the ischemic lesion load.On the other hand, the majority of pathologies mimicking ischemic stroke could be demonstrated only by improving the diagnostic protocol with advanced sequences such as ASL perfusion.To differentiate ischemic stroke from SMs few hours after the onset of neurological symptoms, which is actually a challenge for both neurologists and radiologists, a multimodal MRI approach may demonstrate early signs of vascular impairment re lecting functional hemodynamic changes without causing ischemic lesions.

Contribution to the fi eld statement
The prevalence of SMs in this study is consistent with previous literature, although it is lower than in some MRIbased studies.The authors suggest that performing MR examinations in all stroke cases could potentially increase the incidence of SMs.The optimization of door-to-needle time contributes to the low diagnostic accuracy of clinical https://doi.org/10.29328/journal.jnnd.1001083SMs diagnosis, underscoring the value of implementing MRI in emergency protocols.MRI examination in cases of unclear diagnosis and the utilization of quantitative techniques like MR ASL perfusion can evaluate functional and hemodynamic parameters not explored by conventional imaging.ASL perfusion, a contrast medium-free MRI technique, offers the ability to quantify Cerebral Blood Flow (CBF) and can differentiate various SMs from real stroke based on distinct perfusion patterns.Distinguishing ischemic stroke from SMs shortly after the onset of symptoms is a challenge, but a multimodal MRI approach can reveal early signs of vascular impairment without causing ischemic lesions.

Highlights
• Approximately 30% of sudden neurological de icits are attributed to non-ischemic causes.

Figure 2 :
Figure 2: CT perfusion and Todd's paresis or postictal paresis/paralysis.Stroke code: 62 years old male with symptoms onset as dysarthria, stomachache and syncope, followed by left upper limbs hemiplegia and lower limbs hemiparesis.Clinical History: old right hemisphere ischemic event, no seizure history.a) No-contrast CT: right temporal encephalomalacia as result of old ischemic event.b) CT-angiography did not demonstrate arterial occlusion.c) CT perfusion map CBF: cortico-subcortical hypoperfusion pattern in the right CMA vascular distribution.d) Previous CT perfusion map Tmax (during old stroke: 4 months after): see the Tmax map suggesting a large core on the right CMA vascular territory.

Figure 3 :Figure 4 :
Figure 3: Brain tumor.Stroke code: 74 years old male, presenting with sudden onset of left hemiparesis.a) No-contrast CT: cortical-subcortical hypodensity in the right inferior temporal gyrus and inferior occipital gyrus suggesting edema in the right posterior temporal lobe with mild mass eff ect on the right ventricular system; b)Contrast medium CT: no evidence of pathological parenchymal enhancement; c) CTP (CBF map) shows large hyperperfusion involving the right parietal-temporo-occipital lobes and d)CTA does not demonstrate any arterial occlusion.e) Contrast enhanced T1 MRI images demonstrate inhomogeneous hypointensity of right inferior temporal gyrus and inferior occipital gyrus without BEE leakage.Follow up scans (contrast-enhanced T1 MRI): d) enhancing lesion in the right inferior temporal gyrus and inferior occipital gyrus.Histology demonstrated high grade glioblastoma.e) Post-surgical T1 contrast images show wide surgical cavity surrounded by markedly irregular enhancing ring of pathological tissue.

Figure 5 :Figure 6 :
Figure 5: Multiple Sclerosis.Stroke code: 35 years old female presenting with improving left upper limb paresis.In anamnesis: smoker, oral contraceptive therapy.a) CTA: no arterial occlusions were demonstrated b) CTP did not show asymmetric hypoperfusion and c) No acute or chronic intracranial pathology was present on parenchymal phase.Nevertheless, previous informed consens and the absence of contraindication for e.v.fi brinolysis, at about 2.10 h clinical onset: 52 mg /Kg Actilyse was administered.d) A delayed 3D FLAIR MRI demonstrated an oval shaped hyperintensity greater than 2 cm in the right frontal periventricular white matter, with main axis perpendicular to lateral ventricle.f) Artifactual FLAIR/ DWI mismatch: corresponding hyperintesity on DWI images not due to low ADC (T2-shine through eff ect) g), suggesting vasogenic edema.e) Contrast enhanced T1 MRI: heterogeneous and venular enhancement.Diagnosis: Tumor-like multiple sclerosis.

Figure 7 :
Figure 7: Spinal cord compression.Panel a. Stroke code: 58 years old male presenting with suddenly augmentation right upper limb paresis and paraesthesia.(a) No-contrast brain CT and intracranial CTA (not showed) did not reveal any vascular or parenchymal abnormalities or subacute ischemic lesions MRI did not demonstrate brain areas of restricted diff usion were evident on (b) DWI or FLAIR (c) signal alteration.The non-contrast CT of the cranio-cervical tract shows the odontoid process dislocated superiorly with involvement of the foramen magnum.(d)Panel b.Axial T2weighted MRI images show "owl-eyes" sign at C1/C2 level (e).Intramedullary lesions at C1/C2 level were confi rmed diff usion images (f).Cervical spine CT and sagittal reconstruction (g) and T2 sagittal images revealed an odontoid process subluxation and the focal hyperintensity of cervical spinal cord (h) Diagnosis: Cervical myelopathy.Atlantoaxial instability for degenerative changes caused the spinal cord compression and acute myelopathy.

Table 1 :
Data of patients admitted as suspected stroke and diff erent characteristics of subgroups.

Table 2 :
Prevalence of diff erent discharge diagnosis in our SMs patients and TIAs compared with literature reports.n.a.: not applied.† In the present study haemorrhages are not included as SMs.Haemorrhages are here reported for completeness and comparison with literature data.