Patients with transient neurologic symptoms (TNS) are usually checked based on physicians’ assumptions in the emergency setting; these patients are usually diagnosed with a transient ischemic attack (TIA).[1–3] However, the conventional process has a risk of misdiagnosis and could even delay the exact diagnosis and prompt management of other neurologic diseases.[4,5] The 10% to 49% of patients changed the final diagnosis as having other TIA mimic diseases, such as seizure, posterior reversible encephalopathy (PRES) and reversible cerebral vasoconstriction syndrome (RCVS).[2,3]
There have been attempts to improve the accuracy of diagnosis of true TIA and other mimic diseases. Some studies tried to determine the feasibility of adopting the ABCD score that was originally developed to predict recurrence risk, and others tried to identify important stroke risk factors, such as steno-occlusion of the cerebral artery and cardioembolic risk factors.[2,4,5] Imaging studies also have been used to exclude alternative non-ischemic origins and to gain additional information about the prognosis. The various imaging tools, such as computed tomography, diffusion weighted imaging (DWI), perfusion weighted imaging (PWI) and angiographic examination, has been tested; however, they are still deficient for differentiating other neurologic diseases.[7,8]
Traditionally, contrast extravasation phenomenon has been termed hyperintense acute injury marker (HARM) sign which denoted the radiologic finding of the hyperintense signal within the cerebrospinal fluid (CSF) spaces visualized on postcontrast fluid-attenuated inversion recovery (FLAIR) image. It has been hypothesized that HARM represents contrast leakage into the subpial space due to blood-brain barrier (BBB) disruption (Supplemental Figure 1, http://links.lww.com/MD/C968). In ischemic stroke, HARM signs are associated with reperfusion injury and hemorrhagic transformation.[10,11] In other hand, HARM signs are observed in other disease affecting the BBB, such as subarachnoid hemorrhage, traumatic brain injury, seizure, PRES, and RCVS,[12–17] it was expected to have the diagnostic role.
This study aimed to investigate the incidence and clinical significance of HARM signs in patients initially suspected of having TIA using the prospective stroke and TIA registry, which involves conducting the routine magnetic resonance imaging (MRI) protocol including DWI, PWI, angiography and pre- and post-contrast FLAIR in an early time window.
2.1 Study design and setting
Patients who presented to the emergency department (ED) between July 2015 and December 2016 were consecutively enrolled. Ethical approval for the study was obtained from the local Institutional Review Board with a waiver of informed consent considering the retrospective and observational study design and minimal risk of harm.
2.2 Selection of participants
The study was conducted at an academic hospital located in Seongnam, Republic of Korea, with more than 90,000 visits to the ED each year. All patients who presented to the ED with TNS on arrival at the triage unit of the ED were eligible for enrollment. Among them, patients who arrived within 12 hours of symptom onset and evaluated the brain MRI study under suspicious TIA by neurologist inspection according to the institutional stroke clinical pathway were consecutively identified (Supplemental Figure 2, http://links.lww.com/MD/C968). The research staff retrospectively searched the patient's electronic medical records and imaging storage to obtain clinical and laboratory information. The demographic variables (age, sex), stroke information (time to onset to arrival, stroke severity at baseline and discharge, history of stroke and modified Rankin Scale (mRS)), clinical factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation) were gathered.
2.3 Brain imaging protocol and MRI technique
The uniform MRI protocol was composed of diffusion weighted imaging (DWI, TR/TE, 3800–5000//45–60; b = 1000 s/mm2), axial gradient-recalled echo imaging (TR/TE, 690–1100/15–24), time-of-flight MR angiography, dynamic susceptibility perfusion-weighted imaging (PWI) with administration of contrast material, axial contrast-enhanced T1-weighted imaging (TR/TE, 4000–600/9–12), and non-contrast and axial contrast-enhanced FLAIR imaging. Contrast-enhanced FLAIR images were obtained using a turbo spin-echo sequence with the following parameters: TR/TE, 11,000/120−140; inversion time, 2500 ms; echo-train length, 26; ip angle, 90°; FOV, 216 × 240 mm; acquisition matrix, 256 × 162; and slice thickness, 5 mm. FLAIR images were obtained approximately 5 minutes after IV administration of 15 mL of contrast material (gadobutrol; Gadovist, Bayer HealthCare). MRI was completed on either a 1.5-T Avanto (Siemens Healthineers, Erlangen, Germany) or a 1.5-T and 3-T Achieva (Philips Healthcare, Best, the Netherlands).
2.4 Image analysis
Two readers reviewed all examinations. Both readers were blinded to clinical and laboratory information as well as the diagnosis and indication for the examination. They corroborated lesion identification of HARM on abnormal cortical and sulcal enhancements of FLAIR images with a review of other sequence images; finally, lesion identification was confirmed in consensus by neuroradiologists. DWI positive was defined as b values corresponding to the diffusion-sensitizing gradient were 0 and 1000 s/mm2 on automatically derived the apparent diffusion coefficient maps, which presented the acute cerebral infarction in case of ADC values of less than 580 × 10–6 mm2/s.[18,19]
2.5 Outcomes and review process
The study outcome was the causative disease of HARM, which was finally ascertained by reviewing the institutional electric health recording including the inpatient and outpatient clinic. Based on reviewing the electric health information and results of imaging analysis, we ascertained the final diagnosis of the presence of HARM or not (HARM positive versus HAR negative). In case of HARM positive, presumed the causative disease were classified into
- true TIA with either DWI positive or DWI negative,
- seizure related,
- leptomeningeal malignancy,
- trauma brain injury or
- unclassified encephalopathy.
The unclassified encephalopathy denoted the HARM positive without any presumed causative disease and surveyed the possible condition as like heart failure and cardiomyopathy.
In patients with HARM positive and true TIA, the presence of symptomatic vascular lesions, location, and degree of the steno-occlusive lesion and perfusion defect were additionally investigated.
2.6 Statistical analysis
The baseline characteristics and imaging findings of study subjects were summarized in frequency (percentage) for categorical binary variable, median (interquartile range, IQR) for non-parametric variables, such as time from onset to arrival and NIHSS score (National Institute of Health Stroke Scale) and mean ± standard deviation (SD) for parametric variable (age). Then, baseline characteristics were compared according to the presence of HARM or not (HARM positive versus HARM negative) using the Pearson chi-square test for a binary variable, Whitney Mann U test for non-parametric variables or t test for a parametric variable.
In patients with HARM positive, investigated causative diseases were summarized. The location and degree of symptomatic steno-occlusion of cerebral artery were investigated in patients with HARM positive and true TIA. SPSS software was used for analysis (SPSS version 18.0, IBM corp., USA), and a P value of less than .05 was set for statistical significance.
3.1 Baseline characteristics of study subjects
A total of 174 consecutive subjects became the study subjects. Baseline characteristics of the study subjects were summarized (Table 1). The mean age was 64.0 ± 12.9 years old, and males made up 54.6%. It took a median of 2.2 hours (1.0–4.2 h) from the onset of neurologic symptoms to hospital arrival. On initial imaging study, 17.8% of study subjects presented DWI lesions.
3.2 Burden of HARM and clinical associations
On the enhanced FLAIR images, 18 (10.3%) subjects showed HARM signs (HARM positive). The presence of HARM did not show statistical differences in baseline characteristics (Table 1). The demographic and vascular risk factors did not show significantly different characteristics according to the HARM positive and HARM negative. Also, the presence of HARM was significantly associated with the presence of DWI lesion (P = .002), not with favorable outcome (P = .223).
Among patients had HARM positive, 61.1% were determined to be the TIA. Another causative disease of HARM positive were seizures, PRES, RCVS and unclassified encephalopathy. Two unclassified encephalopathies had dilated cardiomyopathy. In HARM positive, DWI lesions were observed in 7 subjects which were dichotomized into 6 patients of true TIA and one patient of RCVS (Table 2).
In patients with TIA and HARM positive (n = 11), the presence of DWI lesion was not significantly associated with time interval from symptom onset to MR examination (P by Whitney Mann U test = .762), which were estimated by median 4.3 hours (IQR, 2.6–4.9 h) in DWI lesion positive and 3.1 hours (IQR, 1.2–5.2 h) in DWI lesion negative, respectively.
In the case of both HARM positive and DWI lesion positive, it sometimes gave more information about the distribution of reperfusion injury and recanalization that cannot be determined from the distribution of the DWI lesion and angiography study (Fig. 1).
In patients adjudicated as true TIA with HARM, most of them had the symptomatic steno-occlusion lesion of a cerebral artery (Supplemental Table 1, http://links.lww.com/MD/C968). Of them, 2 subjects with true TIA had recent procedures of carotid artery stenting and diagnostic digital subtraction angiography examination.
A patient with RCVS showed HARM signs at the bilateral temporal-occipital area on enhanced FLAIR but not on the non-enhanced FLAIR. Her complaint was transient language disturbance with preceding sudden onset headache 2 days before hospital arrival and suspicions of aphasia for less than 10 minutes. Initial MRA showed multifocal stenosis segments at distal branches of the middle and posterior cerebral arteries that were resolved during the follow-up study (Fig. 2).
This study showed that patients who visited as a result of TNS have approximately 10% of HARM signs in their initial MRI study that are helpful in revealing their true neurologic disease.
Since the patients’ clinical symptoms were transient or rapidly improved, the diagnosis was dependent on clinical decision based on the patients’ history, risk factors, and conventional imaging studies, such as computed tomography and DWI. However, they usually had similar features (Table 1), they may be misdiagnosed with true TIA if enhanced FLAIR had not been used. Our findings suggested that this MRI sequence may have the chance to improve the diagnosis of less prevalent neurologic diseases. Moreover, HARM signs were not affected by the other patient's underlying conditions, such as demographic and vascular risk factors, which was the peculiar marker presenting the pial leakage to CSF space.
HARM on FLAIR sequence has been described as a sign of early blood-brain barrier (BBB) breakdown in various clinical conditions, typically ischemic stroke, and especially the recanalization state after endovascular treatment that is related to reperfusion injury and delayed gadolinium contrast enhancement in the subarachnoid space with and without hemorrhagic event.[9–11,17,21] Also, subarachnoid hemorrhage, traumatic brain injury, seizure, PRES, and RCVS would cause HARM to FLAIR MRI sequences.[15,14,22]
The RCVS can cause the BBB breakdown by sympathetic over-activity and dysregulation of vascular tone and cause many neurologic complications, such as PRES, subarachnoid or intracerebral hemorrhage and even sudden death. Early diagnosis of RCVS is difficult because of the dynamic nature of the disease course and limitations of current non-invasive angiography modalities. Enhanced FLAIR can determine the BBB breakdown and is helpful for early detection.
HARM signs also supported determination of ischemic injury even in the transient state. This study showed that about half of the patients with HARM resulting from ischemic injury had no definite DWI lesion. Since short-duration and sudden hemodynamic instability would cause BBB breakdown without a permanent infarct, the prognosis itself would be favorable. Focus had to be the situation of HARM signs that provoked hemodynamic instability. As noted, 1 event was followed by recent carotid artery stenting. The HARM signs of 2 subjects with unclassified encephalopathy were possibly related to dilated cardiomyopathy which may be the cause of hemodynamic instability.
This study had several limitations. First, it was a retrospective, single-center study with a small cohort that had a risk of selection bias. Though it enrolled consecutive subjects, prospectively confirming the research would give more concrete evidence. Second, we did not analyze the severity of HARM to discern if there is a gradation of injury that may further correlate with the final diagnosis. Correlations between the severity of HARM and diagnosis could possibly exist. Third, MR protocols were set up to innovate and improve the hospital's system under a multidisciplinary effort that might require a higher burden of resources.
Our study reported that HARM signs in those with TNS are noted, and the investigation of their characteristics would help to reveal their final diagnosis. In patients with the true TIA, the HARM signs would give more information, such as extent and location of ischemic insult in addition to the conventional images. In the TIA mimics, it may give evidence of cerebral involvement.
Conceptualization: Jihoon Kang, Hyuksool Kwon, Cheol Kyu Jung, Hee-Joon Bae, Moon-Ku Han, Beom Joon Kim, You Hwan Jo.
Data curation: Jihoon Kang, Hyuksool Kwon.
Formal analysis: Jihoon Kang, Hyuksool Kwon.
Investigation: Jihoon Kang, Hee-Joon Bae, Moon-Ku Han, Beom Joon Kim.
Methodology: Hyuksool Kwon.
Resources: Cheol Kyu Jung.
Writing – original draft: Jihoon Kang.
Writing – review & editing: Jihoon Kang, Hyuksool Kwon, Cheol Kyu Jung, You Hwan Jo.
Jihoon Kang orcid: 0000-0001-5715-6610.
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