Computed Tomography Perfusion Imaging in Spectacular Shrinking Deficit

Computed Tomography Perfusion Imaging in Spectacular Shrinking Deficit

Computed Tomography Perfusion Imaging in Spectacular Shrinking Deficit Vivien H. Lee, MD, Sayona John, MD, Yousef Mohammad, MD, and Shyam Prabhakaran,...

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Computed Tomography Perfusion Imaging in Spectacular Shrinking Deficit Vivien H. Lee, MD, Sayona John, MD, Yousef Mohammad, MD, and Shyam Prabhakaran, MD, MS

Spectacular shrinking deficit (SSD) is characterized by abrupt onset of a major hemispheric stroke syndrome, followed by dramatic and rapid improvement. We retrospectively identified patients with SSD diagnosed at our institution between December 1, 2007, and June 30, 2009. We reviewed computed tomography perfusion (CTP) imaging to determine perfusion defect as a measure of initial ischemic penumbra, and magnetic resonance imaging diffusion-weighted imaging (DWI) to determine the final infarct core. Among the 472 consecutive ischemic stroke patients, 126 (27%) presented with major hemispheric ischemic stroke syndrome, defined as National Institutes of Health Stroke Scale score (NIHSS) $8 in the territory of the middle cerebral artery (MCA) or internal carotid artery (ICA). Out of these patients, we identified 8 SSD patients with available CTP data. In these 8 patients, the mean time to dramatic recovery was 3.4 hours (range, 0.75-7 hours), and the mean time from onset to CTP was 12.7 hours (range, 3-30 hours). All 8 patients had perfusion abnormalities in portions of the MCA territory (partial MCA territory in 5 patients and complete MCA territory in 3 patients). The mean time from onset to MRI DWI was 15.5 hours (range, 7.9-34 hours). Restricted diffusion was present in all patients in the corresponding MCA distribution. Vascular imaging revealed MCA occlusion in 2 patients. Cervical vascular imaging revealed carotid occlusion in 2 patients and high-grade carotid stenosis in 2 patients. The stroke mechanisms were cardioembolism in 2 patients, large artery in 4 patients, and unknown in 2 patients. Four patients had repeat CTP imaging available that demonstrated eventual resolution of the perfusion defect. SSD is associated with a ‘‘shrinking’’ clinical syndrome and a ‘‘shrinking’’ perfusion pattern on CTP that lags behind clinical recovery. CTP imaging corroborates that a larger territory is at risk in SSD and contributes to better understanding of SSD. Key Words: Ischemic stroke— recanalization—transient ischemic attack. Ó 2012 by National Stroke Association

From the Department of Neurological Sciences, Section of Cerebrovascular Disease and Neurological Critical Care, Rush University Medical Center, Chicago, Illinois. Received February 4, 2010; accepted May 21, 2010. Address reprint requests to Vivien H. Lee, MD, Department of Neurological Sciences, Section of Cerebrovascular Disease and Neurological Critical Care, Rush University Medical Center, 1725 West Harrison Street, Suite 1121, Chicago, IL 60612. E-mail: vivien_lee @rush.edu. 1052-3057/$ - see front matter Ó 2012 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2010.05.007

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J.P. Mohr is credited with coining the phrase ‘‘spectacular shrinking deficit’’ (SSD). SSD is typically defined as a major hemispheric ischemic stroke syndrome, followed by dramatic improvement within hours and disappearance of most of the clinical manifestations.1 The mechanism of SSD has been assumed to involve temporary occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA) by an embolus that subsequently migrates distally. SSD has been historically emphasized as an important sign of cardioembolism.1 In this study, we attempted to elucidate the mechanism of SSD using computed tomography perfusion (CTP) imaging.

Journal of Stroke and Cerebrovascular Diseases, Vol. 21, No. 2 (February), 2012: pp 94-101

CT PERFUSION IMAGING IN SPECTACULAR SHRINKING DEFICIT

Materials and Methods With Institutional Review Board approval, we retrospectively identified patients with a clinical diagnosis compatible with SSD admitted to our institution between December 1, 2007, and June, 30 2009. We collected data on demographics, medical history, clinical symptomatology, time to neuroimaging, time to clinical recovery, and time to repeat imaging. SSD was operationally defined as acute focal neurologic symptoms suggestive of a hemispheric MCA or ICA stroke syndrome with an initial National Institutes of Health Stroke Scale (NIHSS) score $8, followed by dramatic improvement within 8 hours to an NIHSS score #4. Presenting symptoms suggesting hemispheric ischemia were severe motor deficits deficits in the face, arm, and leg with or without with sensory symptoms and cortical signs (gaze preference, aphasia, extinction, or neglect). Patients who received intravenous tissue plasminogen activator (IV-tPA) were included, but patients who underwent intra-arterial (IA) therapy were excluded. Patients who underwent CTP within 48 hours after onset were included. We used commercial CTP software available at our institution to map perfusion defects. In addition, CTP and magnetic resonance imaging (MRI) were independently reviewed by the study neurologists. The definition of penumbra (ie, salvageable ischemic tissue) was based on published criteria.2 We used a threshold of relative mean transit time (MTT) .145% (relative to the contralateral hemisphere) and also required that MTT exceed 2 mL/100 g (to exclude core infarct).

Results Clinical Presentation Among 472 consecutive ischemic stroke patients, 126 (27%) presented with hemispheric ischemic stroke syndrome, defined as an NIHSS score $8 in the territory of the MCA. Among these patients, 9 met the diagnosis of SSD (7%), of whom 8 had at least one CTP scan for review. These 8 patients included 7 men (88%) and 1 woman, with a mean age of 62 years (range, 46-81 years). Table 1 summarizes the clinical features of these patients. Six patients presented with right-sided hemispheric syndrome, and 2 presented with left-sided hemispheric syndrome. The mean time to dramatic recovery was 3.4 hours (range, 0.75-7 hours). Among these 8 patients, 5 met the clinical criteria for transient ischemic attack (TIA), and 3 were diagnosed with minor stroke (with a hospital day 2 NIHSS score of 2-4). One patient (case 5) received IV-tPA at an outside hospital at 3 hours, 26 minutes after symptom onset. Case 7 presented to an outside hospital beyond the window for IV-tPA administration. In the remaining 6 patients, IVtPA was considered but was not administered because of the patients’ rapid clinical improvement. The TOAST stroke subtypes3 were cardioembolism in 2 patients, large

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artery in 4 patients, and unknown or cryptogenic in 2 patients. Two patients were started on warfarin therapy (case 4 for mobile thrombus in the aortic arch, and case 6 for atrial fibrillation). Cases 7 and 8 were diagnosed with high-grade symptomatic carotid stenosis. Case 7 underwent carotid angioplasty and stenting because of an intermediate cardiac risk status for endarterectomy (Fig 1), and case 8 underwent carotid endarterectomy. The remaining 4 patients were treated medically with antiplatelet medication and vascular risk factor modification. Three patients had a recurrent cerebrovascular event. Case 2 sustained recurrent right MCA stroke 2 months later due to artery-to-artery embolism from the previously occluded carotid artery. Case 6 experienced worsening of global aphasia 20 hours after symptom onset that resolved within 20 minutes and returned to an NIHSS score of 1 afterward. Case 8 had a return of MCA syndrome symptoms at 5-1/2 hours that resolved within 30 minutes after onset and returned to an NIHSS score of 2.

Neuroimaging The mean time from onset to CTP imaging was 12.7 hours (range, 3-30 hours) (Fig 2). CTP imaging results (Table 2) demonstrated partial perfusion abnormalities in the MCA distribution in 5 patients without arterial lesions and large MCA territory perfusion abnormalities in 3 patients with fixed arterial lesions (cases 4, 7, and 8). Four patients underwent repeat CTP between 2 and 42 days after onset, and all 4 showed eventual normalization of the perfusion abnormality. Repeat CTP imaging performed 2-6 days after stroke onset in cases 1, 6, and 8 showed resolution of the perfusion defect with symmetric and normal hemispheric perfusion. Case 8 demonstrated high-grade carotid stenosis; however, repeat CTP was done before carotid endarterectomy. Case 4 underwent repeat CTP imaging 2 days after stroke onset that showed a persistent large perfusion abnormality in the entire right MCA distribution, but repeat CTP imaging done 42 days after stroke onset was normal. The mean time between onset of symptoms and MRI was 15.5 hours (range, 7.9-34 hours). MRI diffusionweighted imaging (DWI) showed restricted diffusion in the subcortical regions in all patients in the corresponding MCA distribution, and 1 patient (case 2) had prominent cortical and subcortical infarcts. Case 6 also had a punctate area of acute infarct in the contralateral right occipital region, which was suspected to be an asymptomatic radiographic marker of cardioembolism. No hemorrhagic complications were observed. Intracranial vascular imaging with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) was performed in all patients. One patient had an M2 occlusion (case 1), 1 patient had a MCA

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Table 1. Patient characteristics NIHSS score

Patient

Age, years/sex

Clinical signs and symptoms

Initial

Recovery (hours Poststroke after onset) day 1

14

0 (0.75)

0

10

3 (1.95)

0

16

0 (2.33)

0

13

4 (2.55)

4

Left hemiplegia/numbness, dysarthria; right gaze preference Right hemiplegia,global aphasia

15

0 (4)

0

1 (5.5)

0

59 M, hypertension, hyperlipidemia, coronary artery disease

Right hemiplegia,global aphasia

18

2 (7)

2

64 M, hypertension

Left hemiplegia, gaze preference; right homonymous heminanopsia

14

2 (3.5)

2

1

55 M

2

3

46 M, smoker, cocaine user, hypothyroid, diabetes mellitus 81 F, hypertension

4

58 M, ex-smoker

5

status post IV tPA

6

79 M, hypertension, atrial fibrillation, hyperlipidemia

7

8

Left hemiplegia/numbness, dysarthria Left hemiplegia, right gaze preference Left hemiplegia, dysarthria, neglect; right gaze preference Left hemiplegia/numbness, dysarthria

30

Diagnostic testing

Cause of stroke

CTA/MRA: right M2 occlusion; TTE-EF: Unknown 45%; TEE: negative CTA of head and neck: right ICA occlusion; ICA occlusion MRA: right ICA occlusion, decreased right MCA flow; TTE-EF: 55%, Holter: negative CTA: nondiagnostic; MRA: negative; CUS: Unknown negative; TTE-EF: 55%; TEE: refused Cardioembolism CTA: right MCA occlusion; cerebral angiography: right MCA thrombus with stenosis; TTE-EF: 35%; TEE: mobile thrombus in aortic arch CTA: right ICA occlusion, right M2 occlusion; ICA occlusion cerebral angiography: right ICA occlusion, patent right MCA; TTE-EF: 70% CTA: negative; CTA of neck: negative; MRA: Cardioembolism negative; CUS: negative; telemetry: atrial fibrillation; TTE-EF: 55%; TEE: negative ICA stenosis CTA: left ICA stenosis, left MCA occlusion; CUS: left ICA stenosis; cerebral angiography: left ICA 95% stenosed, left MCA patent; TTE-EF: 55% ICA stenosis CTA: right MCA stenosis; CTA of neck: right ICA occlusion; cerebral angiography: right ICA 98% stenosed, right MCA patent; TTE: 70% V.H. LEE ET AL.

Abbreviations: CUS, carotid ultrasound; EF, ejection fraction; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

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Figure 1. Case 7. A 59-year-old male with hypertension, hyperlipidemia, and coronary artery disease presented to an outside ER with globally aphasia and dense right hemiplegia. On arrival to our hospital 7 hours after onset, his NIHSS score improved to 2 (right facial droop and subtle aphasia). (A) CTP showed a large MCA perfusion defect. (B) CTA showed a flow dropout in the left MCA (white arrow), suggesting occlusion. (C) DWI MRI showed acute infarcts in the caudoputamen, sparing most of the cortex. (D) Cerebral angiography confirmed a high-grade left cervical carotid stenosis (single arrow) (E). Intracranially, the left MCA is patent (double arrows). (F). After carotid stenting, the left MCA flow is improved (double arrows).

occlusion (case 4), and 5 patients had patent intracranial arteries (cases 2, 3, 5, 6, and 7). Four patients underwent cerebral angiography (cases 4, 5, 7, and 8) during the acute hospitalization. In 2 of these patients (cases 5 and 7), CTA suggested an MCA (M1 and M2) occlusion, but cerebral angiography subsequently demonstrated a patent MCA with decreased flow in association with a proximal cervical carotid lesion. Another patient (case 4) had MCA occlusion on CTA, but cerebral angiography showed an MCA thrombus with 50% stenosis. It is possible that an MCA occlusion was present on the initial CTA but had recanalized by the time of subsequent cerebral angiography. However, an alternative explanation for the discrepancy between CTA and cerebral angiography is that in the presence of a proximal lesion, slow flowrelated lack of contrast enhancement on CTA gave the false impression of occlusion.

Discussion The natural history of MCA occlusion can be extrapolated from the PROACT II study, which included 180 patients with angiographically confirmed MCA occlusion.4 In the control group, half the patients were dead or moribund (modified Rankin Score [mRS] $4) at 3 months, 17% of patients had a benign outcome (mRS #1), and the 2-hour MCA recanalization rate was 18%.4 Given the dismal natural history of large-artery hemispheric syndromes, the small subset of patients that dramatically improve (ie, SSD) have caught the attention of many clinicians and observers, especially given that SSD patients maintain clinical benefit long-term, with improved outcomes.5-7 SSD has been reported to occur in 12%-14% of patients with initial major hemispheric syndromes.5,8,9 However, the definition of SSD has not been uniform, with some series

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V.H. LEE ET AL.

Figure 2. Neuroimaging for the 8 SSD cases. CTP images (top row) show the region of decreased perfusion (green). Final infarct volume (red) was determined by DWI MRI images (row 2). The numbers below the images in row 1 and 2 indicate time (in hours) after symptom onset. Repeat CTP is shown in rows 3 and 4. The numbers below the images in rows 3 and 4 indicate time (in days) after symptom onset.

requiring recovery within 1 hour and others allowing recovery to occur over days.5,8-11 The lack of standardized criteria makes direct comparison between case series difficult. We defined SSD as #8 hours, because this would be the period relevant for consideration in the window for intra-arterial reperfusion therapies in acute ischemic stroke. A strict time window also excludes patients with later recovery (over days), because this likely represents neurologic improvement that is unrelated to acute reperfusion, but rather due to plasticity.10 Our study, with the more rigorous time window (,8 hours) than most series, found a 7% rate of SSD. We included patients who received IVtPA. IV-tPA improves the likelihood of SSD by improving the chance of clot migration, but the underlying mechanism of rapid recovery is similar (ie, distal clot propagation). Reports on SSD are limited to small case series and case reports. Patients with SSD tend to be younger compared with hemispheric patients without SSD, and earlier recovery is a predictor of long-term outcome.8,9 Patients with SSD compared with patients without SSD have smaller final radiographic infarcts.5,9 However, clinical improvement might not be noticed by the patient, and the diagnosis of SSD often requires witnesses during maximal deficit. In one study, only 50% of stroke patients who experience dramatic

recovery were aware of the magnitude of their maximal neurologic deficit, and only a 25% were aware of their improvement, regardless of right- or left-sided lesions.12 Previous published series suggest that the majority of SSD are due to cardioembolism, ranging from 80% to 94%.8,9,11 However in our study, only 2 of the 8 patients had potential cardiac embolic sources, and 4 patients had proximal large-artery lesions (carotid occlusion or high-grade stenosis). Thus, SSD does not appear to be a specific marker for cardioembolism, but is suggestive of embolism itself (from either a cardiac or large-artery source). Regardless of the etiology of the transient occlusion, the mechanism for the rapid symptom improvement is suggested to involve vessel recanalization. Angiographic case reports confirm that radiographic occlusion of a major cerebral artery followed by early recanalization results in rapid clinical recovery.13 Vascular imaging in SSD typically shows no arterial occlusion or distal occlusion, which would support vessel recanalization as the underlying mechanism.8 In stroke patients who receive IV tPA, there is a higher rate of MCA flow restoration by transcranial Doppler ultrasonography (TCD) in patients with dramatic recovery versus those without dramatic recovery, and the majority of patients who

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Table 2. CT perfusion data in the 8 SSD patients Case

CBV (mL/100g)

CBF (mL/100g/min)

MTT (s)

Relative MTT**

TTP (s)

1 R* L 2 R* L 3 R* L 4 R* L 5 R* L 6R L* 7R L* 8 R* L

20.44 8.85 2.42 8.41 13.81 12.91 10.44 11.97 9.54 7.58 4.35 6.31 5.65 10.54 12.07 11.17

87.96 108.53 17.71 111.77 81.49 206.16 64.29 178.48 61.11 152.36 80.73 33.33 67.14 46.23 55.50 123.27

13.94 4.89 8.22 4.51 10.17 3.76 9.74 4.02 9.36 2.99 3.24 11.35 5.05 13.68 13.04 5.44

285%

28.41 23.80 23.88 20.23 32.38 27.22 24.99 20.30 29.59 25.00 27.27 33.24 25.35 31.56 28.02 23.24

182% 270% 242% 313% 350% 270% 239%

R- right, L- left, CBV- Cerebral blood volume, CBF- Cerebral blood flow, MTT- Mean time to transit, TTP- Time to peak, s- seconds. *Affected hemisphere. **Value measured in the pathological hemisphere expressed as a percentage of the value in the normal hemisphere.

recanalize do so within 60 minutes of IV tPA bolus.6,7 These TCD data suggest that after IV tPA, early and sustained restoration of arterial flow is the mechanism behind dramatic clinical recovery in patients with largeartery occlusions. Although reopening of an occluded vessel is likely the mechanism in most patients, there are a few reports of rapid neurologic improvement in the face of persistent arterial occlusion, suggesting that in a subset of patients, clinical improvement cannot be attributed to recanalization or distal embolus migration.8,14 This latter finding suggests that other mechanisms that mitigate or reverse cerebral ischemia, such as increased collateral flow, might play a role in SSD. In our SSD series, clinical recovery was likely on the basis of antegrade reperfusion, as clinical recovery was not observed in the face of persistent proximal MCA arterial occlusion in any of our patients. Experimental animal studies of temporary MCA occlusion have consistently shown that infarct size and severity correlate with duration of MCA occlusion, with temporary occlusion leading to incomplete infarction. In the rat model, brains undergoing permanent MCA occlusion have large infarcts with cavitation, whereas transient MCA occlusions result in selective neuronal lesions (SNLs), which tend to be more severe in the caudoputamen than the cortex.15,16 Restoration of MCA flow in cats within 8 hours resulted in less severe neurologic deficit and smaller infarcts than did permanent occlusion.17 Primate models of MCA occlusion have demonstrated that long-term ischemia (.8 hours) leads to confluent infarct and total necrosis, whereas release up to 3-4 hours can lead to clinical improvement and pathologically non-confluent deep infarcts and SNLs.18,19 In

case 7, brain MRI (Fig 1, C) demonstrates the standard core infarct seen in animal models of temporary occlusion, with the severe injury predominantly in the caudoputamen. On MRI DWI, SSD typically shows small lesions, and the ischemic changes tend to be apparent on T1- and T2-weighted imaging performed on subacute followup.5,11,14,20 Not surprisingly, CTP imaging performed acutely at the time of maximal deficits in patients with SSD shows decreased perfusion in the hemisphere.21 After clinical recovery, single-photon emission computed tomography (SPECT) detected 88% tissue reperfusion during the first 48 hours in patients with SSD, compared with 17% in those without SSD.9 Confirming animal studies that have shown incomplete infarction or SNLs, and there is evidence in humans that the rescued penumbra is affected by SNLs. A study using quantitative 11Cflumazenil (FMZ) positron emission tomography in 7 patients with SSD compared with 10 age-matched controls revealed that SNLs were more prevalent and extensive in noninfarcted MCA tissue, as evidenced by FMZ binding loss in ultimately noninfarcted brain areas.21 Neuroimaging revealing perfusion-diffusion mismatch in acute stroke is not uncommon. One-third of patients with TIA have a perfusion defect evident on acute MRI perfusion imaging (MRI-P).22 Acute imaging in patients with TIA and stroke has shown that during the early phase of stroke (up to 24 hours), the perfusion deficit is often greater than the lesion demonstrated by DWI, and this occurs in patients with or without eventual expansion of the DWI lesion.23 MRI-P imaging in patients with SSD correlates with SPECT data showing a large initial ‘‘mismatch’’ followed by rapid shrinking of the region at risk

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for infarction on repeat imaging. The volume of the perfusion abnormality may be related to the time from stroke onset. The perfusion volume usually shrinks in the first 12-24 hours after ischemic stroke irrespective of recanalization or recovery.22,23 The natural neuroimaging history of acute stroke is a perfusion defect larger than the ischemic area that does not inevitably progress to infarction, but tends to shrink to some degree. In patients with SSD, radiographic ‘‘shrinking’’ is a marker of clinical recovery and small final infarct volume. SSD patients with clinical TIA may be on the farthest end of the spectrum of perfusion shrinkage and may represent a ‘‘pure’’ perfusion defect that resolves. Acute perfusion imaging in SSD confirms the clinical suspicion of the size of the ischemic area and the territory involved, and also corroborates the clinical evidence that a larger territory was at risk, which contributes to our understanding of acute stroke and the phenomenon of SSD. In our SSD patients, we observed that even after rapidly resolving deficits, CTP was still able to demonstrate residual decreased perfusion in a portion of the MCA territory, suggesting that the radiographic perfusion deficits persist longer than clinical symptoms. The larger penumbra (ie, perfusion lesion) shrinks in a delayed fashion for unclear reasons; a possible explanation is that the threshold for clinical recovery or neurologic symptoms is lower than the threshold for radiographic normalization. However, of interest is that 2 patients (cases 6 and 8) had a stuttering course with transient worsening of their symptoms within 24 hours. The perfusion deficits eventually normalized in all 4 SSD patients with repeat CTP images available. Furthermore, the initial perfusion abnormality was larger and affected the entire MCA territory in the setting of a proximal large-artery lesion (stenosis or occlusion), likely reflecting the proximal flow-limiting lesion. Patients with severe carotid stenosis or occlusion can have extensive MCA territory perfusion delay, as evidenced by prolonged MTT.24 We found that normalization of the perfusion deficit occurred even in the presence of a large-artery high-grade stenosis before treatment (case 8). In SSD, perfusion abnormalities seen on CTP appear to lag behind clinical recovery and can disappear or ‘‘shrink’’ within days. Limitations of our study include the retrospective nature and small number of patients, as well as variability in time between onset and imaging. Given the relative rarity of SSD and the dynamic clinical presentation, misdiagnosis or misidentification of patients is also a potential limitation. In this study, we used CTP imaging because of the relative ease in obtaining these images in the hyperacute setting and shorter acquisition and scanning times. Relative MTT has been validated as an accurate marker of ischemic penumbra, although there is debate as to which perfusion parameters define penumbra.2 MRI-P may be better suited for detecting penumbral or ischemic tissue relative to core infarct (‘‘mismatch’’). Further studies are warranted to better understand acute stroke and the

subset of patients who dramatically improve acutely (ie, those with SSD). The fact that the radiographic reperfusion lags behind clinical recovery in patients with spontaneous improvement should be considered in future acute stroke trials that select patients using perfusion imaging.

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