Marc Malkoff

High Rate of Complete Recanalization and Dramatic Clinical Recovery During tPA Infusion When Continuously Monitored With 2-MHz Transcranial Doppler Monitoring

Background and Purpose—Clot dissolution with tissue plasminogen activator (tPA) can lead to early clinical recovery after stroke. Transcranial Doppler (TCD) with low MHz frequency can determine arterial occlusion and monitor recanalization and may potentiate thrombolysis. Methods—Stroke patients receiving intravenous tPA were monitored during infusion with portable TCD (Multigon 500M; DWL MultiDop-T) and headframe (Marc series; Spencer Technologies). Residual flow signals were obtained from the clot location identified by TCD. National Institutes of Health Stroke Scale (NIHSS) scores were obtained before and after tPA infusion. Results—Forty patients were studied (mean age 70±16 years, baseline NIHSS score 18.6±6.2, tPA bolus at 132±54 minutes from symptom onset). TCD monitoring started at 125±52 minutes and continued for the duration of tPA infusion. The middle cerebral artery was occluded in 30 patients, the internal carotid artery was occluded in 11 patients, the basilar artery was occluded in 3 patien...

Timing of Recanalization After Tissue Plasminogen Activator Therapy Determined by Transcranial Doppler Correlates With Clinical Recovery From Ischemic Stroke

BACKGROUND The duration of cerebral blood flow impairment correlates with irreversibility of brain damage in animal models of cerebral ischemia. Our aim was to correlate clinical recovery from stroke with the timing of arterial recanalization after therapy with intravenous tissue plasminogen activator (tPA). METHODS Patients with symptoms of cerebral ischemia were treated with 0.9 mg/kg tPA IV within 3 hours after stroke onset (standard protocol) or with 0.6 mg/kg at 3 to 6 hours (an experimental institutional review board-approved protocol). National Institutes of Health Stroke Scale (NIHSS) scores were obtained before treatment, at the end of tPA infusion, and at 24 hours; Rankin Scores were obtained at long-term follow-up. Transcranial Doppler (TCD) was used to locate arterial occlusion before tPA and to monitor recanalization (Marc head frame, Spencer Technologies; Multigon 500M, DWL MultiDop-T). Recanalization on TCD was determined according to previously developed criteria. RESULTS Forty patients were studied (age 70+/-16 years, baseline NIHSS score 18.6+/-6.2). A tPA bolus was administered at 132+/-54 minutes from symptom onset. Recanalization on TCD was found at the mean time of 251+/-171 minutes after stroke onset: complete recanalization occurred in 12 (30%) patients and partial recanalization occurred in 16 (40%) patients (maximum observation time 360 minutes). Recanalization occurred within 60 minutes of tPA bolus in 75% of patients who recanalized. The timing of recanalization inversely correlated with early improvement in the NIHSS scores within the next hour (polynomial curve, third order r(2)=0.429, P<0.01) as well as at 24 hours. Complete recanalization was common in patients who had follow-up Rankin Scores if 0 to 1 (P=0.006). No patients had early complete recovery if an occlusion persisted for >300 minutes. CONCLUSIONS The timing of arterial recanalization after tPA therapy as determined with TCD correlates with clinical recovery from stroke and demonstrates a 300-minute window to achieve early complete recovery. These data parallel findings in animal models of cerebral ischemia and confirm the relevance of these models in the prediction of response to reperfusion therapy.

Transcranial Doppler Ultrasound Criteria for Recanalization After Thrombolysis for Middle Cerebral Artery Stroke

BACKGROUND AND PURPOSE Transcranial Doppler (TCD) can demonstrate arterial occlusion and subsequent recanalization in acute ischemic stroke patients treated with intravenous tissue plasminogen activator (tPA). Limited data exist to assess the accuracy of recanalization by TCD criteria. METHODS In patients with acute middle cerebral artery (MCA) occlusion treated with intravenous tPA, we compared posttreatment TCD with angiography (digital subtraction or magnetic resonance). On TCD, complete occlusion was defined by absent or minimal signals, partial occlusion by blunted or dampened signals, and recanalization by normal or stenotic signals. Angiography was evaluated with the Thrombolysis In Myocardial Ischemia (TIMI) grading scale. RESULTS Twenty-five patients were studied (age 61+/-18 years, 16 men and 9 women). TCD was performed at 12+/-16 hours and angiography at 41+/-57 hours after stroke onset, with 52% of studies performed within 3 hours of each other. Recanalization on TCD had the following accuracy parameters compared with angiography: sensitivity 91%, specificity 93%, positive predictive value (PPV) 91%, and negative predictive value (NPV) 93%. To predict partial occlusion (TIMI grade II), TCD had sensitivity of 100%, specificity of 76%, PPV of 44%, and NPV of 100%. TCD predicted the presence of complete occlusion on angiography (TIMI grade 0 or I) with sensitivity of 50%, specificity of 100%, PPV of 100%, and NPV of 75%. TCD flow signals correlated with angiographic patency (chi(2)=24.2, P<0.001). CONCLUSIONS Complete MCA recanalization on TCD accurately predicts angiographic findings. Although a return to normal flow dynamics on TCD was associated with complete angiographic resumption of flow, partial signal improvement on TCD corresponded with persistent occlusion on angiography.

Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial

Microspheres (μS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of μS dose escalation with systemic thrombolysis.

Intravenous Tissue Plasminogen Activator and Flow Improvement in Acute Ischemic Stroke Patients with Internal Carotid Artery Occlusion

Background and Purpose. It has been suggested that intravenous tissue plasminogen activator (TPA) would not lyse the large thrombus associated with internal carotid artery (ICA) occlusion and, therefore, would be ineffective in this setting. Vascular imaging, safety, and outcome of TPA therapy for ICA occlusion is not well described. Our goal was to determine the site of occlusion, early recanalization after TPA infusion, and its relationship to outcome. Methods. We reviewed our database of all stroke patients treated with IV TPA between July 1997 and July 1999. We identified all cases with carotid occlusion suggested by transcranial Doppler (TCD) and angiography. Occlusion and recanalization were assessed by site including proximal ICA (prICA), terminal ICA (tICA), and middle cerebral artery (MCA). Baseline National Institutes of Health Stroke Scale (NIHSS) scores and follow‐up Rankin scores were obtained. Results. We treated 20 patients with carotid occlusion (age 63.9 ± 10.8 years, 11 males, 9 females). Time to TPA infusion after stroke onset was 128 ± 66 minutes. Baseline NIHSS scores were 16.4 ± 5.4. Time to follow‐up was 3.5 ± 4.9 months (2 patients were lost to follow‐up). Occlusion sites were prICA 40%, tICA 70%, and concurrent MCA 45%. Multiple sites were involved in 10/20 patients (50%). Among patients with pretreatment and posttreatment vascular imaging studies (n= 18), recanalization in the prICA and tICA was complete in 10%, partial in 16%, and none in 74%. MCA recanalization was complete in 35%, partial in 24%, and none in 41%. At follow‐up, Rankin 0–1 was found in 8 patients (44%), Rankin 2–3 in 3 (17%), and Rankin 4–5 in 3 (17%). Mortality was 22% (n= 4) including 1 fatal intracerebral hemorrhage. Improvement was closely related to resumption of MCA flow (P < .01). Conclusions. Most patients did not recanalize their ICA occlusion after intravenous TPA therapy. However, recanalization of associated proximal MCA clot, found in 45% of our patients, or improved MCA collateral flow was strongly associated with good outcome.

A Pilot Randomized Clinical Safety Study of Sonothrombolysis Augmentation With Ultrasound-Activated Perflutren-Lipid Microspheres for Acute Ischemic Stroke

Background and Purpose— Ultrasound transiently expands perflutren-lipid microspheres (&mgr;S), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated &mgr;S with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL &mgr;S). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. &mgr;S reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, &mgr;S permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of &mgr;S infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P=0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P=0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P=0.456. Conclusions— Perflutren &mgr;S reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further &mgr;S dose-escalation studies and development of drug delivery to tissues with compromised perfusion.

Is the Benefit of Early Recanalization Sustained at 3 Months? A Prospective Cohort Study

Background and Purpose— Early arterial recanalization can lead to dramatic recovery (DR) during intravenous tissue plasminogen activator (tPA) therapy. However, it remains unclear whether this clinical recovery is sustained 3 months after stroke. Methods— We studied consecutive patients treated with intravenous tPA (0.9 mg/kg within 3 hours) who had M1 or proximal M2 middle cerebral artery occlusion on pretreatment transcranial Doppler according to previously validated criteria. Patients were continuously monitored for 2 hours after tPA bolus to determine complete, partial, or no early recanalization with the Thrombolysis in Brain Ischemia (TIBI) flow grading system. A neurologist obtained the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores independently of transcranial Doppler results. DR was defined as a total NIHSS score of 0 to 3 points, and early recovery (ER) was defined improvement by ≥10 points at 2 hours after tPA bolus. Good long-term outcome was defined as an NIHSS score of 0 to 2 or an mRS score of 0 to 1 at 3 months. Results— Fifty-four patients with proximal middle cerebral artery occlusion had a median prebolus NIHSS score of 16 (range, 6 to 28; 90% with ≥10 points). The tPA bolus was given at 130±32 minutes (median, 120 minutes; 57% treated within the first 2 hours). DR+ER was observed in 50% of patients with early complete recanalization (n=18), 17% with partial recanalization (n=18), and 0% with no early recanalization (n=18) (P =0.025). Overall, DR+ER was observed in 12 patients (22%), and 9 (75%) had good outcome at 3 months in terms of NIHSS (P =0.009) and mRS (P =0.006) scores compared with non-DR and non-ER patients. If early recanalization was complete, 50% of these patients had good outcome at 3 months, and 78% with DR+ER sustained early clinical benefit. If recanalization was partial, 44% had good long-term outcome, and 66% of patients with DR+ER sustained the benefit. If no early recanalization occurred, 22% had good long-term outcome despite the lack of DR within 2 hours of tPA bolus (P =0.046). Mortality was 11%, 11%, and 39% in patients with complete, partial, and no early recanalization, respectively (P =0.025). Reasons for not sustaining DR in patients with early recanalization were subsequent symptomatic intracranial hemorrhage and recurrent ischemic stroke. Conclusions— DR or ER after recanalization within 2 hours after tPA bolus was sustained at 3 months in most patients (75%) in our study. Complete or partial early recanalization leads to better outcome at 3 months after stroke. Fewer patients achieve good long-term outcome without early recanalization.

Specific Transcranial Doppler Flow Findings Related to the Presence and Site of Arterial Occlusion

BACKGROUND AND PURPOSE Transcranial Doppler (TCD) can localize arterial occlusion in stroke patients. Our aim was to evaluate the frequency of specific TCD flow findings with different sites of arterial occlusion. METHODS Using a standard insonation protocol, we prospectively evaluated the frequency of specific TCD findings in patients with or without proximal extracranial or intracranial occlusion determined by digital subtraction or MR angiography. RESULTS Of 190 consecutive patients studied, angiography showed occlusion in 48 patients. With proximal internal carotid artery (ICA) occlusion, TCD showed abnormal middle cerebral artery (MCA) waveforms (AMCAW) in 66.7%, reversed ophthalmic artery (OA) in 70.6%, anterior cross-filling via anterior communicating artery (ACoA) in 78.6%, posterior communicating artery (PCoA) in 71.4%, and contralateral compensatory velocity increase (CVI) in 84.6% of patients. With distal ICA occlusion, TCD showed AMCAW in 88.9%, OA in 16.7%, ACoA in 50%, PCoA in 60%, and CVI in 88.9% of patients. With MCA occlusion, TCD showed AMCAW in 100%, OA in 23.5%, ACoA in 31.3%, PCoA in 23.1%, and CVI in 62.5%. With no anterior circulation occlusion at angiography, TCD showed these parameters in 1.8% to 17. 9%, chi(2) P</=0.003. Parameters localizing anterior circulation occlusion were stenotic terminal ICA velocities 46% versus 10% in patent vessels; flow diversion to perforators 73% versus 1.8%; OA 70. 6% versus 5.6%; ACoA 78.6% versus 8.2%; PCoA 71.4% versus 8.5%, all at P<0.05. In patients with basilar artery (BA) occlusion, ABAW were found in 80% versus 3% (patent BA); flow diversion to anterior vessels in 60% versus 5.7%; BA flow reversal in 20% versus 0%; and PCoA in 100% versus 13.7%, all at P<0.001. No individual parameters differentiated BA from the terminal vertebral occlusion. CONCLUSIONS Specific TCD findings are common with major arterial occlusion and can be used to broaden diagnostic batteries and improve the predictive value of noninvasive screening in stroke patients. TCD findings useful to localize anterior circulation occlusion include collaterals, abnormal waveforms or velocities, and flow diversion to perforators.

Deterioration Following Spontaneous Improvement Sonographic Findings in Patients With Acutely Resolving Symptoms of Cerebral Ischemia

BACKGROUND AND PURPOSE Some stroke patients will deteriorate following improvement (DFI), but the cause of such fluctuation is often unclear. While resolution of neurological deficits is usually related to spontaneous recanalization or restoration of collateral flow, vascular imaging in patients with DFI has not been well characterized. METHODS We prospectively studied patients who presented with a focal neurological deficit that resolved spontaneously within 6 hours of symptom onset. Patients were evaluated with bedside transcranial Doppler (TCD). Digital subtraction angiography (DSA), computed tomographic angiography (CTA), or magnetic resonance angiography (MRA) were performed when feasible. DFI was defined as subsequent worsening of the neurological deficit by >/=4 National Institutes of Health Stroke Scale points within 24 hours of the initial symptom onset. RESULTS We studied 50 consecutive patients presenting at 165+/-96 minutes from symptom onset. Mean age was 61+/-14 years; 50% were females. All patients had TCD at the time of presentation, and 68% had subsequent angiographic examinations (DSA 10%, CTA 4%, and MRA 44%). Overall, large-vessel occlusion on TCD was found in 16% of patients (n=8); stenosis was found in 18% (n=9); 54% (n=27) had normal studies; and 6 patients (12%) had no temporal windows. DFI occurred in 16% (n=8) of the 50 patients: in 62% of patients with TCD and angiographic evidence of occlusion, in 22% with stenosis, and in 4% with normal vascular studies (P<0.001, Phi=0.523, chi(2)=12.05). DFI occurred in 31% of patients with large-vessel atherosclerosis, 23% with cardioembolism, and 9% with small-vessel disease when stroke mechanisms were determined within 2 to 3 days after admission (P=0.2, NS). CONCLUSIONS DFI is strongly associated with the presence of large-vessel occlusion or stenosis of either atherosclerotic or embolic origin. Normal vascular studies and lacunar events were associated with stable spontaneous resolution without subsequent fluctuation. Urgent vascular evaluation may help identify patients with resolving deficits and vascular lesions who may be candidates for new therapies to prevent subsequent deterioration.

Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series.

Background and Purpose— Efforts to increase the availability and shorten the time delivery of intravenous thrombolysis in patients with acute ischemic stroke carry the potential for tissue plasminogen activator administration in patients with diseases other than stroke, that is, stroke mimics (SMs). We aimed to determine safety and to describe outcomes of intravenous thrombolysis in SM. Methods— We retrospectively analyzed stroke registry data of consecutive acute ischemic stroke admissions treated with intravenous thrombolysis over a 6-year-period. The admission National Institutes of Health Stroke Scale score, vascular risk factors, ischemic lesions on brain MRI (routinely performed as part of diagnostic work-up), and discharge modified Rankin Scale scores were documented. Initial stroke diagnosis in the emergency department was compared with final discharge diagnosis. SM diagnosis was based on the absence of ischemic lesions on diffusion-weighted imaging sequences in addition to an alternate discharge diagnosis. Symptomatic intracranial hemorrhage was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by National Institutes of Health Stroke Scale score increase of ≥4 points. Results— Intravenous thrombolysis was administered in 539 patients with acute ischemic stroke (55% men; mean age, 66±15 years). Misdiagnosis of acute ischemic stroke was documented in 56 cases (10.4%; 95% CI, 7.9% to 13.3%). Conversion disorder (26.8%), complicated migraine (19.6%), and seizures (19.6%) were the 3 most common final diagnoses in SM. SMs were younger (mean age, 56±13 years) and had milder baseline stroke severity (median National Institutes of Health Stroke Scale, 6; interquartile range, 4) compared with patients with confirmed acute ischemic stroke (mean age, 67±14 years; median National Institutes of Health Stroke Scale, 8; interquartile range, 10; P<0.001). There was no case of symptomatic intracranial hemorrhage in SMs (0%; 95% CI, 0% to 5.5%); 96% of SMs were functionally independent at hospital discharge (modified Rankin Scale, 0 to 1). Conclusions— Our single-center data indicate favorable safety and outcomes of intravenous thrombolysis administered to SM.