Robert A. Felberg

Thrombolysis in Brain Ischemia (TIBI) Transcranial Doppler Flow Grades Predict Clinical Severity, Early Recovery, and Mortality in Patients Treated With Intravenous Tissue Plasminogen Activator

Background and Purpose— TIMI angiographic classification measures coronary residual flow and recanalization. We developed a Thrombolysis in Brain Ischemia (TIBI) classification by using transcranial Doppler (TCD) to noninvasively monitor intracranial vessel residual flow signals. We examined whether the emergent TCD TIBI classification correlated with stroke severity and outcome in patients treated with intravenously administered tPA (IV-tPA). Methods— TCD examination occurred acutely and on day 2. TIBI flows were determined at distal MCA and basilar artery depths, depending on occlusion site. TIBI waveforms were graded as follows: 0, absent; 1, minimal; 2, blunted; 3, dampened; 4, stenotic; and 5, normal. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours after administration of tPA. Results— One hundred nine IV tPA patients were studied. Mean±SD age was 68±16 years; median NIHSS score before administration of tPA (pre-tPA) was 17.5. The tPA bolus was administered 143±58 minutes and the TCD examination 141±57 minutes after symptom onset. Pre-tPA NIHSS scores were higher in patients with TIBI grade 0 than TIBI grade 4 or 5 flow. TIBI flow improvement to grade 4 or 5 occurred in 35% of patients (19/54) with an initial grade of 0 or 1 and in 52% (12/23) with initial grade 2 or 3. The 24-hour NIHSS scores were higher in follow-up in patients with TIBI grade 0 or 1 than those with TIBI grade 4 or 5 flow. TIBI flow recovery correlated with NIHSS score improvement. Lack of flow recovery predicted worsening or no improvement. In-hospital mortality was 71% (5/7) for patients with posterior circulation occlusions; it was 22% (11/51) for patients with pre-tPA TIBI 0 or 1 compared with 5% (1/19) for those with pre-tPA TIBI 2 or 3 anterior circulation occlusions. Conclusions— Emergent TCD TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in IV-tPA–treated stroke patients. A flow-grade improvement correlated with clinical improvement.

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.

Cell death in experimental intracerebral hemorrhage: The “black hole” model of hemorrhagic damage

Intracerebral hemorrhage (ICH) has a poor prognosis that may be the consequence of the hematomas effect on adjacent and remote brain regions. Little is known about the mechanism, location, and severity of such effects. In this study, rats subjected to intracerebral blood injection were examined at 100 days. Stereology (neuronal count and density) and volume measures in the perihematoma rim, the adjacent and overlying brain, and the substantia nigra pars reticulata (SNr) were compared with contralateral brain regions at 100 days and the perihemorrhage region at 24 hours and 7 days. In addition, cytochrome c release was investigated at 24 hours, 3 days, and 7 days. At 100 days, post‐ICH rats showed no difference in neuronal density in the perihemorrhagic scar region or regions of the striatum immediately surrounding and distal to the perihemorrhage scar. The cell density index in the ipsilateral field was 16.2 ± 3.8 versus the contralateral control field of 15.6 ± 3.2 (not significant). Volume measurements of the ipsilateral striatum revealed a 20% decrease that was compensated by an increase in ipsilateral ventricular size. The area of the initial ICH as measured by magnetic resonance imaging correlated with the degree of atrophy. In the region immediately surrounding the hematoma, cytochrome c immunoreactivity increased at 24 hours and 3 days, and returned toward baseline by day 7. At 24 hours, stereology in the peri‐ICH region showed decreased density in the region where cytochrome c immunoreactivity was the highest. Neuronal density of the ipsilateral SNr was significantly less than the contralateral side (9.6 ± 1.9 vs 11.6 ± 2.3). Histologic damage from ICH occurred mainly in the immediate perihemorrhage region. Except for SNr, we found no evidence of neuronal loss in distal regions. We have termed this continued destruction of neurons, which occurs over at least 3 days as the neurons come into proximity to the hematoma, the “black hole” model of hemorrhagic damage.

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.

Early Dramatic Recovery During Intravenous Tissue Plasminogen Activator Infusion Clinical Pattern and Outcome in Acute Middle Cerebral Artery Stroke

Background and Purpose— Acute-stroke patients receiving standard intravenous tissue plasminogen activator (tPA) have been noted to experience early dramatic recoveries. The prevalence, clinical characteristics, and outcome of patients experiencing dramatic recovery is not well described. Methods— We prospectively studied all patients presenting with acute middle cerebral artery (MCA) stroke syndromes and transcranial Doppler (TCD) evidence of an MCA obstruction. All patients received intravenous tPA per the National Institute of Neurological and Communicative Disorders and Stroke protocol, with serial National Institutes of Health Stroke Scale (NIHSS) scores and continuous TCD monitoring. Dramatic recovery was defined as an improvement of ≥10 NIHSS points or a decrease to an NIHSS score of ≤3 by the end of infusion. Outcome at the end of infusion, at 24 hours, and at long-term follow-up were obtained. The timing and pattern of deficit recovery during dramatic recovery was also studied. Results— Dramatic recovery occurred in 22% of all patients. Compared with patients who did not experience dramatic recovery, those patients who did had significantly lower end-infusion NIHSS (median 2 and range 0 to 16 for dramatic-recovery patients versus median 17 and range 6 to 35 for non–dramatic-recovery patients, P <0.01) and 24-hour NIHSS (median 2 and range 0 to 16 for dramatic-recovery patients versus median 13 and range 2 to 35 for non–dramatic-recovery patients, P <0.01). A long-term modified Rankin Score benefit was noted (median 1 and range 0 to 6 for dramatic-recovery patients versus median 4 and range 0 to 6 for non–dramatic-recovery patients, P <0.01). Baseline clinical characteristics were similar. The only difference was improved TCD-determined flow values at the end of infusion (normal restoration of flow was 58% in dramatic-recovery patients versus 14% in non–dramatic-recovery patients, P <0.01). A characteristic pattern of recovery of deficit was noted. Conclusions— Early dramatic recovery in acute MCA stroke patients treated with intravenous tPA is relatively frequent. The benefit of dramatic recovery is maintained at 24 hours and over the long term. TCD monitoring suggests that dramatic recovery is a result of early restoration of MCA flow during the tPA infusion. The consistent pattern of early clinical recovery may help explain the mechanisms by which thrombolysis improves outcome and could suggest targets for enhancing the therapeutic effect of intravenous tPA.

Activation of Emergency Medical Services for Acute Stroke in a Nonurban Population The T.L.L. Temple Foundation Stroke Project

BACKGROUND AND PURPOSE Activating emergency medical services (EMS) is the most important factor in reducing delay times to hospital arrival for stroke patients. Determining who calls 911 for stroke would allow more efficient targeting of public health initiatives. METHODS The T.L.L. Temple Foundation Stroke Project is an acute stroke surveillance and intervention project in nonurban East Texas. Prospective case ascertainment allowed chart abstraction and structured interviews for all hospitalized stroke patients to determine if EMS was activated, and if so, by whom. RESULTS Of 429 validated strokes, 38.0% activated EMS by calling 911. Logistic regression analysis comparing those who called 911 with those who did not activate EMS found that individuals who were employed were 81% less likely to have EMS activated (OR 0.19, 95% CI 0.04 to 0.63). Of the 163 cases in which 911 was called, the person activating EMS was: self (patient), 4.3%; family member of significant other, 60. 1%; paid caregiver, 18.4%; and coworker or other, 12.9%. Significant associations between the variables age group (P=0.02), insurance status (P=0.007), and living alone (P=0.05) with who called 911 was found on chi(2) analysis. CONCLUSIONS Educational efforts directed at patients themselves at risk for stroke may be of low yield. To increase the use of time dependent acute stroke therapy, interventions may wish to concentrate on family, caregivers, and coworkers of high-risk patients. Large employers may be good targets to increase utilization of EMS services for acute stroke.

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.