Detecting artery occlusion and critical flow diminution in the case of an acute ischemic stroke--methodological pitfalls of common vascular diagnostic methods.

PURPOSE: None of the vascular emergency diagnostic methods commonly used in the case of acute ischemic stroke, i. e. CTA, color-coded duplex sonography (CCDS), MRA, and DSA, is free of restrictions due to physical and physiological characteristics. As a result, misleading results initiating an inappropriate acute therapeutic intervention or hampering a promising one cannot be excluded. We aimed to assess the type and frequency of methodological pitfalls occurring in this situation. MATERIALS AND METHODS: We retrospectively analyzed data of 269 consecutive patients admitted to our stroke unit with a clinical syndrome of an acute stroke. All patients underwent one or more vascular emergency diagnostic methods on a routine basis. RESULTS: 37 patients were excluded because of a final diagnosis other than ischemic stroke. 76 of 232 ischemic stroke patients underwent emergency diagnostic methods with two or more vascular examination techniques. Controversial results occurred in 20 patients and related to the detection and localization of large artery occlusion and its differentiation from a low/slow flow situation and the identification of critical cerebral flow diminution distal to large artery occlusion/severe stenosis. Methodological pitfalls were able to be most reliably resolved by CCDS. Within the whole cohort of ischemic stroke patients, vascular constellations susceptible to misinterpretation were diagnosed in 40 (17.2 %) patients. CONCLUSION: We recommend providing several techniques including CCDS in an emergency stroke setting and applying techniques with respect to diagnostic findings.

Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt.

BACKGROUND: Right-to-left cardiac shunt (RLS) is considered a risk factor for stroke, especially in patients aged <55 years. We aimed to investigate the current management and prognosis in consecutive patients with RLS and otherwise cryptogenic cerebrovascular events. METHODS: In total, 1,126 patients with cryptogenic stroke or TIA were included from 17 German neurology departments. During a mean follow-up of 28.4 months, we assessed current antithrombotic medication, percutaneous device closure (PDC) and recurrent cerebrovascular events in 899 patients (79.8%). Stroke recurrence was compared between 548 patients without RLS and 351 patients with RLS under various prevention regimens. RESULTS: RLS was detected in 35.9% of cryptogenic cerebrovascular patients, but could not be evaluated as an independent predictor for recurrent stroke (adjusted HR 1.6, 95% CI: 0.9-2.7). In RLS-positive patients, the Kaplan-Meier estimate for stroke during the first year was 4.1% (95% CI: 1.9-6.3%) and 1.7% (95% CI: 0.9-2.4%) per year thereafter. At the last follow-up before recurrent stroke or end of study, 117 RLS-positive patients (33.3%) had received a PDC, 154 (43.9%) were receiving antiplatelets, 63 (17.9%) received anticoagulation, and 17 (4.8%) received none of the above. No association with recurrent stroke was found for the secondary preventive regime. CONCLUSION: Our multicenter hospital-based cohort study confirmed low recurrent event rates in RLS patients with otherwise cryptogenic stroke or TIA, as well as a great heterogeneity of current management. Despite the lack of scientific evidence, a substantial number of RLS-positive patients underwent PDC for secondary stroke prevention.

Predictive value of the Essen Stroke Risk Score and Ankle Brachial Index in acute ischaemic stroke patients from 85 German stroke units.

BACKGROUND: Risk stratification can contribute to individualised optimal secondary prevention in patients with cerebrovascular disease. OBJECTIVE: To prospectively investigate the prediction of the Essen Stroke Risk Score (ESRS) and a pathological Ankle Brachial Index (ABI) in consecutive patients hospitalised with acute ischaemic stroke or transient ischaemic attack (TIA) in 85 neurological stroke units throughout Germany. METHODS: 852 patients were prospectively documented on standardised case report forms, including assessment of ESRS and ABI. After 17.5 months, recurrent cerebrovascular events, functional outcome or death could be assessed in 729 patients predominantly via central telephone interview. RESULTS: After discharge from the documenting hospital, recurrent stroke occurred in 41 patients (5.6%) and recurrent TIA in 15 patients (2.1%). 52 patients (7.1%) had died, 33 (4.5%) from cardiovascular causes. Patients with an ESRS > or = 3 (vs <3) had a significantly higher risk of recurrent stroke or cardiovascular death (9.7% vs 5.1%; odds ratio (OR) 2.00, 95% confidence interval (CI) 1.08 to 3.70) and a higher recurrent stroke risk (6.9% vs 3.7%; OR 1.93, 95% CI 0.95 to 3.94). Patients with an ABI < or = 0.9 (vs > 0.9) had a significantly higher risk of recurrent stroke or cardiovascular death (10.4% vs 5.5%; OR 2.00, 95% CI 1.12 to 3.56) and a higher recurrent stroke risk (6.6% vs 4.6%; OR 1.47, 95% CI 0.76 to 2.83). CONCLUSION: Our prospective follow-up study shows a significantly higher rate of recurrent stroke or cardiovascular death and a clear trend for a higher rate of recurrent stroke in patients with acute cerebrovascular events classified as high risk by an ESRS > or = 3 or a pathological ABI.

Recanalization after intravenous thrombolysis: does a recanalization time window exist?

BACKGROUND: To evaluate the time course of major vessel recanalization under IV thrombolysis in relation to functional outcome in acute ischemic stroke. METHODS: A total of 99 patients with an acute anterior circulation vessel occlusion who underwent IV thrombolysis were included. All patients had a standardized admission and follow-up procedure. Color-coded duplex sonography was performed on admission, 30 minutes after thrombolysis, and at 6 and 24 hours after onset of symptoms. Recanalization was classified as complete, partial, and absent. Functional outcome was rated with the modified Rankin Scale on day 30. RESULTS: Complete recanalization occurred significantly more frequently in patients with multiple branch occlusions compared to those with mainstem occlusion (OR 5.33; 95% CI, 2.18 to 13.05; p < 0.0001) and was associated with lower NIH Stroke Scale (NIHSS) scores (p < 0.001). Not the specific time point of recanalization at 6 or 24 hours after stroke onset, but recanalization per se within 24 hours (OR 7.8; 95% CI 2.2 to 28.2; p = 0.002) was significantly associated with a favorable outcome. Multivariate analysis revealed recanalization at any time within 24 hours and NIHSS scores on days 1 and 7 together explaining 75% of the functional outcome variance 30 days after stroke. CONCLUSIONS: Complete recanalization up to 24 hours after stroke onset is significantly associated with the short-term clinical course and functional outcome 30 days after acute stroke.

Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke.

This study aimed at an analysis of glial fibrillary acidic protein (GFAP) in acute ischemic stroke, its association with the neurovascular status and its potential value as monitoring parameter. In 53 consecutive patients, serial venous blood samples were taken on admission, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extracranial and transcranial duplex sonography. Neurologic deficits were quantified by the National Institutes of Health stroke scale, and functional outcome was assessed with the modified Rankin Scale. Mean GFAP values were elevated from admission on with highest levels 48 h after stroke onset. GFAP release was highly correlated with severity of neurologic deficits and infarct volume. In patients with persistent middle cerebral artery occlusion, GFAP increased significantly compared with patients with normal sonographic findings (P = 0.019) and recanalization after thrombolysis resulted in a significant reduced increase (P = 0.038). GFAP concentrations were associated with the functional outcome after 3 months. Release kinetics of GFAP are associated with patients clinical deficits and infarct volume, depend on the neurovascular status on admission and on early recanalization after thrombolysis, and may be used as an additional predictor of the early course and functional outcome.

Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4.

Degeneration or survival of cerebral tissue after ischemic injury depends on the source, intensity, and duration of the insult. In the model of focal ischemia, reduced blood flow results in a cascade of pathophysiologic events, including inflammation, excitotoxicity, and platelet activation at the site of injury. One serine protease that is associated closely with and produced in response to central nervous system (CNS) injury is thrombin. Thrombin enters the injury cascade in brain either via a compromised blood-brain barrier or possibly from endogenous prothrombin. Thrombin mediates its action through the protease-activated receptor family (PAR-1, -3, and -4). PARs belong to the superfamily of G protein-coupled receptors with a 7-transmembrane domain structure and are activated by proteolytic cleavage of their N-terminus. We showed that thrombin can be neuroprotective or deleterious when present at different concentrations before and during oxygen-glucose deprivation, an in vitro model of ischemia. We examined the change in mRNA expression levels of PAR-1 to 4 as a result of transient focal ischemia in rat brain, induced by microinjection of endothelin near the middle cerebral artery. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis, after ischemic insult on the ipsilesional side, PAR-1 was found to be downregulated significantly, whereas PAR-2 mRNA levels decreased only moderately. PAR-3 was upregulated transiently and then downregulated, and PAR-4 mRNA levels showed the most striking (2.5-fold) increase 12 hr after ischemia, in the injured side. In the contralateral hemisphere, mRNA expression was also affected, where decreased mRNA levels were observed for PAR-1, -2, and -3, whereas PAR-4 levels were reduced only after 7 days. Taken together, these data suggest involvement of the thrombin receptors PAR-1, PAR-3, and PAR-4 in the pathophysiology of brain ischemia.

Feasibility and validity of transcranial duplex sonography in patients with acute stroke.

OBJECTIVES: To evaluate in a prospective multicentre setting the feasibility of transcranial colour coded duplex sonography (TCCS) for examination of the middle cerebral artery (MCA) in patients with acute hemispheric stroke, and to assess the validity of sonographic findings in a subgroup of patients who also had a correlative angiographic examination. METHODS: TCCS was performed in 58 consecutive patients within six hours of the onset of a moderate to severe hemispheric stroke. Ultrasound contrast agent (Levovist) was applied if necessary. Thirty two patients also had computed tomography angiography (n=13), magnetic resonance angiography (n=18), or digital subtraction angiography (n=1). In 14 of these patients, both the sonographic and corresponding angiographic examination were performed within six hours of stroke onset (mean time difference between TCCS and angiography 0.8 hours). Eighteen patients, in whom angiography was carried out more than 24 hours after stroke onset, had a follow up TCCS for method comparison (mean time difference 6.1 hours). RESULTS: Initial unenhanced TCCS performed 3.4 (SD 1.2) hours after the onset of symptoms depicted the symptomatic MCA mainstem in 32 patients (55%) (13 occlusions, one stenosis, 18 patent arteries). After signal enhancement, MCA status could be determined in 54 patients (93%) (p<0.05), showing an occlusion in 25, a stenosis in two, and a patent artery in 27 patients. In 31 of the 32 patients who had correlative angiography, TCCS and angiography produced the same diagnosis of the symptomatic MCA (10 occlusions, three stenoses, 18 patent arteries); TCCS was inconclusive in the remaining one. CONCLUSION: TCCS is a feasible, fast, and valid non-invasive bedside method for evaluating the MCA in an acute stroke setting, particularly when contrast enhancement is applied. It may be a valuable and cost effective alternative to computed tomography and magnetic resonance angiography in future stroke trials.

[Clinical presentation and prognosis of brain stem infarcts. An evaluation of the Stroke Databank of the German Stroke Foundation]. / Klinische Präsentation und Prognose von Hirnstamminfarkten. Eine Auswertung der Schlaganfall-Datenbank der Stiftung Deutsche Schlaganfall-Hilfe.

Due to the great variety of clinical classification systems and syndromes, a representative overview of the etiology and prognosis of brain stem infarctions is missing. From the German Stroke Data Bank we therefore investigated 455 patients with visible brainstem infarction on cerebral imaging in comparison to patients with other infarct localizations. Follow-up after 3 and 12 months assessed functional outcome and recurrence of cerebral ischemia. Of 455 patients with acute brainstem infarction, 115 had additional infarctions in other vascular territories. In the remaining 340 patients with isolated brainstem infarction, the classification was: small vessel disease in 36.2%, macroangiopathy in 22.6%, and cardioembolism in 11.2%. After 3 months, 10% of the patients with isolated brainstem infarction had died and 55.6% were functionally independent. Mortality was 43.5% in patients with combined brainstem infarction. Our study highlights the frequency of small vessel disease as well as the relatively favorable prognosis in isolated brainstem infarction and preserved consciousness.

Cessation of embolic signals after antithrombotic prevention is related to reduced risk of recurrent arterioembolic transient ischaemic attack and stroke.

OBJECTIVES: To evaluate the reduction of embolic signals after the initiation of an antithrombotic secondary prevention in patients with recent arterioembolic stroke and to determine the predictive value of decreased microembolism on the risk of early stroke recurrence. METHODS: Eighty six consecutive patients (55 men, 31 women; mean age 60.6 years) with a non-disabling arterioembolic ischaemic event in the anterior circulation within the last 30 days and a medium grade or high grade stenosis (> or =50%) of the ipsilateral carotid or middle cerebral artery underwent 1 hour transcranial Doppler monitoring as part of the admission examinations. Antithrombotic secondary prevention was started after completion of admission. Patients in whom embolic signals were detected underwent a second monitoring within 4 days (mean time 1.8 days). All patients were followed up prospectively to evaluate the relation between presence and persistence of embolic signals and the risk of recurrent transient ischaemic attack (TIA) and stroke within the next 6 weeks. RESULTS: In 44 patients, embolic signals were detected at admission, a mean 5.4 days (range 0 to 21 days) after the initial event. Twenty five were positive for embolic signals also at the second monitoring, in 19 signals had ceased. Forty two patients without embolic signals at admission served as controls. During follow up, six ischaemic events (two stroke, three TIA, one amaurosis fugax) occurred in 25 patients with persisting embolic signals but none in 19 patients in whom signals had ceased by the second monitoring. One patient in the control group had a TIA. The incidence of a recurrent event was 0.45 per 30 patient-days if embolic signals persisted compared with 0.015 if signals could not be detected or had ceased. Persistence of embolic signals was an independent predictor of a recurrent TIA or stroke (adjusted odds ratio 37.0; 95% confidence interval (95% CI) 3.5 to 333; p<0.003). Cessation and decrease of embolic signals was associated with the administration of antiplatelet agents but not with anticoagulation with intravenous heparin (p<0.001). CONCLUSIONS: Rapid cessation of embolic signals detected in patients with recently symptomatic arterial stenosis decreases increased risk of an early ischaemic recurrence. Effect of antithrombotic agents on embolic signals might serve as a marker for their efficacy on preventing stroke recurrence.

Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank.

BACKGROUND AND PURPOSE: Data on risk factors for etiologic subtypes of ischemic stroke are still scant. The aim of this study was to characterize stroke subtypes regarding risk factor profile, outcome, and current treatment strategies. METHODS: We analyzed data from 5017 patients with acute ischemic stroke (42.4% women, aged 65.9+/-14.1 years) who were enrolled in a large multicenter hospital-based stroke data bank. Standardized data assessment and stroke subtype classification were used by all centers. RESULTS: Sex and age distribution, major risk factors and comorbidities, recurrent stroke, treatment strategies, and outcome were all unevenly distributed among stroke subtypes (P<0.001, respectively). Cardioembolism, the most frequent etiology of stroke (25.6%), was particularly common in the elderly (those aged >70 years) and associated with an adverse outcome, a low rate of early stroke recurrence, and frequent use of thrombolytic therapy and intravenous anticoagulation. Large-artery atherosclerosis (20.9%), the most common cause of stroke in middle-aged patients (those aged 45 to 70 years), showed the highest male preponderance, highest rate of early stroke recurrence, and highest prevalence of previous transient ischemic attack, current smoking, and daily alcohol consumption among all subtypes. The highest prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and obesity was found in small-vessel disease (20.5%), which, in turn, was associated with the lowest stroke severity and mortality. CONCLUSIONS: Our results foster the concept of ischemic stroke as a polyetiologic disease with marked differences between subtypes regarding risk factors and outcome. Therefore, studies involving risk factors of ischemic stroke should differentiate between etiologic stroke subtypes.

Acetylsalicylic acid and microembolic events detected by transcranial Doppler in symptomatic arterial stenoses.

BACKGROUND: In patients with symptomatic carotid artery stenosis, high-intensity transient signals detected by transcranial Doppler (TCD) have been related to particulate microemboli originating at the stenotic lesion. The occurrence of these microembolic events within the Doppler spectrum should be influenced by antithrombotic agents of proven efficacy in these patients mainly by reducing cerebral embolism. METHODS: Seventy-four of 192 consecutive patients with symptomatic arterial stenosis in the anterior circulation and clinical symptoms within the last 30 days underwent 1-hour bilateral TCD monitoring. Patients were selected, if they presented temporal bone windows enabling transcranial insonation, revealed normal Doppler CO2 test excluding hemodynamic impairment, had not received antithrombotic therapy other than acetylsalicylic acid (ASA) before sonographic examination, and gave informed consent to 1-hour monitoring which could be performed immediately on admission/presentation of the patient at the Department of Neurology. RESULTS: Microembolic events were detected in 38 patients (51%). The proportion of patients with events among 26 patients without antithrombotic medication was 73% as compared with 40% in 48 patients receiving ASA at the time of TCD monitoring (p = 0.023). Multivariate analysis including time from ischemia to TCD, presence and start of ASA prevention, degree and localization of stenosis, and presence of a single or recurrent ischemia revealed that absence of an ASA prevention (odds ratio OR 7.1, 95% confidence interval CI 1.6-31.4, p = 0.010), recurrent ischemic events (OR 7.1, 95% CI 1.6-32.7, p = 0.011), and extracranial localization of the stenosis (OR 3.8, 95% CI 1.1-13.2, p = 0.038) were independent predictors for microembolic events. CONCLUSION: In patients with symptomatic arterial stenosis, the absence of an ASA medication is associated with the occurrence of TCD-detected microembolic events, suggesting a relation between these events and ASA-sensitive microemboli from the stenotic lesion.

DIAS I: duplex-sonographic assessment of the cerebrovascular status in acute stroke. A useful tool for future stroke trials.

BACKGROUND AND PURPOSE: A number of controlled trials have evaluated the benefit of intravenous thrombolysis in acute stroke with inconsistent results. None of these studies assessed the initial vascular status or provided information regarding the recanalization rate after therapy. Further trials need to clarify whether certain subgroups might possibly benefit more than others from intravenous thrombolysis. Therefore, a fast and valid method for assessment of cerebrovascular status is needed. In this multicenter study, we evaluated the potentials and limitations of color-coded duplex sonography (TCCS) for cerebrovascular status assessment in acute stroke patients before and after therapy. Furthermore, we compared the recanalization rate for patients referred to thrombolytic and conservative medical therapy. METHODS: Fifty-eight patients suffering from hemispheric stroke were enrolled consecutively in 8 centers. Duplex sonography was performed on admission, 2 hours after start of therapy, and 24 hours after onset of symptoms. Therapy was started within 6 hours. RESULTS: Intravenous thrombolysis was performed in 18 patients, conservative medical therapy in 39 patients, and early thromboendarterectomy in 1 patient. The middle cerebral artery (MCA) mainstem was patent in 29 patients (53.7%), occluded in 25 (46.3%), and was not assessable in 4 patients. Recanalization of the occluded MCA after 2 and 24 hours was diagnosed in 50% and 78% of the patients treated with rtPA and in 0% and 8% in the conservatively treated patients. CONCLUSIONS: Intravenous thrombolysis is highly effective in restoring blood flow after MCA occlusion. TCCS is suitable for assessment of the cerebrovascular status in acute stroke and therefore might define therapeutically relevant subgroups of patients in future stroke trials on the basis of their vascular pathology.

Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage.

BACKGROUND AND PURPOSE: The study aimed to investigate the predictive value of neurobiochemical markers of brain damage (protein S-100B and neuron-specific enolase [NSE]) with respect to early neurobehavioral outcome after stroke. METHODS: We investigated 58 patients with completed stroke who were admitted to the stroke unit of the Department of Neurology at Magdeburg University. Serial venous blood samples were taken after admission and during the first 4 days, and protein S-100B and NSE were analyzed by the use of immunoluminometric assays. In all patients, lesion topography and vascular supply were analyzed and volume of infarcted brain areas was calculated. The neurological status was evaluated by a standardized neurological examination and the National Institutes of Health Stroke Scale (NIHSS) on admission, at days 1 and 4 on the stroke unit, at day 10, and at discharge from the hospital. Comprehensive neuropsychological examinations were performed in all patients with first-ever stroke event and supratentorial brain infarctions. Functional outcome was measured with the Barthel score at discharge from the hospital. RESULTS: NSE and protein S-100B concentrations were significantly correlated with both volume of infarcted brain areas and NIHSS scores. Patients with an adverse neurological outcome had a significantly higher and significantly longer release of both markers. Neuropsychological impairment was associated with higher protein S-100B release, but this did not reach statistical significance. CONCLUSIONS: Serum concentrations and kinetics of protein S-100B and NSE have a high predictive value for early neurobehavioral outcome after acute stroke. Protein S-100B concentrations at days 2 to 4 after acute stroke may provide valuable information for both neurological status and functional impairment at discharge from the acute care hospital.

Rapid decline of cerebral microemboli of arterial origin after intravenous acetylsalicylic acid.

BACKGROUND AND PURPOSE: The present study investigated the influence of the antiplatelet agent acetylsalicylic acid (ASA) on cerebral microembolism as detected by transcranial Doppler sonography (TCD). METHODS: Nine patients with recent transient ischemic attack or minor stroke of arterial origin were investigated. Eight had not received an antiplatelet or anticoagulant medication before TCD, and in 1 patient a preexisting ASA medication (100 mg/d) had not been changed since the onset of stroke symptoms. An initial 1-hour TCD monitoring was extended for an additional 2.5 hours after an intravenous bolus injection of 500 mg ASA and was repeated for 1 hour on the following day. RESULTS: Microembolic signals (MES) were detected in all patients only on the symptomatic side. After the ASA bolus injection, a significant drop of the MES rate was found in 7 patients, all without previous medication, starting 30 minutes after the application (mean per hour=25.1 [range, 6 to 66] versus mean per hour=6.4 [range, 0 to 14]). In 3 of these patients, platelet aggregation tests were performed that demonstrated normal aggregation before bolus injection and inhibited aggregability as early as 30 minutes after bolus injection. The rate of MES remained unchanged in 1 patient without antiplatelet medication. The ninth patient, who had suffered an ischemic event on ASA, showed only a transient decrease of MES frequency. CONCLUSIONS: In patients with recent stroke of arterial origin, intravenous ASA can rapidly reduce cerebral microemboli as detected by TCD. Microemboli might be a useful parameter to monitor early effects of antiplatelet therapy.

Diagnostic impact and prognostic relevance of early contrast-enhanced transcranial color-coded duplex sonography in acute stroke.

BACKGROUND AND PURPOSE: We sought to evaluate the diagnostic value of echo-enhanced transcranial color-coded duplex sonography (TCCD) and the clinical relevance of vascular pathology assessed by sonography for early clinical outcome in acute ischemic stroke. METHODS: We present 23 consecutive patients with an anterior circulation stroke in whom clinical examination, CT, and ultrasonography were performed within 5 hours after the onset of symptoms. Transcranial Doppler sonography (TCD) and unenhanced and contrast-enhanced TCCD (Levovist, 4 g, 300 mg/mL) were compared for their ability to detect middle cerebral artery (MCA) occlusion and flow velocity reduction suggesting hemodynamic impairment in the MCA distribution pathway. Sonographic examination times were registered. Baseline clinical characteristics and CT findings were assessed. Neurological deficit was quantified according to the National Institutes of Health Stroke Scale score, with an early clinical improvement defined as decrease of the score by 4 or more points or a complete resolution of the deficit on day 4. RESULTS: Contrast-enhanced TCCD enabled diagnosis of intracranial vascular pathology in 20 affected hemispheres, whereas unenhanced TCCD and TCD were conclusive in 7 and 14 hemispheres, respectively (P=0.0001). Contrast-enhanced TCCD was superior in evaluating distal carotid (carotid-T) occlusion and differentiating major vessel occlusions from patent arteries with flow velocity diminution. Mean examination time for enhanced TCCD ranged from 5 to 7 minutes, depending on the number of investigated vessels (without or with MCA branches). Logistic regression selected a patent MCA without reduced blood flow velocity as the only independent predictor for an early clinical improvement (P<0.01). CONCLUSIONS: Contrast-enhanced TCCD is a promising tool for early prognosis in anterior circulation stroke. It is considered superior to unenhanced TCCD and TCD.