Effect of body positioning during transcranial Doppler detection of right-to-left shunts.

We adopted an expanded transcranial Doppler (TCD) protocol to evaluate if additional injections of agitated saline in different positions would improve shunt detection or grading. We report the safety and feasibility of this expanded contrast TCD protocol. Patients with ischemic stroke were evaluated. The standard protocol for RLS detection was followed and expanded after the initial injection in the supine position to the right lateral decubitus, upright sitting, and sitting with right lateral leaning. Changes in blood pressure, heart rate, and any subjective complaints were noted. Changes in body position and additional agitated saline injections were tolerated. Right-to-left shunt (RLS) was detected in 35% of patients (n = 55). If the initial supine testing was negative, all subsequent positions/injections were also negative for RLS. However, if the supine injection was positive for RLS, the change in body positions increased the microbubble (microB) count in eight of 19 (42%) RLS-positive patients. The mean microB count in RLS-positive patients was 20 (95% CI: 9-32). The use of three additional body positions increased the microB count to 73 (95% CI: 13-132). The highest microB yield was achieved in the upright sitting position. Our findings support the safety and feasibility of the expanded TCD protocol. If the initial supine Valsalva-aided contrast TCD test is negative, there may be no need to study the patient in additional positions. However, if microB are detected in the supine position, additional testing for RLS in alternative positions may be found to be worthwhile.

Thrombotic occlusion of the common carotid artery (CCA) in acute ischemic stroke treated with intravenous tissue plasminogen activator (TPA).

Although common carotid artery (CCA) occlusions are rare, acute clinical presentations vary from mild to devastating strokes primarily due to tandem occlusions in the intracranial arteries. Three patients with acute CCA occlusions were treated with systemic tissue plasminogen activator (TPA). Blood pressures were kept at the upper limits allowed with TPA therapy with fluid balance and the 'head-down' position. Recanalization occurred in intracranial vessels only. Marked early neurological improvement occurred in two of three patients. CCA occlusions should not be considered contra-indication to systemic thrombolysis.

tPA by telephone: extending the benefits of a comprehensive stroke center.

The use of tissue plasminogen activator (tPA) in community hospitals has been limited by a lack of neurologic support. The authors developed a telephone network to support community emergency departments (EDs) in the use of tPA. Their experience demonstrates equivalent results for patients treated by telephone and those treated in-house. Their number of tPA-treated patients increased 72%. Requirements included willingness of community EDs to use tPA and willingness of the stroke center to provide support.

Cerebral venous thrombosis: combined intrathrombus rtPA and intravenous heparin.

BACKGROUND AND PURPOSE: We chose to evaluate the safety and efficacy of combined intrathrombus rtPA and intravenous heparin in cerebral venous thrombosis (CVT). METHODS: We treated 12 patients with symptoms of 1 to 40 days' duration (eg, headache, somnolence, focal deficits, seizures, and nausea and vomiting). Pretreatment MRI disclosed subtle hemorrhagic venous infarction in 4 patients, obvious hemorrhagic infarction in 2, small parenchymal hemorrhage from recent pallidotomy in 1, and no focal lesion in 5. Magnetic resonance venography and contrast venography identified thrombi in the superior sagittal sinus (SSS) in 3 patients; transverse/sigmoid sinus (TS/SS) in 2; SSS and both TS/SS in 1; SSS and 1 TS/SS in 5; and SSS, 1 TS/SS, and straight sinus in 1 patient. A loading dose of rtPA was instilled throughout the clot at 1 mg/cm, followed by continuous intrathrombus infusion at 1 to 2 mg/h. Intravenous heparin was infused concomitantly. RESULTS: Flow was restored completely in 6 patients and partially in 3, with a mean rtPA dose of 46 mg (range, 23 to 128 mg) at a mean time of 29 hours (range, 13 to 77 hours). Symptoms improved in these 9 patients concomitantly with flow restoration. Flow could not be restored in 3 patients. In 1 of them, treatment was stopped when little progress had been made, and fibrinogen level dropped to 118 mg/dL. In the other 2 patients, hemorrhagic worsening occurred, and treatment was abbreviated after initial rtPA dosing. In 1 of these, the hematoma was evacuated. CONCLUSIONS: Our experience with intrathrombus rtPA in conjunction with intravenous heparin in patients with CVT is encouraging. This therapy should probably be regarded as unsafe in patients with obvious hemorrhage. Time to restore flow may be faster than with urokinase (an average of 71 hours has been reported for 29 documented patients). Further evaluation of rtPA with heparin in CVT is warranted.

Differences in stroke between white, Hispanic, and Native American patients: the Barrow Neurological Institute stroke database.

BACKGROUND AND PURPOSE: Identification of specific features of stroke in minority populations should lead to more effectively focused treatment and prevention. METHODS: We examined 1290 white (WHI), 242 Hispanic (HIS), 83 Native American (NA), and 101 other stroke and transient ischemic attack (TIA) patients hospitalized at the Barrow Neurological Institute from 1990 through 1996. RESULTS: Chi-square analysis detected significant (P<.05) differences as follows: (1) Stroke types--lacunes more prevalent in NA than WHI and HIS (30% versus 16% and 15%); cardioembolic more prevalent in WHI than HIS (16% versus 9%, NA 14%); hemorrhages more prevalent in HIS than WHI and NA (48% versus 37% and 27%); (2) Risk factors--hypertension more prevalent in HIS than WHI (72% versus 66%; NA 71%); diabetes more prevalent in NA than HIS and WHI (62% versus 36% and 17%); cigarette smoking more prevalent in WHI than HIS and NA (61% versus 46% and 41%); cardiac disease more prevalent in WHI than HIS (34% versus 24%; NA 27%); heavier alcohol intake in NA than HIS than WHI (43% versus 24% versus 17%). There were no significant outcome differences between races for any stroke type. ANOVA detected significantly lower mean age at stroke onset in NA than HIS than WHI (56 versus 61 versus 69 years). CONCLUSIONS: There are significant differences in prevalence of risk factors and stroke types between WHI, HIS, and NA in our hospital-based population. Although the three races appear to respond to risk factors similarly, Hispanics may be especially susceptible to hemorrhage. Further evaluation of these observations in community-based studies will be important.

Absence of pontine lesions in narcolepsy.

A recent study reporting pontine lesions on magnetic resonance imaging in three patients with idiopathic narcolepsy postulated that the lesions represented tissue change secondary to long duration of disease. We studied twelve narcoleptic patients with MRI to validate these findings. The diagnosis of narcolepsy was established with both clinical and electrophysiological criteria in all twelve patients. Pontine lesions were present in two patients, both of whom were hypertensive. The lesions were associated with similar lesions in the hemispheres and were indistinguishable from ischemic change. No lesions were evident in the other ten patients, eight of whom were normotensive, and six of whom had narcolepsy for more than 37 years. We were unable to confirm the presence of pontine lesions specific to narcolepsy.

Association of the expression of an SR-cyclophilin with myeloid cell differentiation.

The role of a 150-kD SR-cyclophilin (NK-TR1) in monocyte differentiation was investigated. Using an antipeptide monoclonal antibody, we have detected NK-TR1 in human peripheral blood monocytes and HL-60 cells. Unstimulated monocytes showed a low intracellular level of NK-TR1 protein that increased over 3 days of lipopolysaccharide + interferon-gamma treatment, consistent with the kinetics of monocyte differentiation. Normal HL-60 cells also had a low level of NK-TR1 protein, and exposure to 1.25% dimethyl sulfoxide (DMSO) resulted in a marked transient increase in expression that returned to basal levels before the development of granulocyte differentiation-associated biochemical changes. Phorbol myristate acetate, a promoter of monocytic differentiation in HL-60 cells, also caused a significant increase in NK-TR1 over basal levels. Transfection of a vector expressing NK-TR1 antisense RNA into HL-60 cells suppressed DMSO-mediated growth arrest. In addition, the development of a more mature phenotype, as measured by expression of CD16, and the ability to reduce nitroblue tetrazoleum dye was inhibited in transfectants when compared with controls. These results are consistent with the hypothesis that the NK-TR1 gene product is required for the progression towards a mature differentiated phenotype.

Middle cerebral artery endarterectomy: experience with two cases.

BACKGROUND: Atherosclerotic stenosis of the middle cerebral artery (MCA) is uncommon and long-term prognosis is not well defined. Methods of treating stenosis of the MCA range from the administration of anticoagulants to endarterectomy. METHODS: We present two cases of patients with focal symptomatic stenosis of the MCA with evidence of focally decreased cerebral blood flow and compromise of cerebral blood flow reserves on xenon-enhanced computed tomography (Xe CT) scanning. Endarterectomies were performed after unsuccessful anticoagulation therapy. RESULTS: Both patients underwent successful endarterectomies of the MCA. Improvement in cerebral blood flow postoperatively was documented for both patients. At last follow-up neither patient had demonstrated any additional ischemic episodes. CONCLUSIONS: Atherosclerotic stenosis of the MCA may be responsible for distal emboli and compromised hemodynamics, and endarterectomy of this vessel may provide definitive therapy.

Intrathrombus administration of tissue plasminogen activator in acute cerebrovascular occlusion.

Intraarterial thrombolysis for acute cerebrovascular occlusion has achieved recanalization at a 50-90% rate. Clinical outcome has been unpredictable. The authors sought to test the hypothesis that intrathrombus administration of recombinant tissue plasminogen activator (rt-PA) would improve recanalization rate and to assess the possibility that clinical outcome would be predicted by the extent of collateral flow. Seven patients with acute cerebrovascular occlusion (less than six hours in 6, twenty-four hours in 1) were treated with intrathrombus rt-PA at 1 mg/minute. Examinations were scored on a five-point motor scale. Collateral flow was assessed angiographically. Vessels recanalized in 5 patients, 3 of whom had good outcomes. Vessels failed to recanalize in 2 patients, 1 of whom had good outcome. Good collateral flow was evident in all 4 patients with good outcome and in none of those with poor outcome. Intrathrombus administration of rt-PA is technically feasible. Favorable clinical outcome is more likely in the presence of good collateral flow. In the absence of good collateral flow, ultra-early intervention may be necessary.

Utility of magnetic resonance angiography and carotid ultrasound in the evaluation of carotid stenosis.

We assessed the utility of noninvasive methods for clinical decision-making in carotid stenosis. We compared the results from magnetic resonance angiography (MRA), carotid ultrasound (CUS), and conventional carotid angiography (CCA) for 39 arteries. Noninvasive studies were graded by a 5-point diameter scale. Conventional angiograms were evaluated for percent stenosis using the North American Symptomatic Carotid Endarterectomy Trial criteria and diameter of residual lumen by caliper. Agreement was 64% between MRA and CCA, 72% between CUS and CCA, and 77% between MRA and CUS. For vessels measuring greater than 60% stenosis by CCA, sensitivity was 100% for both MRA and CUS. Specificities were 65% (MRA) and 71% (CUS), reflecting the tendency for MRA and CUS to overestimate stenosis. MRA and CUS correlated with residual lumen, even in some cases where they disagreed with the percent stenosis. We conclude that patients with normal arteries or mild stenosis as determined by MRA and CUS may be excluded from further evaluation, whereas patients with highergrade lesions should be evaluated with CCA prior to consideration for surgery. Close correlation between the results of MRA and CUS, as well as their apparent correlation with residual lumen, suggests that MRA and CUS may more accurately reflect carotid flow than does calculated percent stenosis.

Natural killer (NK) cell lytic dysfunction and putative NK cell receptor expression abnormality in members of a family with chromosome 3p-linked von Hippel-Lindau disease.

UNLABELLED: BACKGROUND. Using antibodies to a putative natural killer (NK) cell receptor (pNKR), we recently cloned a novel cDNA and localized this gene to the short arm of human chromosome 3, region 3p21-3p24. Individuals susceptible to or clinically manifesting von Hippel-Lindau disease (VHL) have a genetic defect telomeric to this region on chromosome 3. This defect, resulting in VHL, is manifested by a high incidence of certain tumors. PURPOSE: Based on the location of this gene, we sought to determine if VHL patients have a defect in gene expression of pNKR. METHODS: Because of the proximity of the VHL and pNKR genetic regions, the variable expression of VHL tumors, and the ability of NK cells to target tumor cells, we investigated NK cell activity and other aspects of the immunologic status in 40 members (four branches) of a family with a high incidence of VHL tumors. RESULTS: Individuals affected with VHL and lacking in normal surface expression of pNKR had virtually no NK cell lytic activity. Analysis of genotypes and phenotypes of all subjects revealed that the greatest difference in NK cell lytic activity (P = .0002) was seen when family members exhibited both VHL and pNKR surface expression defects, compared with normal relatives who had neither defect. Furthermore, the lack of NK cell activity strongly correlated (P = .0005) with abnormal pNKR protein surface expression. Of particular interest, individuals who lacked NK cell activity had normal numbers of NK cells. In addition, analysis of leukocyte subsets indicated normal numbers of T and B cells, monocytes, and NK cells in both affected and normal individuals. CONCLUSIONS: These data indicate that although all affected individuals have the cell population responsible for NK cell activity, many have cells low in expression of pNKR and lack functional NK cell activity. Overall, these results indicate that, in addition to a predisposition to the development of neoplasms, VHL patients have a defect in a specific mechanism of natural immunosurveillance that correlates with a defect in expression of a novel large granular lymphocyte pNKR protein.

Mechanism of target cell recognition by CD3- LGL. I. Development of a monoclonal antibody to a K562-associated target cell antigen.

In an attempt to identify the target recognition molecule(s) involved in the interaction between CD3- large granular lymphocyte (LGL) and a tumor cell target, monoclonal antibodies (mAb) to NK-susceptible K562 tumor cell membrane glycoproteins were developed. After screening by ELISA for reactivity to K562 membrane glycoproteins, two monoclonal antibodies were identified (mAb 35 and mAb 36). One of the monoclonal antibodies (mAb 36) was found to inhibit conjugation between LGL and K562 target cells and also to inhibit lysis of K562 by LGL. Upon further testing, mAb 36 also inhibited the binding between LGL and other NK-susceptible target cells, e.g., Daudi and Molt 4. In contrast, mAb 35, even though binding to K562, did not inhibit the binding of LGL to tumor targets and therefore was used as an isotype control. When mAb 36 was utilized as an affinity matrix, bound proteins specifically inhibited CD3- LGL-K562 conjugation. Experiments involving tunicamycin treatment of tumor target cells demonstrated that mAb 36 recognized a carbohydrate moiety rather than the protein core. Therefore, these data suggested that the target cell recognition molecule which is recognized by mAb 36 appears to be a membrane carbohydrate-associated molecule.

Thromboendarterectomy of the symptomatic occluded internal carotid artery.

A retrospective review of 42 patients (mean age 61.4 years) with surgically managed symptomatic internal carotid artery occlusion is reported. A standardized surgical protocol aimed at restoration of flow in the vessel was used. Presenting symptoms included hemispheric transient ischemic attacks in 68% of patients, new fixed neurological deficits in 28%, amaurosis fugax in 28%, and stroke-in-evolution in 9%. Twenty-four arteries were successfully reopened. A proximal remnant angioplasty (stumpectomy) was performed alone in nine patients or in combination with an external carotid endarterectomy in nine. In four patients with persisting symptoms who failed to achieve primary restoration of flow, a superficial temporal-to-middle cerebral artery bypass procedure was performed. The permanent surgical morbidity rate was 2% and the surgical mortality rate was 0%. Transient postoperative deficits were present in three patients (7%). Follow-up review at a mean of 40 months was obtained in 39 patients (93%). Following surgical intervention, five patients died of unrelated causes, two had neurological events consistent with a transient cerebral ischemic attack, and two had vertebrobasilar insufficiency. No patient suffered from stroke. Of the 24 successfully reopened vessels, follow-up ultrasound evaluations were obtained in 17 (73%) at a mean of 28 months after surgery. In 15 patients (88%) the vessels were widely patent, one (5.8%) had stenosis greater than 70%, and one (5.8%) showed asymptomatic reocclusion. Reopening occluded internal carotid arteries in selected patients is associated with low surgical morbidity and mortality rates. Further studies are necessary to determine the impact of this surgical therapy on the natural history of this condition.

Hemodilution therapy for lacunar stroke: Treatment results in 10 consecutive cases.

Because precipitous neurological deterioration occurred during blood pressure reduction in a seminal case of lacunar infarction, nine subsequent patients with acute partial or evolving lacunar deficits were treated with hemodilution and blood pressure nonintervention to test the hypothesis that lacunar infarction represents perfusion failure. Isovolemic hemodilution was performed using hetastarch with target hematocrit of 30-33. Pretreatment brain computed tomography, carotid ultrasound, and echocardiography were normal. Nine patients recovered normal neurological function, and two regained complete functional independence in close temporal correlation with hemodilution and within 7 days of symptom onset. Magnetic resonance imaging of the brain demonstrated appropriate single white matter lesions in nine cases. No specific risk factor combination could be identified. No patient has had recurrent stroke in follow-up from 18 to 36 months. Response to hemodilution suggests the possibility of a hemodynamic pathophysiology. Successful treatment requires (a) blood pressure nonintervention and (b) hemodilution prior to severe clinical deterioration. A controlled trial seems indicated.

Mechanism of target cell recognition by natural killer cells: characterization of a novel triggering molecule restricted to CD3- large granular lymphocytes.

In an attempt to identify a molecule in target recognition by CD3- large granular lymphocytes (LGL), we have generated a rabbit antiidiotypic (anti-ID) serum against a monoclonal antibody (mAb 36) that reacted with the cell membrane of K562. Flow cytometry analysis demonstrated that the anti-ID serum bound selectively to CD3- LGL and that F(ab')2 fragments of the anti-ID serum blocked both target cell binding and lysis by NK cells. Stimulation of CD3- LGL with F(ab')2 fragments resulted in the release of serine esterases and the secretion of interferon gamma. Furthermore, anti-ID F(ab')2 antibodies crosslinked to anti-DNP F(ab')2 mediated directed cytotoxicity of a non-natural killer (NK)-susceptible mouse target (YAC-1) via this surface ligand. These functional reactivities were only removed by adsorption with the specific idiotype. Protein analysis showed that the anti-ID serum immunoprecipitated 80-, 110-, and 150-kD proteins. Using this anti-ID, a partial cDNA was cloned and an antipeptide antiserum was made against the portion of the predicted amino acid sequence that corresponded to a portion of the ID binding region. This antipeptide serum exhibited similar functional and biochemical reactivities to those observed with the anti-ID serum. These data suggest that the cell surface moiety recognized by the anti-ID and anti-p104 is novel and is selectively involved in both recognition and triggering of NK-mediated lytic function.