Meir Lichtenstein

Crossed Cerebellar Diaschisis and Brain Recovery After Stroke

BACKGROUND AND PURPOSE Although crossed cerebellar diaschisis is well recognized after stroke, there is controversy concerning its clinical correlations and serial changes, and little is known about its prognostic value. METHODS We studied crossed cerebellar diaschisis and cerebral hypoperfusion in 47 patients with acute middle cerebral cortical infarction using 99mTc-hexamethylpropyleneamine oxime and single-photon emission computed tomography within 72 hours of stroke onset. Thirty-one of these patients had outcome studies at 3 months; 15 of the 31 underwent an additional scan after acetazolamide injection. Tissue loss was determined with computed tomography, performed at outcome in 28 patients. Clinical stroke severity was assessed with the Canadian Neurological Scale and Barthel Index. Cerebellar blood flow asymmetry was studied in 22 healthy, age-matched control subjects. RESULTS Cerebellar blood flow asymmetry was significant in patients (mean +/- SE, 9.76 +/- 0.78%; P < .001) but not in control subjects (-0.22 +/- 0.56%). Crossed cerebellar diaschisis was strongly associated with infarct hypoperfusion volume at both acute (regression coefficient +/- SEb, b = 6.76 +/- 0.65; P < .001) and outcome stages (b = 6.13 +/- 0.63; P < .001). Cross-sectionally over the first 72 hours, infarct hypoperfusion volume decreased by 2% for each hour from onset (P < .05), while crossed cerebellar diaschisis remained unchanged. Canadian Neurological Scale score at the acute stage was negatively associated with acute crossed cerebellar diaschisis (b = -0.10 +/- 0.05; P < .05) after allowing for infarct hypoperfusion volume. Crossed cerebellar diaschisis did not change between acute-stage, outcome, and postacetazolamide scans. Acute-stage crossed cerebellar diaschisis predicted outcome Barthel Index score (b = -0.28 +/- 0.14; P = .05) and tissue loss (b = 3.81 +/- 0.96; P < .001) but was no longer an independent prognostic factor after allowing for acute-stage infarct hypoperfusion volume. CONCLUSIONS This study shows that crossed cerebellar diaschisis is a functional phenomenon that correlates with both stroke severity and infarct hypoperfusion volume and persists despite neurological recovery. Although acute-stage crossed cerebellar diaschisis has no prognostic value independent of acute-stage hypoperfusion volume, it might indicate the proportion of nutritional to nonnutritional perfusion at the infarct site and hence be useful in the evaluation of reperfusion therapies in the acute stage.

Spontaneous Reperfusion After Ischemic Stroke Is Associated With Improved Outcome

BACKGROUND AND PURPOSE The rationale behind thrombolytic therapy in acute ischemic stroke is penumbral salvage by rapid restoration of cerebral blood flow. The relationship, however, between early reperfusion (potentially composed of both nutritional and nonnutritional components) and outcome remains unclear. METHODS To establish the relationship between reperfusion parameters and outcome variables (Canadian Neurological Scale, Barthel Index, outcome CT scans), we used 99Tc-hexamethylpropyleneamine oxime (99Tc-HMPAO) single-photon emission CT (SPECT) to examine 41 acute ischemic stroke patients. All patients had at least 2 SPECT studies (24 with 3 studies), and none had been treated with thrombolytic or other acute investigational drugs. RESULTS A total of 106 studies were performed. Mean time to acute study was 9.2 hours; that for subacute study was 42 hours and for outcome study was 150 days. Hypoperfusion (HP) volumes at each of the 3 time points correlated with outcome clinical state and final infarct size. Both early reperfusion (61% of patients) and nutritional reperfusion alone (56%), which is early reperfusion maintained at outcome, were associated with improvement in clinical state and better functional outcome. Early HP volume change (acute minus subacute HP volume) and total HP volume change (acute minus outcome HP volume) also correlated with clinical improvement and better outcome. CONCLUSIONS This study establishes the benefit of spontaneous reperfusion after ischemic stroke and emphasizes the prognostic value of HP deficit volumes. 99Tc-HMPAO SPECT may be used to screen patients and group them according to perfusion deficit in acute stroke trials, thereby decreasing patient numbers required to show drug effect.

Correlations between cerebral arterial velocities, blood flow, and delayed ischemia after subarachnoid hemorrhage.

Elevated middle cerebral erythrocyte velocities and tissue hypoperfusion have been correlated with delayed ischemia after subarachnoid hemorrhage, but few studies have compared serial arterial velocities with cerebral blood flow and neurological deficits. Methods Serial measurements of middle cerebral velocities, using transcranial Doppler ultrasonogra-phy, were performed in 34 patients after subarachnoid hemorrhage and correlated with cerebral blood flow, measured in 20 of the 34 using single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime and neurological evidence of delayed ischemia. Results In 16 patients without delayed ischemia, eight had evidence of vasospasm (>120 cm/sec), but only one of seven had hypoperfusion, suggesting that vasospasm might be more common than hypoperfusion in this group (p=0.1). In 10 patients with delayed ischemia and a lateralizing deficit, both asymmetrical middle cerebral vasospasm (eight of nine with vasospasm) and hypoperfusion (six of six studied) were concordant with the clinically ischemic hemisphere (p<0.05). Vasospasm occurred with nonlateralized delayed ischemia in seven of eight patients and with hypoperfusion in five of six, affecting the anterior cerebral territory in three. Conclusions Concordant vasospasm and hypoperfusion were most often present in patients with delayed ischemia and lateralizing neurological deficits. Discordant results reflect inherent limitations and the different levels of the circulation monitored by the two techniques.

Radioembolization in Combination with Systemic Chemotherapy as First-line Therapy for Liver Metastases from Colorectal Cancer

PURPOSE To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE. RESULTS Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity. CONCLUSIONS The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

A controlled trial of cisapride in anorexia nervosa.

To determine the efficacy of cisapride, 10 mg three times daily, in improving gastric emptying, reducing distress during meals, and facilitating weight gain in anorexia nervosa, we conducted an 8-week, randomized, double-blind, placebo-controlled trial on 29 inpatients. Measures included scintigraphic gastric emptying studies at 0, 2, 4, and 8 weeks; subjective distress during meals measured by visual analogue scales; self-rating of degree of global improvement in symptoms associated with eating at end of study; and weight measured weekly. Gastric emptying improved significantly but equally in both groups over the study period. Yet subjective measures were better in the cisapride group; they rated themselves as more hungry (p = .02) and more improved on the global measure of change in symptoms (p = .02). Even so, the cisapride group did not gain more weight. The correlation between gastric emptying and weight gain was modest (r = .30; p = .11), and between gastric emptying and the subjective measures, virtually absent.

A single-photon emission computed tomography study of hypoperfusion after subarachnoid hemorrhage.

We used single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime in 18 studies on 13 patients with subarachnoid hemorrhage to determine whether any changes in cerebral blood flow could be correlated with clinical or computed tomographic evidence of delayed ischemia. Among the seven patients without focal neurologic deficits, regional cerebral hypoperfusion was demonstrated in only one who died. Among the 10 patients with aneurysmal subarachnoid hemorrhage, one died before surgery, and six developed postoperative delayed ischemic deficits, of whom two died. Among the patients with angiographically documented aneurysms, regional hypoperfusion correlated with the presence and severity of delayed neurologic deficits, whereas correlative computed tomographic scans showed either early infarction or no relevant abnormality. This technique facilitates early diagnosis of cerebral tissue hypoperfusion due to vasospasm after subarachnoid hemorrhage.

Cerebral hypoperfusion in stroke prognosis and brain recovery.

Background and Purpose The value of acute cerebral blood flow measurements in stroke prognosis is controversial. No previous study has determined whether acute perfusion deficits independently add to a validated clinical prognostic score. We aimed to compare the value of acute hypoperfusion deficits with a quantitative clinical score in stroke prognosis and to correlate the changes in perfusion with brain recovery. Methods Volumetric analysis of regional hypoperfusion was performed in 38 patients with middle cerebral infarction within 72 hours of onset by use of single photon emission computed tomography and 99mTc hexamethylpropylene amine oxime. Stroke severity was assessed by the Canadian Neurological Score and Barthel Index. Allens prognostic score was determined acutely in all patients. Clinical outcome was evaluated in 36 of 38 patients, of whom 18 had repeat blood flow studies. Results Acute hypoperfusion correlated with both the outcome Barthel Index (P < .001, r=-.61) and Canadian Neurological Score (P < .001, r=-.64). Allens score correlated better with both the outcome Barthel Index (P < .001, r=.80) and Canadian Neurological Score (P < .001, r=.81). Acute hypoperfusion deficits, after allowing for Allens score, independently predicted neurological but not functional outcome. Despite overall neurological improvement, mean hypoperfusion increased on the repeat blood flow studies (P<.05). Conclusions Volumetric analysis of acute regional hypoperfusion within 72 hours of onset predicts stroke outcome after 3 months, but Allens score is a better prognostic method. Neurological recovery is not associated with chronic infarct reperfusion. (Stroke. 1993;24:1691-1696.)

Nimodipine and Perfusion Changes After Stroke

BACKGROUND AND PURPOSE Meta-analysis of previous trials of oral nimodipine in acute stroke has suggested a benefit when commenced within 12 hours of onset. We sought to study the effect of oral nimodipine on reperfusion after acute stroke and the relation between reperfusion and outcome. METHODS Fifty patients with acute middle cerebral artery territory cortical infarction were blindly randomized within 12 hours of onset to either oral nimodipine (30 mg every 6 hours) or placebo. Treatment was continued for 2 weeks. Cerebral blood flow was assessed with the use of 99mTc-hexamethylpropyleneamine oxime single-photon emission CT before therapy, 24 hours later, and at 3 months. Hypoperfusion was measured by a validated volumetric technique. Neurological impairment and functional outcome were assessed with the Canadian Neurological Scale and Barthel Index, respectively. Tissue loss was measured with CT at 3 months. Four patients were excluded from analysis for technical reasons. RESULTS Twenty-three patients received nimodipine, and 23 received placebo. In the nimodipine group, there was early reperfusion that was not maintained at outcome (P=0.01). In the placebo group, mean infarct hypoperfusion volumes showed no overall change. Nonnutritional reperfusion in nimodipine-treated patients was associated with adverse neurological (P=0.05) and functional outcome (P=0.06). There was, however, no difference in clinical outcome between the 2 groups. CONCLUSIONS Oral nimodipine administered within 12 hours enhanced acute reperfusion, but this was largely nonnutritional. Larger studies using a shorter treatment delay are required to evaluate the clinical efficacy of nimodipine in acute ischemic stroke.

Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis

This study used a randomized, 2 × 2 factorial design to evaluate over 2 years the effect of intranasal salmon calcitonin and intramuscular nandrolone decanoate on bone mass in elderly women with established osteoporosis. The study was double masked in relation to calcitonin and open in relation to nandrolone decanoate. One hundred and twenty-three women aged 60–88 years who had sustained a previous osteoporotic fracture, or had osteopenia, were recruited through an outpatient clinic. Women were assigned to one of four groups: (1) daily placebo nasal spray, (2) 400 IU intranasal calcitonin daily, (3) 20 intramuscular injections of 50 mg nandrolone decanoate (given as two courses of 10 injections) plus placebo nasal spray, or (4) 20 injections of 50 mg nandrolone decanoate plus 400 IU intranasal calcitonin daily. All subjects received 1000 mg calcium supplementation daily. Outcomes measured included changes in bone mineral density (BMD) at the lumbar spine, as measured by dual-energy quantitative computed tomography (DEQCT), in BMD of the proximal femur, and BMD and bone mineral content (BMC) of the lumbar spine and forearm, as measured by dual-energy X-ray absorptiometry (DXA). Significant positive changes from baseline in DXA BMC at the lumbar spine were observed over 2 years in the calcitonin group (5.0±1.9%, mean ± SE) and in the nandrolone deconate group (4.7±1.9%) but not in the placebo group (1.1±2.2%) or the combined therapy group (0.7±1.8%). Modelling based on the 2×2 factorial design revealed that nandrolone decanoate was associated with a 3.8±1.8% (p<0.05) gain in DXA BMD at the proximal femur. Modelling also revealed that calcitonin treatment was associated with a loss of 11.5±4.7% in DEQCT BMD at the lumbar spine and a loss of 3.7±1.8% in DXA BMD at the proximal femur (p<0.05). There was in vivo antagonism between the two medications of 7.9±3.9% for DXA BMC at the lumbar spine. Both agents caused positive changes from baseline in lumbar spine BMC. Nandrolone decanoate had beneficial effects on BMD at the proximal femur. This dose of intranasal calcitonin was associated with deleterious effects on trabecular BMD at the lumbar spine and total BMD at the proximal femur. There may be significant clinical antagonism between these two medications.

Heterogeneity of the human transferrin receptor and use of anti-transferrin receptor antibodies to detect tumours in vivo.

The human transferrin receptor (TFR) which is present on dividing cells, many tumours and erthyroid precursors is readily identified using specific monoclonal antibodies. A new anti‐human TFR monoclonal antibody, HuLy‐m9, is described and its distribution on cell lines, normal and tumour tissue was examined and compared with two other anti‐TFR monoclonal antibodies, namely, OKT9 and 5E9. The three antibodies were shown to recognise different epitopes on the surface of the TFR and have different reactivities with in vitro cell lines. Peptide map analyses of the TFR recognised by each monoclonal antibody from the same cell line were identical; however, differences were observed between cell lines. 131I‐radiolabelled HuLy‐m9 was used to successfully localise a nasopharyngeal carcinoma in vivo.