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Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m(2) every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended.

Venous thromboembolism prophylaxis with low molecular weight heparin or unfractionated heparin is recommended in acute ischaemic stroke, but which regimen provides optimum treatment is uncertain. We aimed to compare the efficacy and safety of enoxaparin with that of unfractionated heparin for patients with stroke.1762 patients with acute ischaemic stroke who were unable to walk unassisted were randomly assigned within 48 h of symptoms to receive either enoxaparin 40 mg subcutaneously once daily or unfractionated heparin 5000 U subcutaneously every 12 h for 10 days (range 6-14). Patients were stratified by National Institutes of Health Stroke Scale (NIHSS) score (severe strokeor =14, less severe stroke14). The primary efficacy endpoint was the composite of symptomatic or asymptomatic deep vein thrombosis, symptomatic pulmonary embolism, or fatal pulmonary embolism. Primary safety endpoints were symptomatic intracranial haemorrhage, major extracranial haemorrhage, and all-cause mortality. This study is registered with ClinicalTrials.gov, number NCT00077805.In the efficacy population (ie, one or more dose received, presence of deep vein thrombosis or pulmonary embolism, or assessment for venous thromboembolism), enoxaparin (n=666) and unfractionated heparin (669) were given for 10.5 days (SD 3.2). Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] vs 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, p=0.0001; difference -7.9%, -11.6 to -4.2); this reduction was consistent for patients with an NIHSS score of 14 or more (26 [16%] vs 52 [30%]; p=0.0036) or less than 14 (42 [8%] vs 69 [14%]; p=0.0044). The occurrence of any bleeding was similar with enoxaparin (69 [8%]) or unfractionated heparin (71 [8%]; p=0.83). The frequency of the composite of symptomatic intracranial and major extracranial haemorrhage was small and closely similar between groups (enoxaparin 11 [1%] vs unfractionated heparin 6 [1%]; p=0.23). We noted no difference for symptomatic intracranial haemorrhage between groups (4 [1%] vs 6 [1%], respectively; p=0.55); the rate of major extracranial bleeding was higher with enoxaparin than with unfractionated heparin (7 [1%] vs 0; p=0.015).Our results suggest that for patients with acute ischaemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits to risk ratio and convenience of once daily administration.

BACKGROUND: Transesophageal echocardiography (TEE) has improved the diagnostic evaluation of ischemic stroke patients, permitting detection of potential cardiac sources of embolism. The present study aimed to evaluate the distribution of potential cardioembolic sources in young versus older stroke patients and their clinical implication for recurrent vascular events. Two hundred and twenty-eight patients with undetermined ischemic stroke were enrolled in the study. METHODS: All patients were submitted to transthoracic and to TEE examination. The mean follow-up period was 43 +/- 19 months. RESULTS: The overall detection of cardiac sources of embolism was significantly higher in younger than in older patients (P = 0.006). Atrial septal abnormalities were more prevalent in the younger than in the older population (P = 0.006), whereas complicated aortic plaques were detected more often in older patients. During the follow-up period of 4-5 years, we identified 40 recurrent stroke episodes or vascular deaths. As expected, there was a significant difference in recurrent vascular events and death of older patients compared to the younger ones (P = 0.025). CONCLUSIONS: The present study demonstrates that atrial septal abnormalities and aortic atheromas are the most prevalent echocardiographic findings in young and elderly stroke patients, respectively. Complicated aortic atheroma is strictly correlated with recurrent cerebral vascular events or death.

The expression of corticotrophin-releasing factor (CRF) receptors in cerebral arteries and arterioles suggests that CRF may modulate cerebral blood flow (CBF). In the present study, the effects of CRF, CRF-like peptides and the CRF broad spectrum antagonist DPhe-CRF on CBF have been investigated under normal physiologic conditions and in the margins of focal ischaemic insult. The experiments were carried out in anaesthetised and ventilated rats. Changes in CBF after subarachnoid microapplication of CRF and related peptides were assessed with a laser-Doppler flowmetry (LDF) probe. In the ischaemic animals, agents were injected approximately 60 minutes after permanent middle cerebral artery occlusion (MCAo). Microapplication of CRF and related peptides in normal rats into the subarachnoid space produced sustained concentration-dependent increases in CBF. This effect was attenuated by co-application with DPhe-CRF, which did not alter CBF itself. A second microapplication of CRF 30 min after the first failed to produce increases in CBF in normal animals. Microapplication of CRF in the subarachnoid space overlying the ischaemic cortex effected minor increases in CBF whereas D-Phe-CRF had no significant effect on CBF. Activation of the CRF peptidergic system increases CBF in the rat. Repeated activation of CRF receptors results in tachyphylaxis of the vasodilator response. CRF vasodilator response is still present after MCAo in the ischaemic penumbra, suggesting that the CRF peptidergic system may modulate CBF in ischaemic stroke.

We performed a post-marketing study of patients with multiple sclerosis (MS) attending the outpatient service to evaluate the impact of interferon beta-1b (IFNbeta-1b) in the daily clinical setting. The absolute changes in relapse frequency and in the mean EDSS score over a three-year period were compared between 83 patients with relapsing remitting MS treated with IFNbeta-1b and 83 RRMS patients who did not take the drug. Annualized relapse frequency significantly decreased in patients undergoing therapy while no statistically significant changes in EDSS score were observed. These findings point out the role of post-marketing studies in evaluating the impact of approved drugs in the daily clinical setting in terms of safety and tolerability. Furthermore, our results confirm the positive effect of immunomodulatory treatment in decreasing the occurrence of inflammatory events.

Background and Purpose —Transesophageal echocardiography (TEE) has detected a high prevalence of patent foramen ovale (PFO) in stroke patients, but the clinical implications of the distinctive characteristics of this patency are still a matter of debate. Methods —We studied 350 patients with acute ischemic stroke or transient ischemic attack (TIA) within 1 week of admission. Of these, 101 (29%) were identified by contrast TEE to have a PFO; 86 patients (25%) were cryptogenic stroke patients, and 163 were excluded because of the presence of a definite or possible arterial or clinical evidence of a source of emboli or small-vessel disease. Thirteen PFO subjects without a history of embolism were designated as the control group. All PFO and cryptogenic stroke patients were followed up by neurological visits. Results —Compared with controls, PFO patients with acute stroke or TIA more frequently presented with a right-to-left shunt at rest and a higher membrane mobility ( P P =0.05). Conclusions —The association of right-to-left shunting at rest and high membrane mobility, as detected by contrast TEE, seems to identify PFO patients with cerebrovascular ischemic events who are at higher risk for recurrent brain embolism.

The [14C]2-deoxyglucose method was applied to measure the effects of the synthetic cannabinoid agonist WIN 55212-2 intravenous administration on glucose utilization in the rat brain. Two doses of the drug, that have been reported previously to increase extracellular dopamine concentrations in the shell of the nucleus accumbens, were used (0.15-0.30 mg/kg). At the lower dose, WIN 55212-2 increased energy metabolism selectively in the accumbens shell. Conversely, the higher dose of the drug reduced glucose utilization in the hippocampal formation and ventromedial thalamic nucleus without affecting energy metabolism in the accumbens shell. These results may be useful to further understanding the addictive potentials of cannabinoid drugs.

Objective—Recently, a strong correlation between the increase in hypointense lesion load on T1 weighted spin echo images, and the increase in disability was reported. Although the eVect of interferon-‚ has been demonstrated both in reducing exacerbation rate, frequency of enhancing lesions, and accumulation of disease burden on T2 weighted images, the impact on the accumulation of hypointense lesions has not yet been evaluated. The aims of the present study were: (a) to assess for the first time the eVect of interferon-‚-1a on T1 weighted MRI hypointense lesion volume; and (b) to evaluate the relation between changes on hypointense, hyperintense, and enhancing lesion volume before and during interferon-‚-1a treatment in relapsing-remitting multiple sclerosis. Methods—After a baseline scan and 6 month pretreatment period, 67 patients with relapsing-remitting multiple sclerosis were treated with interferon-‚-1a by subcutaneous injection three times a week during a 12 month treatment period. All patients had MRI every month during the 6 month pretreatment period and for the first 9 months of the treatment period. A final MRI was also performed at the end of the 12 month treatment period. Results—There was a significant increase in the mean hyperintense lesion volume during the pretreatment phase (6 months) and a slight decrease during the treatment period (12 months), whereas the hypointense lesion volume increased significantly before treatment and remained substantially stable during treatment. There was a significant correlation between changes in hypointense and hyperintense lesion volume during the observation period, but not during treatment. The monthly mean volume of Gadolinium-DTPA enhancing lesions was significantly higher during the pretreatment than the treatment period, and the enhancing lesion volume correlated with changes of hyperintense and hypointense lesion volumes only during the observation period. Conclusion—These data suggest that interferon-‚-1a has a stabilising eVect on T1 weighted hypointense lesion volume. (J Neurol Neurosurg Psychiatry 1999;67:579‐584)

The development of neutralizing antibodies (NAbs) to interferon (IFN) is a common phenomenon of IFN beta therapy for relapsing-remitting multiple sclerosis (RRMS) patients. Here we examine the specificity of NAbs developed during therapy for RRMS with recombinant interferon (rIFN) beta-1a or rIFN beta-1b, and study the effect of switching from rIFN beta-1a to rIFN beta-1b on the incidence and specificity of NAbs. The relative ability to neutralize rIFN beta-1a and beta-1b was assayed in sera positive for NAbs derived from RRMS patients treated with either rIFN beta-1a (N=9) or rIFN beta-1b (N=16), while the incidence and specificity of NAbs to IFN beta developed during therapy were studied in 50 RRMS patients who were treated for two years with rIFN beta-1a followed by a further year either switching to rIFN beta-1b (N=34) or continuing treatment with rIFN beta-1a (N=16). The results show that all positive sera, independent of the source, may recognize both forms of rIFN beta and that a further year of treatment does not significantly affect the incidence and specificity of the NAbs developed during the first two years of treatment even if treatment is switched to a different type of IFN beta. The data then suggests that it is unlikely that the administration of rIFN beta-1b to anti-rIFN beta-1a NAbs-positive patients can overcome the inhibitory effect exerted by the serum antibodies (and vice versa), and that a further period of treatment with IFN beta-1b in patients previously treated with rIFN beta-1a does not significantly change the pattern of antibody response to IFN beta.

Summary Background Thrombolysis for acute ischaemic stroke has been investigated in several clinical trials, with variable results. We have assessed the safety and efficacy of intravenous thrombolysis with alteplase (0·9 mg/kg bodyweight) within 6 h of stroke onset. Methods This non-angiographic, randomised, double-blind, trial enrolled 800 patients in Europe, Australia, and New Zealand. Computed tomography was used to exclude patients with signs of major infarction. Alteplase (n=409) and placebo (n=391) were randomly assigned with stratification for time since symptom onset (0–3 h or 3–6 h). The primary endpoint was the modified Rankin scale (mRS) at 90 days, dichotomised for favourable (score 0–1) and unfavourable (score 2–6) outcome. Analyses were by intention to treat. Findings 165 (40·3%) alteplase-group patients and 143 (36·6%) placebo-group patients had favourable mRS outcomes (absolute difference 3·7%, p=0·277). In a post-hoc analysis of mRS scores dichotomised for death or dependency, 222 (54·3%) alteplase-group and 180 (46·0%) placebo-group patients had favourable outcomes (score 0–2; absolute difference 8·3%, p=0·024). Treatment differences were similar whether patients were treated within 3 h or 3–6 h. 85 (10·6%) patients died, with no difference between treatment groups at day 90·14 days (43 alteplase, 42 placebo). Symptomatic intracranial haemorrhage occurred in 36 (8·8%) alteplase-group patients and 13 (3·4%) placebo-group patients. Interpretation The results do not confirm a statistical benefit for alteplase. However, we believe the trend towards efficacy should be interpreted in the light of evidence from previous trials. Despite the increased risk of intracranial haemorrhage, thrombolysis with alteplase at a dose of 0·9 mg/kg in selected patients may lead to a clinically relevant improvement in outcome.

The aim of this study was to investigate whether a concomitant treatment with recombinant interferon beta 1a (rIFN beta-1a) modifies the effect of steroids on the blood-brain barrier (BBB) in relapsing remitting MS patients, as evaluated by enhanced MRI of the brain. We evaluated 19 patients with a clinical relapse treated only with intravenous methylprednisolone (IVMP; 1 g daily for 6 days), and 10 patients who experienced a clinical relapse and were treated with IVMP (1 g daily for 6 days) during an rIFN beta-1a treatment period. The number and volume of enhancing lesions were analyzed on four serial MR images obtained at monthly intervals (one scan before and three scans after IVMP treatment). A significant reduction in the mean number and volume of enhancing lesions was seen in the first scan after IVMP treatment in all patients. However, while persistently low enhancement was seen in the follow-up scans of patients treated with rIFN beta-1a, a rebound effect (i.e., increase in the number and volume of gadolinium-enhancing lesions) was observed in the other patients during the follow-up. These data suggest that rIFN beta-1a prolongs the beneficial effect of steroids on the BBB.

Stroke is the third leading cause of death, after cardiac disease and cancer, in most industrialised countries. Moreover, stroke is an important cause of long term disability and is the most common life-threatening neurological disease. During past years, there has been a declining trend in stroke incidence, mortality and case-fatality; the reasons for this are unclear and there is no evidence of the persistence of this favourable trend since 1980. The improved knowledge and, consequently, improved management of stroke risk factors and new trends in acute stroke treatment seem to account for this evolution. We present a review of stroke epidemiology, aetiology and emergency clinical and diagnostic aspects, paying particular attention to ischaemic strokes, which have been the subject of most of the research and clinical trials carried out in recent years. Moreover, we propose a brief guideline for diagnosis of stroke in the acute phase.

Background and Purpose —Determinants of long-term outcome are not well defined in minor stroke patients. This study aims to evaluate which factors are independent long-term predictors of death and major stroke recurrence in a cohort of minor ischemic strokes. Methods —A cohort of 322 patients with first-ever minor ischemic strokes (mean age, 55 years; 89% were treated with antiplatelet or anticoagulant drugs) with minor (Rankin score=2) or no disability (Rankin score P Results —The 10-year mortality rate was 32%, with a relative risk of 1.7 (95% CI, 1.4 to 2.1) compared with the age- and sex-matched general population. The 10-year recurrence rate of major strokes was 14%. The hazard ratio (95% CI) of death was 1.1 (1.05 to 1.09) for age (1-year increments), 3.4 (2.2 to 5.2) for minor disability, 1.8 (1.1 to 3.1) for myocardial infarction (MI), 2.0 (1.1 to 3.7) for nonvalvular atrial fibrillation, and 1.8 (1.2 to 2.7) for hypercholesterolemia. The hazard ratio (95% CI) of major stroke recurrence was 2.8 (1.3 to 6.2) for recurrent minor strokes, 3.1 (1.9 to 4.6) for nonlacunar stroke, 2.9 (1.3 to 6.8) for MI, and 3.0 (1.4 to 6.4) for hypertension. Conclusions —In minor ischemic strokes, age, minor disability, MI, nonvalvular atrial fibrillation, and hypercholesterolemia increase the risk of death; recurrent minor strokes, nonlacunar stroke, MI, and hypertension increase the risk of major stroke.

No data are available on the autonomic system during sleep in patients with stroke. The purpose of this study was to determine the influence of acute ischemic stroke on the autonomic cardiovascular system during sleep, and to correlate autonomic activity with the clinical status of patients. Ten patients with ischemic stroke in the middle cerebral artery were studied by means of an all-night polysomnographic recording within the 1st week of the onset of symptoms and at the 3-week follow-up examination. Power spectrum analysis of the heart rate variability was performed using an autoregressive algorithm in 180 consecutive electrocardiographic RR intervals. Spectral power was calculated in 3 main frequency bands: high frequency (HF), 0.15–0.4 Hz; low frequency (LF), 0.04–0.15 Hz; very low frequency (VLF)

Vasculitis is inflammation of blood vessel walls, which produces dysfunction in both the peripheral and central nervous system (CNS). Cerebral ischemia is the major cause for neurological manifestations of CNS vasculitis. Unfortunately, a universally accepted classification of vasculitis has not emerged. Vasculitis affecting the CNS alone is referred to as primary angiitis of the CNS; secondary vasculitis occurs in association with a variety of conditions, including infections, drug abuse, lymphoproliferative disease and connective tissue diseases. The pathogenesis of vasculitis includes different immunological mechanisms. Recently, anti-neutrophil cytoplasmatic antibody (ANCA) has been demonstrated to play an active role in the immunopathogenesis of the vasculitis. Diagnosis of vasculitis depends on a combination of clinical, radiographic and pathologic features. A wide spectrum of clinical features may occur. The most typical clinical picture of CNS vasculitis is troke, encephalopathy or seizures. Assays for ANCA, serum cytokines, antibodies to endothelial cell antigens have been reported to be useful in diagnosing or monitoring the disease activity. The gold standard in diagnosis is confirmation of vasculitis in a biopsy specimen. Angiography may suggest the diagnosis but no abnormalities are pathognomonic. Ideally, the therapy of each vasculitis would focus on the specific immunologic mechanism causing the disease. Such specific interventions are not yet available. In general the most important approaches induce global immunosuppression. The goal of therapy, however, is to prevent recurrence of disease.

The potential role of magnetic resonance imaging (MRI) in differentiating between specific causes of cognitive decline in patients with vascular dementia (VD) has not yet been fully established. We therefore decided to assess the supratentorial cerebral contents in 24 patients with a diagnosis of probable VD and in 24 normal subjects, matched for age and education level, using MRI volumetric parameters obtained by means of a quantitative method. The volumes of subarachnoid and ventricular spaces, cerebral tissue, and hyperintense areas on T2-weighted images were calculated. In order to reduce interindividual variability caused by differences in intracranial size, each absolute measurement was normalized to the relative size of the intracranial volume. In addition, we calculated the ratio between the areas of the corpus callosum (CC) and supratentorial brain at the same level on the T1-weighted image midsagittal plane. The MRI data were correlated with the deterioration of cognitive functions. Patients with VD showed significantly lower cerebral tissue volume and CC area, and higher ventricular space volume than normal subjects. Furthermore, the total volume of the T2 signal alterations was higher in VD patients than in normal subjects. In VD patients, this volume was found to be proportional to the increase in the volume of the ventricular space. On the other hand, no correlation was found between the volume of the T2 signal alterations and the area of the CC. The degree of global cognitive dysfunction and the score of each neuropsychological test did not show any correlation with the MRI data. Our results suggest that ventricular enlargement in VD patients is correlated with the increase in volume of the T2 signal abnormalities, but that the degree of global cognitive dysfunction is not influenced by the volume of these T2 signal abnormalities. Furthermore, the CC atrophy does not influence the score of any neuropsychological test or the degree of global cognitive dysfunction.

OBJECTIVE: To evaluate whether recombinant human interferon-beta-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI. The study also evaluated the effect on six-monthly T2 weighted abnormality and relapse frequency. METHODS: After a baseline scan and a six month pretreatment period, 68 patients were randomly assigned to receive either 3 MIU or 9 MIU of interferon-beta-1a by subcutaneous injection three times a week for six months. All patients were examined by Gd enhanced MRI every month in both pretreatment and treatment periods. The evaluation of Gd enhancing lesions was performed blind at the end of the study. RESULTS: The mean number of Gd enhancing lesions was higher during the pretreatment period than during treatment. This difference was statistically significant for the two different dose subgroups (3.5 v 1.8, P < 0.001 for the 3 MIU group and 2.4 v 0.9, P < 0.001 for the 9 MIU group, corresponding to a reduction of 49% and 64% respectively). The mean volume of Gd enhancing lesions also significantly decreased by 61% (3 MIU group) and 73% (9 MIU group). These reductions were evident only after the first month of treatment. The six-monthly rate of new lesions as seen in T2 weighted images showed a similar trend of reduction with treatment (65% and 70% respectively). Lesion volume on T2 scans significantly increased during the pretreatment period whereas it remained almost stable during the treatment period in both groups. Clinical relapse rate was significantly reduced by treatment (53% for the 3 MIU group, P < 0.001; 69% for the 9 MIU group, P < 0.001). CONCLUSION: Interferon-beta-1a seemed effective in reducing disease activity in relapsing-remitting multiple sclerosis at both the doses used.

We prospectively studied 160 patients (18–47 years of age) with TIA (18) or ischemic stroke (142). Eighty-five subjects were under the age of 40. All patients underwent noninvasive ultrasound studies (transcranial doppler and echocardiography), plus a battery of laboratory studies including coagulation and antibodies tests and blood lactate-pyruvate. Angiographic studies were performed in 42% of patients (33% with DSA and 9% with MRA). The most common etiologies were found to be cardioembolic (more common in the 18–39 age group) and atherothromboticic (more common in the 40–47 age group). Autoimmune conditions affected 12.5% of patients, while arterial dissections affected 11%. In 10% of patients the etiology of the cerebral ischemic event could not be determined, in spite of an extensive and expensive workout Hence, a set of guidelines aimed at optimizing, in terms of cost-benefit, a protocol of investigations in young adults with ischemic stroke is tentatively proposed.

Objective: To estimate the prevalence and outcome of symptomatic internal carotid artery lesions in young adults. Design: Multicentre hospital based observational study with five year follow up. Setting: Seven neurological departments in northern and central Italy. Subjects: 240 patients (115 men) aged 15-44 with a recent transient ischaemic attack or stroke in the carotid territory. Main outcome measures: (a) Prevalence of symptomatic internal carotid artery stenosis or occlusion detected by continuous wave Doppler ultrasonography at entry; (b) incidence rates of cerebral, cardiac, and non-vascular death; non-fatal stroke; and non-fatal myocardial infarction. Results: Carotid stenoses of 50-99% and occlusions were found in 38 patients (15.8%). Both conditions were significantly more frequent in patients aged over 35 and in those with hypertension, diabetes mellitus, and stroke at entry. The standardised mortality ratio at five years was 10.5 (95% confidence interval 5.0 to 19.3). Survival of patients with stenoses of 0-49% and occlusions was significantly better than that of patients with stenoses of 50-99%. Carotid stenosis of 50-99% was an independent predictor of death (hazard ratio 7.9; 95% confidence interval 2.2 to 29) and non-fatal stroke (hazard ratio 7.4; 1.5 to 37.4). Conclusions: The prevalence of carotid stenosis or occlusion in young adults after a cerebrovascular event is low. Though patients with high grade symptomatic carotid stenosis are at risk of non-fatal and fatal events, patients with internal artery occlusion apparently have a benign prognosis. Key messages Key messages Young adults with a history of transient ischaemic attack and stroke have a low prevalence of high grade symptomatic carotid artery stenosis and occlusion The five year prognosis is apparently benign in patients aged 15-44 with internal carotid artery occlusion but poor (in terms of fatal and non-fatal events) in the presence of high grade carotid stenosis Primary and secondary medical prevention of cerebral ischaemia based on routine Doppler examinations should be initiated early in subjects at risk Endarterectomy should be considered even in young adults with ipsilateral carotid artery stenosis of 70-99% to halt the progression of arterial lesions and improve prognosis

Twenty-five patients underwent transcranial Doppler and single photon emission tomography within 6 h of the onset of symptoms of a first-ever acute hemispheric brain infarction, and 1 week later. Quan

Because there is uncertainty about the role of atherogenic and nonatherogenic risk factors for cerebral ischemia in the young, we carried out a multicenter, hospital-based, case-control study. 333 pat

We applied the technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) split-dose method in order to evaluate the feasibility of assessing cerebral blood flow (CBF) changes with single photon emission tomography (SPET) during a motor activation task. Eleven normal subjects were studied using the Tomomatic 564 (Medimatic, DK). Five subjects were studied twice at rest and 6 subjects at rest and during a motor task performance (finger opposition movements). A total of 28 mCi of 99mTc-HMPAO was injected in 2 doses with a 1:3 ratio. The first scan was obtained after injection of 7 mCi at rest in all subjects. The second scan was obtained a few minutes later, after injection of the remaining dose (21 mCi), under similar resting conditions or during a motor task performance. The mean brain uptake was proportional to the amount of tracer injected and to the acquisition time for both the first scan (5263±1266 counts × mCi × min) and the second (5034.4±966 counts × mCi × min). The grey/white matter ratio was 1.67±0.019 and 1.67±0.097 for the two scans, respectively. A three-way analysis of variance (ANOVA) for repeated measure showed no significant effects of side, slice and region of interest (ROI) on the CBF in the 5 subjects studied twice at rest, and the mean regional CBF change was −0.2%±5%. In the 6 subjects studied at rest and during motor activation, the image subtraction analysis showed a significant CBF increase in the primary motor cortex contralateral to the stimulated side (15%±7%, n=6) and medially in the supplementary motor area (22%±12%, n=4). Our results indicate that the split-dose method allows the detection of a local CBF response to motor activation using 99mTc-HMPAO in a single imaging session.

T cell clones derived from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) were analysed for their capacity to produce interleukin 2 (IL-2), interleukin 4 (IL-4), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). They were also compared with liver-infiltrating T cell clones from patients with chronic active hepatitis. All the CSF T clones (both CD4+ and CD8+) produced large amounts of IFN-gamma and particularly of TNF-alpha, that was synthesized in a significantly larger amount than compared clones. Moreover, they were capable of secreting IL-2, but not IL-4. From our results, we conclude that first, the CSF CD4+ T clones could constitute a subset with functional properties similar to the T helper 1 (Th1)/inflammatory cell subset of the mouse; and second, the large amounts of TNF produced by CSF T cell clones strongly suggests a significant role for this cytokine as well as of IFN-gamma in MS immunopathogenesis.

The pharmacological approach to acute ischemic stroke has been characterized so far by negative results, thus generating a generalized pessimistic opinion on the possibihties of effective treatment. Indeed, drug efficacy would have been better assessed and generated more enthusiasm if clinical trials had been conducted in accordance with more adequate guidelines based on the pathophysiology of brain circulation The essential ingredients for correctly planning a study on acute stroke therapy are the following: (a) knowledge about the mechanisms of ischemic injury at brain tissue level; (b) availability of pharmacologic agents influencing those mechanisms based on experimental data; (c) possibilities of clinical application, within appropriate temporal limits and (d) organization of an adequate team, including multiple cooperating clinical services as required. Controversies on the reliability of animal models are reported in the literature. Some authors emphasize the unavailability of models reproducing human disease (1), whereas others, and we are among them, believe that experimental models are important, since they provide useful indications for clinical application (2). Relevance to new therapeutic approaches to ischemic stroke treatment should also be recognized because current epidemiological studies suggest an increase in stroke incidence in the 1980s (3). Experimental evidence reveals the existence of an ischemic penumbra around the infarcted area in which neurons, although functionally inhibited by cerebral blood flow reduction, are liable to complete recovery if blood flow is promptly restored (4). Hence, a time is available for short-lasting therapeutic window, whose temporal limits are as yet not completely defined. According to pathological evidence, after transient ligation of the middle cerebral artery (MCA) in the cat, cerebral infarction develops 0I11y when the occlusion lasts over 2 h, and reaches its maximum severity after 6 h (5). Obviously, a residual collateral flow allows such persistence of tissue viability. One can argue that young healthy cats are different from atherothrombotic stroke patients, and Caplan and Stein correctly remind us not to downgrade the etiopathogenic aspects of individual cases (6). Nevertheless, the time interval between onset and treatment remains fundamental, as good results of early thrombolysis in myocardial ischemia have demonstrated (7). This interval will depend, among other factors, on the residual (collateral) flow in the early period of cerebral ischemia. This issue has been analyzed in a consecutive series of 80 acute ischemic strokes in the territory of the MCA (8). Within 6 h from onset, each enrolled patient was submitted to transcranial Doppler sonography (TCD) and cerebral angiography. Intracranial occlusions at angiography probably related to embolic sources were found in 58 cases (66%). Of 40 occluded patients followed up by TCD, 11 showed spontaneous recanalization. None had clinical improvement. Patients with occlusion were considered to have good collateral circulation when the vessels distal to occlusion were fully visualized at angiography within 5 s of the end of contrast medium injection. Not surprisingly, those with poor or absent collateral filling had the worst clinical outcome.

Background and Purpose— The Prevention of VTE after Acute Ischemic Stroke with LMWH (PREVAIL) study demonstrated that enoxaparin was superior to unfractionated heparin (UFH) in preventing venous thromboembolism in patients with ischemic stroke and was associated with a small but statistically significant increase in extracranial hemorrhage rates. In this PREVAIL subanalysis, we evaluate the long-term neurological outcomes associated with the use of enoxaparin compared with UFH. We also determine predictors of stroke progression. Methods— Acute ischemic stroke patients aged ≥18 years, who could not walk unassisted, were randomized to receive enoxaparin (40 mg once daily) or UFH (5000 U every 12 hours) for 10 days. Patients were stratified according to baseline stroke severity using the National Institutes of Health Stroke Scale score. End points for this analysis included stroke progression (≥4-point increase in National Institutes of Health Stroke Scale score), neurological outcomes up to 3 months postrandomization (assessed using National Institutes of Health Stroke Scale score and modified Rankin Scale score), and incidence of intracranial hemorrhage. Results— Stroke progression occurred in 45 of 877 (5.1%) patients in the enoxaparin group and 42 of 872 (4.8%) of those receiving UFH. Similar improvements in National Institutes of Health Stroke Scale and modified Rankin Scale scores were observed in both groups over the 90-day follow-up period. Incidence of intracranial hemorrhage was comparable between groups (20 of 877 [2.3%] and 22 of 872 [2.5%] in enoxaparin and UFH groups, respectively). Baseline National Institutes of Health Stroke Scale score, hyperlipidemia, and Hispanic ethnicity were independent predictors of stroke progression. Conclusions— The clinical benefits associated with use of enoxaparin for venous thromboembolism prophylaxis in patients with acute ischemic stroke are not associated with poorer long-term neurological outcomes or increased rates of symptomatic intracranial hemorrhage compared with UFH.

One hundred and nine elderly patients suffering from mild to moderate cognitive impairment fulfilling NINCDS-ADRDA criteria for probable dementia of the Alzheimer type were treated for 6 months with a new nootropic drug, aniracetam (Ro 13-5057) in a double-blind randomized study versus placebo. The two treatment groups were comparable at baseline for demographic and behaviourial parameters and symptomatology. Patients underwent clinical, behaviourial and psychometric evaluation every other month. The aniracetam group differed significantly from the placebo group by the end of the study and also showed a statistically significant improvement versus baseline in the psychobehavioural parameters, while in the placebo group a steady deterioration was observed. Tolerability to aniracetam was excellent.

As reported in the literature, the moderate ischemia zone characterized by a rapid restoration of spontaneous and evoked electrical activity following reperfusion (up to 2 h of ischemia) is ''fully reversible''. But returning to the normal conditions does not prevent selective neuronal death, probably influenced by excitatory neurotransmitters. On the basis of animal studies, it is argued that several hours of ‘ischemic penumbra’ will eventually increase the neuronal loss even with a restoration of electrical activity. We studied acute-stroke cases (blood partition coefficient between damaged and normal hemisphere) with single-photon emission tomography (SPECT) using 99mTc hexamethyl-propylamine oxime as a tracer for cerebral perfusion imaging. The limits of moderate ischemia (penumbra) associated with the tissue survival structure (CT scanning) are discussed. We aim to define, in the early stage of the disease, the ischemic threshold compatible with a thrombolytic therapy and no unacceptable hemorrhagic risk. Clinical recovery can roughly, but in a clinically relevant way, evaluate neuronal death in ischemic penumbra in humans.

Cerebral blood flow (CBF) and cerebral plasma volume (CPV) were measured under steady-state hyperglycemic conditions in the hemispheres and brainstem-cerebellum of conscious rats. There groups of hyperglycemic animals each having a different level of plasma glucose concentration, 25, 33.3, 44.4 mmol/l, and a normoglycemic control group were studied. CBF was not affected at the hyperglycemic levels of 25 and 33.3 mmol/l. Mean hemispheric and brainstem-cerebellum CBF values appeared lower than in controls at the highest glycemic level although the differences were not statistically significant. CPV was found to be unchanged at the hyperglycemic level of 25 mmol/l, while it was found to be increased in the hemispheres of the animals whose plasma glucose concentration had been elevated to 33.3 and 44.4 mmol/l. The results of the study do not support the claim that hyperglycemia may enhance ischemic brain injury by reducing CBF.

Retrospective and cross-sectional studies have suggested that both bacterial and viral infections may be risk factors for atherosclerosis, ischemic stroke and acute coronary events. The correlation between Chlamydia pneumoniae and atherosclerosis remains a source of controversy. Our case-control study is aimed at evaluating the frequency of C. pneumoniae infection in a cohort of young adults with recent cerebrovascular disease and in particular etiologic stroke subtypes. Chlamydia pneumoniae IgG, IgM and IgA antibodies were evaluated by microimmunofluorescence method and antibody titers to both recombinant antigens chlamydial outer protein 2 and 60-kDa chlamydial heat shock protein (HSP60) by ELISA. The two groups differed with regard to the prevalence of C. pneumoniae IgA (P < 0.001) and IgG (P < 0.0001), as well as the titer of anti-R-HSP60 IgG (P < 0.001). We found an increase in IgA titers, suggestive of persistent, chronic active infection, in 16 patients in whom the etiology of the cerebral ischemic event was large-vessel atherothrombosis. Persistent, active C. pneumoniae infection may be an additional risk factor for ischemic stroke mainly of atherotrombotic origin in young subjects. However, a large-scale prospective confirmation of our findings is required.

Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment.We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage.Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002).The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.

Treatment with acetyl L-carnitine (ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis (MS). To compare the efficacy of ALCAR with that of amantadine, one of the drugs most widely used to treat MS-related fatigue, 36 MS patients presenting fatigue were enrolled in a randomised, double-blind, crossover study. Patients were treated for 3 months with either amantadine (100 mg twice daily) or ALCAR (1 g twice daily). After a 3-month washout period, they crossed over to the alternative treatment for 3 months. Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale (FSS), the primary endpoint of the study. Secondary outcome variables were: Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI) and Social Experience Checklist (SEC). Six patients withdrew from the study because of adverse reactions (five on amantadine and one on ALCAR). Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039). There were no significant effects for any of the secondary outcome variables. The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue.

Background: Trafermin (basic fibroblast growth factor) has been shown to reduce infarct volume in acute ischemic stroke models, and to promote functional recovery and new synapse formation when given to animals with completed cerebral infarction. A previous study in acute stroke patients suggested that trafermin was safe and well tolerated when given over a 3-hour period over a wide dose range. Methods and Results: Double-blind, parallel group, placebo-controlled trial of a single 24-hour intravenous infusion of trafermin. Patients having onset of stroke symptoms within 6 h and a baseline score of ≧7 on the NIH Stroke Scale (≧2 motor) were randomized to receive 5 or 10 mg of trafermin or placebo intravenously infused over 24 h. The primary efficacy outcome was a categorized combination of the Barthel and Rankin scales assessed at 90 days. A total of 286 patients had been enrolled at 55 sites in 11 countries when the sponsor directed that enrollment be stopped because an interim analysis of efficacy data predicted too small a chance of demonstrating a statistically significant benefit after recruitment of the planned 900 patients. The 5-mg group showed a slight but nonsignificant advantage over placebo (OR 1.2, 95% CI 0.72–2.00, p = 0.48); the 10-mg group showed a nonsignificant disadvantage (OR 0.74, 95% CI 0.44–1.22, p = 0.24). Mortality rates at 90 days were 17% in the 5-mg group, 24% in the 10-mg group and 18% in the placebo group. Treatment with trafermin was associated with an increased leukocytosis and a decrease in blood pressure: mean decrease in systolic blood pressure from baseline was 19 mm Hg in the 5-mg group, 22 mm Hg in the 10-mg group and 8 mm Hg in the placebo group. In a post hoc subgroup analysis, patients in the 5-mg group treated more than 5 h after the onset of symptoms showed an apparent advantage over placebo (OR 2.1, 95% CI 1.00–4.41, p = 0.044; after age adjustment: OR 1.9, 95% CI 0.91–4.13, p = 0.08). Conclusions: With the proper treatment regimen, trafermin can likely be given safely to stroke patients. The 5-mg dose showed a trend toward a treatment advantage. The ideal time window for this agent may exceed 5 h. This may open new avenues for acute stroke therapy, aiming at enhancing recovery mechanisms rather than immediate neuroprotection.

Ischemic stroke in young adults is rare (5%–10% of all ischemic strokes) and, in absence of other risk factors, may be associated with migraine. We describe the case of a 34-year-old woman, with a history of migraine without aura, who presented a sudden onset of headache with Horner's syndrome, and in whom neuroimaging showed evidence compatible with fibromuscular dysplasia (FMD) and arterial dissection of the extracranial internal carotid artery (ICA) and the carotid siphon. In our opinion, in young women with a long history of migraine, a careful study of the extracranial and intracranial arteries would be useful, although the cost/benefit ratio does not at present justify such a procedure. Our aim in the future is, therefore, to study a larger sample of migraine patients in order to find those patients who are most at risk of arterial dissection and who should, consequently, be carefully studied.

Ischaemic penumbra is defined as the area of brain tissue that maintains some blood flow following ischaemic accident. This zone may be rescued by both neuroprotection and arterial revascularization. Early thrombolysis has been used with encouraging results since 1995 in several trials testing both streptokinase and recombinant tissue plasminogen activator (r-TPA): the r-TPA results are definitely more positive than those of streptokinase, despite an increased incidence of symptomatic haemorrhagic transformation, r-TPA significantly reducing death or dependency at the end of follow-up. Despite the fact that some experimental periods of application of these therapeutic strategies demonstrated real cost-effective benefits, only 1% of patients reaching hospital in time for thrombolysis are currently treated. This is because the profile of patients at risk of haemorrhagic transformation, which is definitely the most feared side-effect of thrombolysis in stroke, is yet to be clearly defined. Extended computerized tomography (CT) signs of the index stroke have been repeatedly indicated as reliable predictors of haemorrhagic transformation even if currently there are significant discrepancies in the criteria adopted by different researchers to define early CT signs. Based on experimental ischaemia, strategies for protecting the basal lamina during thrombolysis are suggested: neuroprotection is the second approach to stroke therapy; pharmacological reperfusion and brain protection are probably mutually dependent.

The aim of the present study was to assess whether or not there is any correlation between magnetic resonance imaging (MRI) abnormalities and excessive daytime sleepiness (EDS) in a consecutive series of patients with myotonic dystrophy (MD). The influences of nocturnal breathing abnormalities and sleep morphology on EDS were also evaluated. Ten MD patients were studied by means of an all-night polysomnographic recording, the multiple sleep latency test (MSLT) and MRI. Diagnosis of MD was established on the basis of the clinical and electrophysiological evidence of myotonia as well as of the characteristic genetic pattern. No patient had respiratory failure. Polysomnography and MSLT were also evaluated in ten healthy age-matched controls under the same environmental conditions. The mean MSLT value was significantly lower in patients than in controls. Five of the ten patients were found to have pathological EDS. The quantitative sleep variables and the nocturnal apnoeas in these five patients were not significantly different from those of the patients without EDS. As two patients did not undergo MRI because of claustrophobia, the MRI data were considered in eight patients. Corpus callosum (CC) atrophy was detected in four patients, whereas three patients showed hyperintense areas in the white matter. No correlation was found between EDS and MRI indexes of subcortical atrophy as well as volume of the hyperintense areas. By contrast, a correlation was found between the MSLT value and the reduction in the anterior area of the CC. Our data suggest that CC atrophy might occur in MD patients, and that the size of the CC anterior area might be associated with EDS.

In a recent Viewpoint article, Rook and Stanford1xRook, G.A.W. and Stanford, J.L. Immunol. Today. 1998; 19: 113–116Abstract | Full Text PDF | PubMed | Scopus (0)See all References1 propose to explain increased incidences of atopy and autoimmunity with the decreased exposure to microbes in developed countries (an event referred to as ‘Westernization’). They ascribe this effect to two different mechanisms, namely an incorrect cytokine balance [prevalence of T helper 2 (Th2) type responses] for allergy and a faulty fine-tuning of crossreactive T cells for autoimmunity. In addition, they touch upon implications for vaccination and immunotherapy.We fully endorse the interesting thought on the possible link between microbe deprivation and the rising prevalence of atopy and autoimmunity in recent decades. Our comment is based on experimental and clinical data that might account for the increase of both conditions, with relevant therapeutical implications.According to a canonical view of the Th1/Th2 paradigm, the increased incidence of both atopy and organ-specific autoimmune diseases is unexpected. The Th2 profile of atopy should protect from autoimmunity and, conversely, the Th1 profile of the latter should protect from atopy. Rook and Stanford are therefore forced to ‘split’ the influence of microbe deprivation, suggesting that atopy is favoured when the exposure to Th1 microbes (i.e. Mycobacterium tuberculosis) is reduced, whereas autoimmunity is linked to microbe deprivation through different, still ill-defined mechanisms. Further data apparently confuting a Th1/Th2 dichotomy come from developing countries, where the exposure to Th2-nurturing parasite infections does not impair responsiveness to M. tuberculosis and might protect against allergic diseases2xCookson, W.O. and Moffatt, M.F. Science. 1997; 275: 41–42Crossref | PubMed | Scopus (245)See all References, 3xYemaneberhan, H., Bekele, Z., Venn, A., Lewis, S., Parry, E., and Britton, J. Lancet. 1997; 350: 85–90Abstract | Full Text | Full Text PDF | PubMed | Scopus (270)See all References.Moreover, the case of microbial vaccinations in Th1-mediated organ-specific autoimmune diseases argues against a simple cytokine imbalance as a mechanism to explain the protective effects of microbe exposure. Beneficial effects of adjuvant therapy (i.e. an immunostimulatory approach known to prevalently induce Th1 responses) were reported in experimental models of autoimmune diseases and in patients with insulin-dependent diabetes mellitus (IDDM)4xShehadeh, N., Calcinaro, F., Bradley, B.J. et al. Lancet. 1994; 343: 706–707Abstract | PubMed | Scopus (114)See all References4. A clinical and magnetic resonance imaging assessment of the safety of adjuvant therapy with bacille Calmette–Guerin (BCG) vaccination in multiple sclerosis (MS) has led us to conclude that this approach is highly secure (G. Ristori et al., unpublished) and possibly effective in reducing disease activity.Together, these observations led to the hypothesis that a protective exposure to potential pathogens depends on balanced Th1/Th2 responses (rather than polarized responses counteracting the imbalance invoked by Rook and Stanford) and well-orchestrated effector pathways favouring a healthy outcome in the host–microbe interplay5xAllen, J.E. and Maizels, R.M. Immunol. Today. 1997; 18: 387–392Abstract | Full Text PDF | PubMed | Scopus (243)See all References5. Susceptibility to dysfunctional immunopathology seems to emerge when such protective microbial exposure fails, as in the case of: (1) microbe deprivation, seen in the relative increase of immunopathological conditions in recent decades possibly due to ‘Westernization’; or (2) overt infection, for example, the well-known relationship between infectious episodes and onset/relapses of autoimmune or atopic disorders. The innate immune system might be the common pathway that conveys these effects, being capable of instructing the specificity and the functional characteristics of the adaptive response6xFearon, D.T. and Locksley, R.M. Science. 1996; 272: 50–54Crossref | PubMedSee all References6. Recent evidence of a dysregulated innate immune system in at least some autoimmune diseases7xRistori, G., Laurenti, F., Stacchini, P. et al. J. Neuroimmunol. 1998; 88: 9–12Abstract | Full Text | Full Text PDF | PubMed | Scopus (12)See all References7 supports this view.

The frequency of myocardial infarction and sudden death is increased between 6 AM and noon. To determine whether the same is true for the onset of ischemic stroke, we studied 426 consecutive patients within 12 hours after the onset of their first hemispheric stroke. The frequency of onset of hemispheric stroke was significantly (p = 0.0001) higher from 6:01 AM to noon (56.1%) than from 12:01 PM to 6 PM (20.2%), from 6:01 PM to midnight (8.2%), and from 12:01 AM to 6 AM (15.5%). The identification of periods of high risk for vascular events may have important therapeutic implications, such as matching drug effects with vulnerability.

Background and Purpose —The purpose of our study was to investigate whether emergency transcranial Doppler (TCD) findings and their modifications over the first 48 hours are related to early neurological changes in acute ischemic stroke patients. Methods —Ninety-three patients underwent CT scan within 5 hours of a first-ever ischemic hemispheric stroke, and TCD serial examinations at 6, 24, and 48 hours after stroke onset. We classified TCD findings as follows: normal; middle cerebral artery (MCA) asymmetry (asymmetry index between affected and contralateral MCAs below –21%); and MCA no-flow (absence of flow signal from the affected MCA in the presence of ipsilateral anterior and posterior cerebral artery signals through the same acoustic window). We considered early deterioration and early improvement to be a decrease or an increase of 1 or more points, respectively, in the Canadian Neurological Scale score over the same period. Results —At 6-hour TCD examination, MCA asymmetry and MCA no-flow were present in 6 (22%) and 2 (7%), respectively, of 27 improving patients; in 20 (43%) and 10 (22%) of 46 stable patients, and in 9 (45%) and 8 (40%) of 20 deteriorating patients. TCD findings were normal in the remaining patients ( P =0.001). At serial TCD, we detected early (within 24 hours) recanalization (from no-flow to asymmetry or normal and from asymmetry to normal) in 2 (25%) improving patients, in 7 (23%) stable patients, and in 5 (29%) deteriorating patients and late (between 24 and 48 hours) recanalization in 4 (50%) improving patients, in 6 (20%) stable patients, and in none of the deteriorating patients ( P =0.03, χ 2 for trend, improving versus nonimproving irrespective of the timing of recanalization). One deteriorating patient (5%) developed a no-flow from an initial MCA asymmetry. Logistic regression selected normal TCD (odds ratio [OR], 0.17; 95% confidence interval [CI], 0.06 to 0.46) as an independent predictor of early improvement and abnormal TCD (asymmetry plus no-flow) (OR, 5.02; 95% CI, 1.31 to 19.3) as an independent predictor of early deterioration. Conclusions —TCD examination within 6 hours after stroke can help to predict both early deterioration and early improvement. Serial TCD shows that propagation of arterial occlusion is rarely related to early deterioration, whereas the fact that it can detect early recanalization (within 24 hours) in deteriorating patients and both early and late recanalization (after 24 hours) in improving patients suggests the existence of individual time frames for tissue recovery.

Sixty-eight patients with relapsing-remitting multiple sclerosis (RRMS) were treated with 3 million or 9 million i.u. of recombinant interferon-beta1a (recIFN-beta1a) s.c. three times a week for 2 years. Their sera were tested for antibodies neutralizing the IFN (NAb) in a bioassay. Sera with titers > or = 1:20 were considered positive. We detected NAb in 3.2%, 13.8%, and 15.9% of the patients in sera obtained at 3, 6, and 24 months, respectively. The incidence was not related to the IFN dose. Interestingly, during the 6 month baseline period before the start of the study, relapse rates, baseline disability, and the volume of lesions on T2-weighted images were significantly higher in patients who developed NAb during treatment. Because of interpatient variability, no definitive relationship was observed between NAb formation and loss of clinical or magnetic resonance imaging (MRI) response.