The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimed ...to assess the possible influence of pregnancy and delivery on the clinical course of multiple sclerosis. We report here the 2‐year post‐partum follow‐up and an analysis of clinical factors which might predict the likelihood of a relapse in the 3 months after delivery. The relapse rate in each trimester up to the end of the second year post‐partum was compared with that in the pre‐pregnancy year. Clinical predictors of the presence or absence of a post‐partum relapse were analysed by logistic regression analysis. Using the best multivariate model, women were classified as having or not having a post‐partum relapse predicted, and this was compared with the observed outcome. The results showed that, compared with the pre‐pregnancy year, there was a reduction in the relapse rate during pregnancy, most marked in the third trimester, and a marked increase in the first 3 months after delivery. Thereafter, from the second trimester onwards and for the following 21 months, the annualized relapse rate fell slightly but did not differ significantly from the relapse rate recorded in the pre‐pregnancy year. Despite the increased risk for the 3 months post‐partum, 72% of the women did not experience any relapse during this period. Confirmed disability continued to progress steadily during the study period. Three indices, an increased relapse rate in the pre‐pregnancy year, an increased relapse rate during pregnancy and a higher DSS (Kurtzke’s Disability Status Scale) score at pregnancy onset, significantly correlated with the occurrence of a post‐partum relapse. Neither epidural analgesia nor breast‐feeding was predictive. When comparing the predicted and observed status, however, only 72% of the women were correctly classified by the multivariate model. In conclusion, the results for the second year post‐partum confirm that the relapse rate remains similar to that of the pre‐pregnancy year, after an increase in the first trimester following delivery. Women with greater disease activity in the year before pregnancy and during pregnancy have a higher risk of relapse in the post‐ partum 3 months. This is, however, not sufficient to identify in advance women with multiple sclerosis who are more likely to relapse, especially for planning therapeutic trials aiming to prevent post‐partum relapses.
The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial. The aim of this ...trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures.
Patients with rectal carcinoma located in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and not involving more than two-thirds circumference, were randomly assigned to one of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13 fractions over 17 days) versus the same EBRT with boost (85 Gy in three fractions) using endocavitary contact x-ray.
Between 1996 and 2001, 88 patients were enrolled onto the study. A significant improvement was seen in favor of the contact x-ray boost for complete clinical response (24% v 2%) and for a complete or near-complete sterilization of the operative specimen (57% v 34%). A significant increase in sphincter preservation was observed in the boost group (76% v 44%; P =.004). At a median follow-up of 35 months, there was no difference in morbidity, local relapse, and 2-year overall survival.
A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome.
The combination of radiation, fluorouracil, and oxaliplatin in locally advanced rectal cancer has been shown to be feasible in a phase I trial. The purpose of this phase II trial was to assess ...tolerance and efficacy of this regimen in a preoperative setting.
Between May 2000 and October 2001, 40 operable patients were entered onto the study. Radiotherapy was delivered with a three-field technique to a dose of 50 Gy over 5 weeks with a concomitant boost approach. Two cycles of chemotherapy were given synchronously on weeks 1 and 5, with oxaliplatin 130 mg/m(2) on day 1 followed by 5-day continuous infusion of fluorouracil 350 mg/m(2) and L-folinic acid 100 mg/m(2). Surgery was planned 5 weeks later.
All patients completed treatment without modification except one who experienced grade 3/4 toxicity. Grade 3 toxicity was seen in seven patients. Surgery was performed in all patients after a mean interval time of 5 weeks. An objective clinical response was seen in 30 patients (75%). Sphincter-saving surgery was possible in 26 patients. No postoperative deaths occurred. In four patients (10%), a reoperation was necessary (anastomotic fistula, n = 2; pelvic abscess, n = 2). In six cases the operative specimen was sterilized (15%), and in 12 cases (30%), only few residual cells were detected.
Such a combined preoperative chemoradiotherapy and oxaliplatin-containing regimen is well tolerated with no increase in surgical toxicity. The good response rate observed warrants its use in further clinical trials.
The optimal timing of surgery after preoperative radiotherapy in rectal cancer is unknown. The aim of this trial was to evaluate the role of the interval between preoperative radiotherapy and ...surgery.
Patients with rectal carcinoma accessible to rectal digital examination, staged T2 to T3, NX, M0, were randomized before radiotherapy (39 Gy in 13 fractions) into two groups: in the short interval (SI) group, surgery had to be performed within 2 weeks after completion of radiation therapy, compared with 6 to 8 weeks in the long interval (LI) group. Between 1991 and 1995, 201 patients were enrolled onto the study.
A long interval between preoperative radiotherapy and surgery was associated with a significantly better clinical tumor response (53. 1% in the SI group v 71.7% in the LI group, P =.007) and pathologic downstaging (10.3% in the SI group v 26% in the LI group, P =.005). At a median follow-up of 33 months, there were no differences in morbidity, local relapse, and short-term survival between the two groups. Sphincter-preserving surgery was performed in 76% of cases in the LI group versus 68% in the SI group (P = 0.27).
A long interval between preoperative irradiation and surgery provides increased tumor downstaging with no detrimental effect on toxicity and early clinical results. When sphincter preservation is questionable, a long interval may increase the chance of a successful sphincter-saving surgery.
Intravenous tissue plasminogen activator improves outcome after ischemic stroke when given within 3 hours of symptoms onset in carefully selected patients. However, only a small proportion of acute ...stroke patients are currently eligible for thrombolysis, mainly because of excessive delay to hospital presentation. We sought to determine the factors associated with early admission in a French stroke unit.
We prospectively studied the admission delay of acute stroke patients in a French stroke unit during a 12-month period ending July 1999. Univariate and multivariate regression analyses were performed to evaluate the factors influencing early stroke unit admission and transport by the Emergency Medical Services (EMS) or Fire Department (FD) ambulances.
One hundred sixty-six patients were primarily admitted to the stroke unit, with a median admission time of 4 hours 5 minutes. Twenty-nine percent presented within 3 hours of symptoms onset and 75% within 6 hours. Univariate analysis showed that early stroke unit arrival was significantly associated with the following factors: female sex, stroke severity assessed by the National Institutes of Health Stroke Scale score, lowered consciousness, sudden onset of stroke, not living alone, recognition of symptoms by bystanders, and transport by EMS or FD ambulances. Age, ethnicity, level of education, employment status, nocturnal onset, distance from place of stroke to the stroke unit, stroke lesion location, presence of brain hemorrhage, and awareness about the symptoms and risk factors of stroke had no measurable effect on early admission. A multivariate regression model demonstrated that the most significant factors associated with early stroke unit arrival were transport by EMS or FD ambulances and sudden onset of stroke. Female sex and not living alone were also significantly associated with early admission in the multivariate model. Multivariate analysis of the mode of transport showed that transport by EMS or FD ambulances was significantly more frequent among female patients, when stroke symptoms were recognized by bystanders, and when the general practitioner was not the first medical contact.
The present study shows that hospital arrival within the first hours of stroke is feasible in a French stroke unit. As many as 75% of the patients are admitted within the first 6 hours of stroke. This is the first study demonstrating that stroke unit admission in France is fastest in patients brought to the hospital by EMS or FD ambulances. However, only 35% of stroke patients activate the emergency telephone system and are currently transported by EMS or FD ambulances. French stroke patients should be encouraged to seek immediate medical attention by using the emergency telephone system, and stroke management should be reprioritized in the French EMS as a time-dependent medical emergency, with the same level of organization and expertise currently applied to myocardial infarction.
To quantify and study the distribution of innervation of the left atrium and the pulmonary veins in humans.
Damage to cardiac nerves has been hypothesized as the explanation for successful ...radiofrequency ablation of atrial fibrillation.
From January 2003 to September 2003, histologic and quantitative studies of innervation of the left atrium and the pulmonary veins was performed in 43 consecutive necropsied adult hearts (30 men and 3 women; mean age 45.5 +/- 12.4 years). The left atrium was sectioned in 1-cm slices from left to right, with the plane of section perpendicular to the long axis of the heart. Sections of the pulmonary veins at their ostia and sections 1 cm away of this structure also were obtained. Nerve fiber density was counted manually for each case and expressed as the mean number per slice.
Numerous epicardial nerve fibers and ganglia having distinct patterns of distribution in the left atrium were found. Nerve density was significantly higher at the ostia of the four pulmonary veins than in their distal part (7.1 +/- 2.1 vs 5.2 +/- 1.3 for left upper pulmonary vein; 6.3 +/- 1.5 vs 5.2 +/- 1.7 for right upper pulmonary vein; 7.4 +/- 2 vs 5.9 +/- 2 for left lower pulmonary vein; 6.7 +/- 1.8 vs 3.9 +/- 1.3 for right lower pulmonary vein). The left superior vein was significantly more innervated than the right inferior vein (12.3 +/- 3 vs 10.6 +/- 1.4). Gradients of innervation were found from right to left (9.8 +/- 4.6 vs 18.5 +/- 6.6, P < .05) and from the front to the rear of the atrium (17.2 +/- 6.4 vs 20.7 +/- 6.5, P < .05). The same heterogeneous distribution was observed at the myocardial level but with thinner nerve fibers, making quantification difficult. Only very thin nerve fibers were present in the endocardium.
The human left atrium exhibits several gradients of innervation at discrete sites. These findings may have clinical implications for radiofrequency ablation of atrial fibrillation.
We hypothesized that pretreatment magnetic resonance imaging (MRI) parameters might predict clinical outcome, recanalization and final infarct size in acute ischemic stroke patients treated by ...intravenous recombinant tissue plasminogen activator (rt-PA). MRI was performed prior to thrombolysis and at day 1 with the following sequences: magnetic resonance angiography (MRA), T2*-gradient echo (GE) imaging, diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). Final infarct size was assessed at day 60 by T2-weighted imaging (T2-WI). The National Institutes of Health Stroke Scale (NIHSS) score was assessed prior to rt-PA therapy and the modified Rankin Scale (m-RS) score was assessed at day 60. A poor outcome was defined as a day 60 m-RS score >2. Univariate and multivariate logistic regression analyses were used to identify the predictors of clinical outcome, recanalization and infarct size. Forty-nine patients fulfilled the inclusion criteria. Baseline NIHSS score was the best independent indicator of clinical outcome (
p=0.002). A worse clinical outcome was observed in patients with tandem internal carotid artery (ICA)+middle cerebral artery (MCA) occlusion versus other sites of arterial occlusion (
p=0.009), and in patients with larger pretreatment PWI (
p=0.001) and DWI (
p=0.01) lesion volumes. Two factors predict a low rate of recanalization: a proximal site of arterial occlusion (
p=0.02) and a delayed time to peak (TTP) on pretreatment PWI (
p=0.05). The final infarct size was correlated with pretreatment DWI lesion volume (
p=0.025). Recanalization was associated with a lower final infarct size (
p=0.003). In conclusion, a severe baseline NIHSS score, a critical level of pretreatment DWI/PWI parameters and a proximal site of occlusion are predictive of a worse outcome after IV rt-PA for acute ischemic stroke.
Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset ...of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan–Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing–remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.
The influence of the patterns of onset of multiple sclerosis and relapses of the disease on the time course of irreversible disability is controversial.
In 1844 patients with multiple sclerosis who ...were followed for a mean (+/- SD) of 11 +/- 10 years, we determined the time of the clinical onset of the disease, the initial course (relapsing-remitting or progressive) and the subsequent course (relapsing-remitting, secondary progressive, or primary progressive), the times of relapses, the time to the onset of irreversible disability, and the time course of progressive, irreversible disability. We used three scores on the Kurtzke Disability Status Scale (range, 0 to 10, with higher scores indicating more severe disability) as measures of the severity and progression of disability: a score of 4 (limited walking ability but able to walk for more than 500 m without aid or rest), a score of 6 (ability to walk with unilateral support no more than 100 m without rest), and a score of 7 (ability to walk no more than 10 m without rest while leaning against a wall or holding onto furniture for support). We used Kaplan-Meier analyses to determine the influence of relapses on the time to the onset of irreversible disability.
The median times from the onset of multiple sclerosis to the assignment of a score of 4, a score of 6, and a score of 7 on the disability scale were longer among the 1562 patients with a relapsing-remitting onset of disease (11.4, 23.1, and 33.1 years, respectively) than among the 282 patients who had progressive disease from the onset (0.0, 7.1, and 13.4 years, respectively; P<0.001 for all comparisons). In contrast, the times from the assignment of a score of 4 to a score of 6 were similar in the two groups (5.7 and 5.4 years, P=0.74). The time course of progressive, irreversible disease among patients with the primary progressive type of multiple sclerosis was not affected by the presence or absence of superimposed relapses.
Among patients with multiple sclerosis, relapses do not significantly influence the progression of irreversible disability.
To determine the prognostic role of late auditory (N100) and cognitive evoked potentials (MMN) for awakening in a cohort of comatose patients categorized by etiology.
The authors prospectively ...studied a series of 346 comatose patients. Coma was caused by stroke (n = 125), trauma (n = 96), anoxia (n = 64), complications of neurosurgery (n = 54), and encephalitis (n = 7). Patients were followed for 12 months and classified as awake or unawake. Univariate and multivariate analyses were performed using regression logistic and Cox models.
Pupillary light reflex, N100, middle-latency auditory evoked potentials, age, and etiology were the most discriminating factors for awakening. Statistical analysis showed that pupillary reflex was the strongest prognostic variable for awakening (estimated probability 79.7%). The estimated probability of awakening rose to 87% when N100 was present and to 89.9% when middle-latency evoked potentials (MLAEPs) were present. It was 13.7% when pupillary reflex was absent in anoxic patients. When MMN was present, 88.6% of patients awakened. No patient in whom MMN was present became permanently vegetative.
Pupillary reflex is the strongest prognostic variable, followed by N100 and MLAEPs allowing a reliable model for awakening. The presence of MMN is a predictor of awakening and precludes comatose patients from moving to a permanent vegetative state. Evaluation of primary sensory cortex and higher-order processes by middle-latency-, late, and cognitive evoked potentials should be performed in the prognosis for awakening in comatose patients.
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