A randomized, multicentre, open-label, parallel-group trial of the tolerability of interferon beta-1a (Rebif) administered by autoinjection or manual injection in relapsing-remitting multiple sclerosis.

Injection site reactions (ISRs) are a common side effect of subcutaneous interferon beta therapy, particularly during initiation of therapy. Retrospective analysis of two clinical trials showed that patients using an autoinjector experienced fewer ISRs than patients administering interferon beta manually. This randomized, open-label trial compared the occurrence of ISRs in relapsing remitting multiple sclerosis patients subcutaneously injecting interferon beta-1a manually or with autoinjector. In total, 1825 patients (autoinjector, 932; manual injection, 893) were included in the intention-to-treat analysis. Significantly fewer patients using the autoinjector experienced ISRs, based on physician assessment, compared with manual injection (78.7% versus 85.4%; P <0.001). There was no statistical difference on primary study endpoint: number of patients experiencing moderate to severe ISRs after 12 weeks' therapy (25.3% versus 23.2%, P =0.449). The patient-reported proportion of any ISR during the treatment period was significantly greater for the manual injection group (71.8% versus 66. 1%; P<0.001). The decreased incidence of ISRs with the autoinjector compared to manual injection seen in this short-term study, coupled with ease of use of the autoinjector, suggest that it could improve compliance, and therefore therapeutic outcomes in some patients.

Pregnancy outcomes during treatment with interferon beta-1a in patients with multiple sclerosis.

BACKGROUND: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. METHODS: We examined individual patient data from eight clinical trials with IFNbeta-1a. RESULTS: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy). CONCLUSIONS: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Exacerbation or unmasking of focal neurologic deficits by sedatives.

BACKGROUND: Transient focal neurologic deficits have been observed in patients emerging from brain tumor or carotid surgery, and a pharmacologic effect of anesthetic agents has been proposed as the cause of such neurologic dysfunction. Therefore, the effect of sedation with midazolam or fentanyl on motor neurologic function was studied prospectively and preoperatively in patients with carotid disease or mass lesions of the brain. METHODS: Fifty-four unpremedicated adult patients with carotid disease or a brain tumor were given small intravenous doses of either 2.8 +/- 1.3 mg midazolam or 170 +/- 60 micrograms fentanyl in the preoperative period. A thorough motor examination was performed at baseline and after sedation by an individual who was unaware of the details of the patient's disease or symptoms. A mental status examination also was performed to control for the effects of inattentiveness or lack of cooperation during the neurologic examination. RESULTS: Patients were sedated mildly but were fully cooperative. Focal motor deterioration occurred after sedation in 30% of patients, and the incidence was similar in patients in the fentanyl and midazolam groups. Among patients with a focal motor abnormality on baseline examination or a resolved prior motor deficit, 73% had exacerbation or unmasking of these signs by sedation, whereas no patient without a prior history of motor dysfunction had a sedative-induced change. Sedative-induced changes in neurologic function ranged from unilateral mild weakness to complete plegia, but appeared to be transient in nature. CONCLUSIONS: Sedation with midazolam or fentanyl can transiently exacerbate or unmask focal motor deficits in patients with prior motor dysfunction.

Preoperative cerebrovascular symptoms and electroencephalographic abnormalities do not predict cerebral ischemia during carotid endarterectomy.

BACKGROUND AND PURPOSE: The purpose of this prospective study was to establish (1) whether patients with neurological symptoms scheduled for carotid endarterectomy had an increased incidence of electroencephalographic (EEG) abnormalities during awake baseline recordings, (2) whether these symptoms and EEG abnormalities predicted ischemic EEG pattern changes at carotid artery cross-clamp, and (3) whether there was an association between age, presence of EEG baseline abnormalities, and ischemic pattern changes at carotid artery cross-clamp. METHODS: We reviewed the medical record of each patient scheduled to undergo carotid endarterectomy and recorded the patient's age and history of previous neurological symptoms. We then continuously monitored and analyzed 16 channels of anteroposterior bipolar EEG and two of referential derivations from at least 5 minutes before induction of anesthesia and throughout the operation. RESULTS: We completed 394 consecutive studies. Preoperative neurological symptoms were related to EEG abnormalities in awake patients (P < .001) and to EEG asymmetries in anesthetized patients (P < .001). Abnormal awake EEG findings were associated with asymmetries after anesthesia (P < .0001). Twenty-eight percent of both symptomatic (70/249) and asymptomatic (41/145) patients had EEG ischemic pattern changes at carotid artery cross-clamp. Neither neurological symptoms nor EEG abnormalities were associated with age or the development of EEG ischemic pattern changes at carotid artery cross-clamp. CONCLUSIONS: Despite the strong association between a history of cerebral ischemic symptoms and preoperative EEG abnormalities in patients undergoing carotid endarterectomy, patients who have suffered strokes or transient ischemic events are at no greater risk of having EEG evidence of cerebral ischemia during carotid artery cross-clamp than patients without symptoms and with normal baseline EEGs. We conclude that preoperative EEG abnormalities in symptomatic patients are not due to age or to insufficiency of regional cerebral blood flow.

Anterior communicating artery collateral flow protection against ischemic change during carotid endarterectomy.

The purpose of this study was to determine whether preoperative angiographic patterns of collateral cerebral blood flow correlate with protection against intraoperative electroencephalographic (EEG) evidence of cerebral ischemia caused by carotid artery cross-clamping during carotid endarterectomy. Previous studies have shown that contralateral carotid artery occlusion and intracranial stenoses are associated with cerebral ischemia during carotid endarterectomy; however, the angiographic collateral flow patterns associated with cerebral ischemia have not been identified. This paper reports a retrospective study of 67 patients who underwent two- to four-vessel cerebral angiography followed by carotid endarterectomy with 16-channel EEG monitoring. The angiograms were reviewed for extracranial occlusive disease and collateral flow patterns, and the EEG recordings were analyzed for ischemic changes during carotid artery cross-clamping. Statistical analysis was by Fisher's exact test. Cross-filling of the anterior and middle cerebral arteries from the contralateral carotid artery through the anterior communicating artery correlated with a decreased incidence of EEG ischemic changes. Only 21% of patients with this collateral flow pattern showed ischemic changes compared to 50% of patients without this pattern (p < 0.03). Three angiographic findings occurring in combination on the side contralateral to surgery correlated with EEG ischemia: 1) occlusion of the contralateral internal carotid artery (five of seven or 71%, p < 0.03); 2) collateral flow from the external carotid circulation to the internal carotid circulation via the ophthalmic artery; and 3) collateral flow from the posterior circulation to the contralateral anterior circulation via the posterior communicating artery. The data presented here corroborate the correlation between contralateral carotid artery occlusion and cerebral ischemia during carotid endarterectomy. They also demonstrate that cross-filling of the anterior and middle cerebral arteries by the contralateral carotid artery protects against such ischemia. This collateral flow may serve as an indicator of tolerance to carotid artery cross-clamping.

Loss of somatosensory evoked potentials during intramedullary spinal cord surgery predicts postoperative neurologic deficits in motor function [corrected].

STUDY OBJECTIVES: To estimate the sensitivity and specificity of somatosensory evoked potentials (SSEPs) for predicting new postoperative motor neurologic deficits during intramedullary spinal cord surgery; to establish whether SSEPs more accurately predicted postoperative deficits in position and vibration sense than in strength. DESIGN: Prospective open and retrospective study. SETTING: University-affiliated hospital. PATIENTS: 20 patients with intramedullary spinal cord tumors scheduled for surgery with intraoperative SSEPs. INTERVENTIONS: Median, ulnar, and tibial nerve cortical and subcortical SSEPs were recorded continuously. MEASUREMENTS AND MAIN RESULTS: Conventional intraoperative SSEP criteria considered indicative of neurologic injury were modified and defined as either the complete and permanent loss of the SSEP or the simultaneous amplitude reduction of 50% or greater in the nearest recording electrode rostral to the surgical site and 0.5 millisecond increase in the central latency. Our definition required confirmation of both amplitude and latency changes on a repeated average. All patients had 1 or more SSEPs, which were reproducible and sufficiently stable for analysis throughout the operation. Six patients developed new postoperative neurologic deficits. One had new motor deficits in an extremity from which no baseline SSEPs could be elicited. In each of the other 5 patients, significant SSEP changes preceded the postoperative motor deficits in the extremity or extremities monitored. In no patient without a new postoperative motor deficit was there a significant change in the SSEP. In only 2 of these 5 patients was there a documented postoperative loss or diminution in vibration or position sense. CONCLUSIONS: Intraoperative SSEP changes during intramedullary spinal cord surgery are a sensitive predictor of new postoperative motor deficits, but such changes may not correlate reliably with postoperative deficits in position or vibration sense. In this setting SSEP monitoring serves primarily to reassure the operating team that, when the SSEPs remain constant, the surgery has not caused additional injury.

Computer-derived density spectral array in detection of mild analog electroencephalographic ischemic pattern changes during carotid endarterectomy.

The purpose of this prospective study was twofold: 1) to determine the sensitivity and specificity of computer-derived density spectral array in detecting analog electroencephalographic (EEG) ischemic pattern changes during carotid artery cross-clamping in patients undergoing carotid endarterectomy; and 2) to assess the ability of density spectral array to identify such changes in comparison with the degree and type of change seen in the analog EEG ischemic pattern. Sixteen channels of anteroposterior bipolar and two to four channels of referential electroencephalography with four channels of density spectral array were monitored simultaneously during carotid endarterectomy in 103 patients under general anesthesia. Two "observers" interpreted the density spectral array and the analog electroencephalograms, one during and immediately after the operations and the other 6 months after completion of all surgery. Analyses were conducted to establish both the number of patients with analog EEG ischemic changes and the number of ischemia events during carotid artery cross-clamping. Observer A indicated that the density spectral array identified analog EEG ischemic changes in 21 of 29 patients, for a sensitivity of 72% (specificity 99%), whereas Observer B's results showed that the density spectral array identified analog EEG ischemic changes in 16 of 27 patients, for a sensitivity of 59% (specificity 96%). Density spectral array detection of analog EEG ischemic changes based on severity classifications were 61% and 18% in the mild group, 70% and 71% in the moderate group, and 95% in the severe group, indicating a relationship between density spectral array sensitivity and severity of analog EEG ischemic change, with p = 0.02 and p = 0.004 for the two observers. The kappa statistics for observer reproducibility were highly significant, with k = 0.95 for analog EEG ischemic changes and 0.85 for density spectral array changes. It is concluded that density spectral array does not reliably detect mild analog EEG pattern changes of cerebral ischemia and is not a reliable substitute for 16-channel analog EEG monitoring of cerebral ischemia during carotid endarterectomy.

An antispasticity effect of threonine in multiple sclerosis.

To determine whether the naturally occurring amino acid threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a randomized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a non-sedating, nontoxic approach to the management of spasticity in multiple sclerosis.