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Objective: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments., Methods: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive., Results: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%])., Conclusion: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis., Classification of Evidence: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed. On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A). The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U). Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U). There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C). The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.

Objective: To review the use of transcranial Doppler ultrasonography (TCD) and transcranial color-coded sonography (TCCS) for diagnosis., Methods: The authors searched the literature for evidence of 1) if TCD provides useful information in specific clinical settings; 2) if using this information improves clinical decision making, as reflected by improved patient outcomes; and 3) if TCD is preferable to other diagnostic tests in these clinical situations., Results: TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk (Type A, Class I) and the detection and monitoring of angiographic vasospasm after spontaneous subarachnoid hemorrhage (Type A, Class I to II). TCD and TCCS provide important information and may have value for detection of intracranial steno-occlusive disease (Type B, Class II to III), vasomotor reactivity testing (Type B, Class II to III), detection of cerebral circulatory arrest/brain death (Type A, Class II), monitoring carotid endarterectomy (Type B, Class II to III), monitoring cerebral thrombolysis (Type B, Class II to III), and monitoring coronary artery bypass graft operations (Type B to C, Class II to III). Contrast-enhanced TCD/TCCS can also provide useful information in right-to-left cardiac/extracardiac shunts (Type A, Class II), intracranial occlusive disease (Type B, Class II to IV), and hemorrhagic cerebrovascular disease (Type B, Class II to IV), although other techniques may be preferable in these settings.

To determine which patients are prone to side effects from interferon beta-1b and which side effects are most troublesome, we studied 72 patients with clinically definite MS who were started on interferon beta-1b after its release and found that the side effects significantly associated with treatment included skin reactions, flu-like symptoms, fatigue, leukopenia, new or worsened depression, and new or worsened headache. Of these, only fatigue and depression were significantly associated with discontinuance of therapy. Moreover, the course of disease before initiation of treatment also had a significant impact on the likelihood of discontinuing medication. Thus, despite an apparently similar therapeutic benefit (as judged by the similarly reduced attack rate in each group), patients with a secondary chronic progressive course were more likely to discontinue treatment (63%) than patients with either a relapsing/progressive course (18%) or a remitting/relapsing course (7%). Indeed, in the final regression equation, the only factors significantly related (r = 0.875) to the discontinuance of therapy were fatigue (p < 0.0001), a fatigue-depression interaction (p < 0.0001), and a chronic progressive course of disease (p<0.0001). Thus, if future clinical trials are to provide useful information on the value of interferon beta-1b in progressive MS, the side effects of fatigue and depression will need to be ameliorated to limit the drop-out rate from such trials.

There are conflicting reports concerning attenuation of the frontal N30 component of the median-derived somatosensory evoked potential in patients with Parkinson's disease (PD). We found that the mean N30 latency (28.03 +/- 2.50 msec) and amplitude (2.30 +/- 1.58 microV) obtained with stimulation of the affected arm of 10 patients with predominantly unilateral PD were not significantly different from those obtained from the unaffected arm (mean latency, 28.14 +/- 2.47 msec; mean amplitude, 2.43 +/- 1.65 microV) or from 10 age-matched controls (mean latency, 29.01 +/- 1.88 msec; mean amplitude, 1.92 +/- 0.64 microV). Three patients had an N30 of abnormal amplitude; in two, responses were absent with stimulation of either side, and in one there was a response asymmetry exceeding the normal range, with the smaller response elicited from the affected arm. Thus, only one of 10 patients had a diminished N30 consistent with the clinical findings. We conclude that the N30 is unlikely to be clinically useful in the assessment of patients with PD.

We investigated the relationship between sensory discrimination and the selection of appropriate responses in subjects performing two different reaction-time tasks, in which three auditory stimuli were presented in random order and with a different likelihood of occurrence. Subjects anticipated the need to make different responses based on the likelihood that a particular stimulus would occur on a particular trial. This was determined by the occurrence and distribution of premovement potentials prior to the stimulus, which were consistent with preparation to respond to the most frequently occurring stimulus. These anticipatory cerebral events, however, could be altered after recognition that this frequent stimulus had not occurred. Thus, after the occurrence of a stimulus other than the anticipated frequent tone, the scalp distribution of cerebral potentials changed in a manner suggesting that the next most frequently occurring stimulus was anticipated. Nonetheless, subjects were able to respond to the least probable stimulus both accurately and rapidly despite a failure to anticipate it correctly, as judged by the cerebral "lateralized readiness potential." These results indicate that stimulus evaluation and response selection are integrated and dynamic cerebral processes, and raise doubt about the functional significance of the so-called premovement readiness potential.

We compared the diagnostic utility of EMG, F wave and H-reflex studies, and peroneal and dermatomal SEPs in evaluating 28 patients with clinically unequivocal L-5 or S-1 compressive root lesions. The single most useful electrophysiologic technique was EMG, which often provided evidence of denervation in a myotomal pattern when other electrophysiologic findings were normal. We found abnormal late responses in 14 patients, but always in association with EMG abnormalities. Peroneal-derived SEPs were always normal. Dermatomal SEPs confirmed the diagnosis in seven patients, including two in whom other electrophysiologic studies were normal.

We examined the cassette-recorded 24-hour ambulatory EEG findings in children who had either clinically definite seizures or episodic behavioral disturbances not regarded as epileptic on clinical grounds. Among 40 epileptic patients, 22 had one or more attacks during the 24-hour recording session. In 15 of these patients all clinical attacks had appropriate ictal electrographic accompaniments; in another 6 some (but not all) attacks did so. Among 55 children with nonepileptic spells clinically, the 24-hour recording was uninterpretable for technical reasons in one, and in 30 it provided no relevant information because there were no recorded clinical or electrographic attacks. In the remaining 24 patients, one or more clinical attacks were captured, and in no instance was there any accompanying electrographic change. Our findings indicate that the absence of ictal EEG changes during attacks cannot be used in isolation to make a diagnosis of pseudoseizures, but support such a diagnosis made on clinical grounds. The more important role of the ambulatory EEG is to exclude a diagnosis of nonepileptic attacks by demonstrating electrographic seizure activity accompanying typical clinical attacks. Whether the technique will have a useful role in the evaluation of patients when the nature of an episodic disturbance of cerebral function is unclear clinically remains to be established, but will require long-term follow-up to validate any conclusions reached by the electrophysiologic technique.

Stimulus-related and event-related components of the visual evoked potential were recorded in three separate tasks that required language comprehension or spatial discrimination. Task-dependent asymmetries in the evoked potential were found for both the language task and one of the tasks involving spatial discrimination. Moreover, an identical stimulus presented in two different contexts elicited potentials with a significantly different distribution over the two sides of the head. These asymmetries were largely confined to the event-related components and presumably reflect task-dependent differences in neural processing. Reaction-time studies for these tasks, however, indicated that these asymmetries occurred too late to arise from neural structures responsible for language comprehension or spatial discrimination per se, and must therefore reflect subsequent neural events.