The coexistence of tics and dystonia.

We studied nine patients with motor and phonic tics and other features of Tourette's syndrome, who developed persistent dystonia in addition to their tics. All, except one, were males (mean age, 35.8 years; range, 8 to 59 years), and had onset of tics prior to age 18 years (mean age, 9 years; range, 1.5 to 17 years). None of the patients were treated with neuroleptic drugs prior to the onset of dystonia. Torticollis and blepharospasm were the most common forms of dystonia. Seven patients had a history of tics in first degree relatives. While these patients were seen in a specialized movement disorder clinic and may, therefore, represent a population with atypical and more severe symptoms, the high prevalence rate of dystonia (5.0% of all patients with Tourette's syndrome seen in the clinic) suggests that some patients with tics may have an increased risk for dystonia.

Clinical safety of serial monthly administrations of gadopentetate dimeglumine in patients with multiple sclerosis: implications for natural history and early-phase treatment trials.

Serial contrast magnetic resonance imaging (MRI) has played an increasingly important role in understanding natural-history and early-treatment trials of multiple sclerosis patients. The purpose of this study is to determine whether the serial administration of gadopentetate dimeglumine at the conventional dose has any demonstrable effect on routine hematologic or serum chemistries. This study followed 56 patients with multiple sclerosis in a longitudinal natural-history trial using contrast-enhanced MRI scans over a four-year period between 1988 and 1993. Patients received between 3 and 53 doses of gadopentetate dimeglumine at 0.1 mmol/kg intravenously. A retrospective review of regular blood screening tests over this period identified no significant effect either on routine hematologic studies, as defined by complete blood count (hemoglobin, hematocrit, platelet and white blood cell counts, and mean corpuscular volume); standard serum chemistry studies, including electrolytes (sodium, potassium, chloride) and renal and liver function tests; or serum iron profiles. We conclude, therefore, that serial contrast-enhanced MRIs can be used safely as an outcome measure for Phase I/II evaluations of new therapies for multiple sclerosis.

Interferon beta results in immediate reduction of contrast-enhanced MRI lesions in multiple sclerosis patients followed by weekly MRI.

Interferon beta-1a and -1b reduce the frequency and severity of clinical exacerbations, and reduce both T2-weighted and contrast-enhanced MRI activity in patients with multiple sclerosis (MS). Several recent reports suggest that at the initiation of treatment there may be transient worsening of symptoms associated with the induction of interferon gamma-secreting cells. We studied eight MS patients with weekly brain MRI's after starting interferon beta treatment, and found immediate reduction in the number of contrast-enhancing lesions. Several patients did experience recurrence of previous symptoms without concomitant opening of the blood brain barrier on contrast-enhanced MRI. These data suggest that the symptoms described after the initiation of interferon beta are not associated with new disease activity, but rather may be related to preexisting lesions. This has implications for both understanding the immunopathogenesis of the disease and for its treatment.

A safety and pharmacokinetic study of intravenous natalizumab in patients with MS.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

Characterization of MRI response to treatment with interferon beta-1b: contrast-enhancing MRI lesion frequency as a primary outcome measure.

MRI is a valuable tool to examine the pathophysiology and natural history of multiple sclerosis (MS), and several large multicenter trials have utilized MRI as a secondary outcome measures. We previously examined the effect of interferon beta-1b on contrast-enhancing lesions on MRI using a baseline versus treatment design, and found that on treatment there is a reduction in mean frequency of enhancing lesions over the group. Using an expanded number of patients and the same trial design, we examined the individual response to treatment more extensively. We find that the effect seen previously is still present, and that there is heterogeneity in the amount of decrease in contrast-enhancing lesions. This expanded number of patients and trial design allows for the discussion of new criteria for individual response to treatment, which are applied in the current trial. These approaches may be useful in the examination, early testing, and comparison of experimental therapeutic agents in MS as well as in the characterization of patients who do or do not have a response seen on MRI.

Changes in the amount of diseased white matter over time in patients with relapsing-remitting multiple sclerosis.

MRI is a sensitive technique for assessing disease activity in MS. Diseased white matter (WM) can be identified on T2-weighted images, and active disease is reflected by abnormalities in the blood-brain barrier (BBB) shown on T1-weighted images after administration of paramagnetic contrast agents. Active disease may be demonstrated by contrast-enhanced MRI in patients with early, mild relapsing-remitting (RR) MS even during periods of clinical stability, which indicates that MS is an active process even during the early phase of the illness. To examine the amount of abnormal WM at frequent intervals over time, we studied seven mildly affected RRMS patients, all of whom had frequent contrast-enhancing lesions. These RRMS patients were imaged monthly for 26 to 36 months at 1.5 tesla; the area of abnormal increased WM signal was calculated by image-processing software that utilizes both the T2- and T1-weighted images. All patients showed fluctuations over time in amount of abnormal WM signal, which reflected factors such as the amount of BBB breakdown (measured by number or area of enhancing lesions) and measurement error. All seven RRMS patients, however, showed an overall increase in abnormal WM. Because of the fluctuations between individual measurements, the increase was most accurately reflected when the mean of the first 6 months' measurements was compared with the mean of the final 6 months' measurements, or when a linear regression model was applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: relationship to course, gender, and age.

MRI has provided insight into the pathophysiology and course of MS, particularly through the use of a paramagnetic contrast agent that allows visualization of blood-brain barrier (BBB) breakdown. Neither the overall frequency of BBB breakdown in MS patients nor the characteristics associated with BBB breakdown in MS are known. We studied 68 relapsing-remitting MS (RRMS) patients with three monthly MRIs to examine these questions. Seventy-eight percent of the RRMS patients studied had evidence of BBB breakdown on at least one MRI. While there was a great deal of variability among patients in terms of mean enhancing lesion frequency, BBB breakdown was associated with younger age at onset of disease, measured by age at first symptom or age at diagnosis, and more severe disease as measured by Expanded Disability Status Scale scores equal to or greater than 4.0. We found no relationship between BBB breakdown and duration of disease or gender. We conclude that BBB breakdown is a relatively common phenomenon in RRMS patients and may be most commonly found in patients with more aggressive disease and younger onset. These findings have implications for clinical trials that use MRI as an outcome measure.

Expression pattern of activation and adhesion molecules on peripheral blood CD4+ T-lymphocytes in relapsing-remitting multiple sclerosis patients: a serial analysis.

We studied the expression of various cell surface molecules (CD25, CD28, CD29, CD45RO, CD56, LFA-1, VLA-4) on peripheral blood CD4+ T-cells in 6 relapsing-remitting multiple sclerosis (RR-MS) patients. Furthermore, changes in the expression pattern of these surface markers during intervals of increased disease activity, which was measured by gadolinium (Gd-DTPA) magnetic resonance imaging (MRI) were examined. Although several patients showed signs of increased disease activity during the observation period, this was not paralleled by a relevant change in the expression of these activation and adhesion molecules.

Effect of technique variation on sensory nerve conduction characteristics.

The impact of technique variation on the wave-form characteristics of the evoked sensory potential was determined from the median and ulnar nerves of healthy subjects. The conduction characteristics of latency, amplitude, and duration were determined for orthodromic and antidromic techniques of stimulation as measured under each of three recording modes: 1) single evoked response, 2) superimposition, and 3) electronic averaging. Variation in the technique of stimulation significantly affected each of the three wave-form characteristics. Peak latency and duration of the evoked sensory potential were longer in antidromic stimulation. The amplitude of the sensory potential varied significantly with both recording and stimulating techniques. The amplitude of the sensory response was larger in antidromic stimulation than in orthodromic stimulation and also was found to be smaller with electronic averaging than with the other recording modes in both antidromic and orthodromic conduction techniques. This degree of variation requires that standardized techniques of methodology be established with the development of normal values for the particular laboratory.

Multidimensional scaling of pictorial informativeness.

The dimensions used in the judgment of the informativeness of picture sections were investigated by means of a recently proposed methodology, multidimensional similarity analysis. 10 judges (college students) rated the informational similarity of 32 areas within a single picture. The five extracted dimensions accounted for 86% of the judgmental variance and were all readily interpretable. These dimensions were discussed with respect to an earlier study in which eye movements of subjects viewing this picture were recorded.

Sensorimotor cortex gamma-aminobutyric acid concentration correlates with impaired performance in patients with MS.

BACKGROUND AND PURPOSE: Abnormalities in GABA concentration [GABA] have been associated with several neuropsychiatric disorders, and research has suggested that GABA may play a role in sensorimotor cortex function. We sought to determine whether identifying a change in [GABA] within the sensorimotor cortex of patients with MS has any effect on motor function and would provide information about the adaptive/compensatory mechanisms involved in the attempt to maintain motor function during disease progression. MATERIALS AND METHODS: In 19 healthy controls and 30 patients with MS, we assessed task performance with the MS Functional Composite scale and its components (T25FW test, 9HPT, and PASAT). With in vivo MR spectroscopy, we measured [GABA] in the sensorimotor cortex and determined correlations between [GABA] and task performance. We also assessed the association between [GABA] and cortical activation volume after a bilateral finger-tapping task. RESULTS: [GABA] was inversely correlated with 9HPT scores in patients with MS, indicating a worsening of performance with increased [GABA]. No significant correlation was observed between [GABA] and T25FW or PASAT scores. [GABA] was directly correlated with primary motor cortex activation volume after the finger-tapping task in patients with MS. CONCLUSIONS: These results suggest that cortical [GABA] may be a marker of function and reorganization/adaptation of cortical gray matter in MS.