Auditory brainstem responses in postconcussion syndrome.

Evidence that head injuries can shear nerve fibers and end bulbs in the tracts between the diencephalon and brainstem led us to hypothesize that auditory brainstem responses might be abnormal in patients with postconcussion syndrome. We recorded brainstem responses in 11 patients and 12 control subjects. Comparing the two populations, our chief finding was that the patients showed significant delays for wave 3. This finding indicates organic changes involving a region at least as central as the superior olivary complex, thus refuting many authors' claims that the syndrome is entirely psychogenic.

Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis.

BACKGROUND: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). OBJECTIVE: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. DESIGN AND METHODS: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. RESULTS: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). CONCLUSIONS: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Correlates of brain-stem oculomotor disorders in multiple sclerosis. Magnetic resonance imaging.

Three patients with focal brain-stem oculomotor disturbances (nuclear sixth nerve syndrome, sixth nerve palsy, bilateral internuclear ophthalmoplegia) as a consequence of multiple sclerosis have been studied with high-volume delayed computed tomography and high-field magnetic resonance imaging. In all of them, high-volume delayed computed tomography was inconclusive in the brain stem, but magnetic resonance imaging showed an area of prolonged T1 and/or T2 in the region appropriate to the oculomotor findings. Magnetic resonance imaging is the imaging technique of choice of small plaques in the brain stem. It can considerably aid clinicotopographic correlation in multiple sclerosis.

NMR studies in experimental allergic encephalomyelitis (EAE): normalization of T1 and T2 with parenchymal cellular infiltration.

The central nervous system (CNS) of guinea pigs undergoing acute experimental allergic encephalomyelitis (EAE) induced by whole CNS shows a characteristic progression of proton NMR relaxation times that correlates with pathologic features of the disease. Specifically, T1 was prolonged during meningeal infiltration and perivascular inflammation. T2 was increased with demyelination. Both proton T1 and T2 values, however, were normalized in active lesions containing an extensive cellular response (encephalitis, myelitis).

A referendum on clinical trial research in multiple sclerosis: the opinion of the participants at the Jekyll Island workshop.

Sixty-two experienced multiple sclerosis (MS) investigators attending a research workshop were asked their opinions about clinical trial design, outcome measures, and treatment. Respondents favored repeated clinical observations of neurologic function (eg, Expanded Disability Status Scale or Ambulation Index) over the opinion of a blinded physician and changes on magnetic resonance imaging. There was agreement that stable MS should not be treated with immunosuppressives. Corticosteroids were rated the most effective treatment for recent disease activity. Total lymphoid irradiation and immunosuppressives were judged more potent for the long-term management of progressive disease. No treatment, however, received the support of more than 11% of the respondents for being of "considerable efficacy" in the long-term management of MS. Most favored a placebo-controlled design in future trials. In order to judge the acceptability of current trial design, participants were asked to act as patient surrogates and to indicate whether they would agree to participate in 4 randomized trials for which they would be eligible. The majority consented to participate in the 3 major trials currently under way, and most refused to enroll in the 1 trial that had never been initiated.

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography.

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.

Torsional nystagmus: quantitative features and possible pathogenesis.

We measured eye rotations in three planes in a patient with acquired, torsional nystagmus. This nystagmus had linear or increasing-velocity waveforms, was increased after active pitch rotations of the head, and was suppressed by convergence. Magnetic resonance imaging demonstrated a midpontine lesion that was probably a venous angioma. We postulate that torsional nystagmus in this patient was due to disruption of central vestibular connections.

The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial.

In the randomized, placebo-controlled, physician-blinded Canadian cooperative trial of cyclophosphamide and plasma exchange, neither active treatment regimens (group I: i.v. cyclophosphamide and prednisone; group II: weekly plasma exchange, oral cyclophosphamide, and prednisone) were superior to placebo (group III: sham plasma exchange and placebo medications) using the blinded, evaluating neurologists' assessments of disease course (primary analysis). All patients were examined by both a blinded and an unblinded neurologist at each assessment in this trial. We compared the blinded and unblinded neurologists' judgment of treatment response and analyzed the clinical behavior of patients who correctly guessed their treatment. The unblinded (but not the blinded) neurologists' scores demonstrated an apparent treatment benefit at 6, 12, and 24 months for the group II patients (not group I or placebo; p < 0.05, two-tailed). There were no significant differences in the time to treatment failure or in the proportions of patients improved, stable, or worse between the group II and group III patients who correctly guessed their treatment assignments and those who did not. Physician blinding prevented an erroneous conclusion about treatment efficacy (false positive, type 1 error).

Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. The Canadian Cooperation MS Study Group.

We describe the interrater variability in the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Two physicians blinded to their previous assessments and to each other's scores consecutively examined 168 patients (545 paired examinations). Perfect agreement on the assignment of the disability scores ranged from 48% (cerebellar functional group) to 69% (EDSS and pyramidal functional group). Only 31% to 62% of this agreement occurred independently of that expected by chance (kappa). With the exception of the cerebellar and sensory functional groups, agreement within 1 step occurred in at least 92% of cases. These findings suggest that differences of a single step on these scales may not reflect an important functional change. We recommend that at least a 2-step change (1.0 point on the EDSS and 2 points on the FS) is needed to be confident of an important change in the degree of disability or response to treatment in this disease.

Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double-blind study.

We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 "booster" treatments in the next 6 months; 41 control patients received "air" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.

Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators.

OBJECTIVE: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of >/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score /= 0.5 point for an enrollment EDSS score of >/= 5.5) not associated with an acute relapse. RESULTS: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). CONCLUSION: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators.

OBJECTIVE: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. BACKGROUND: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. METHODS: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. RESULTS: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as "black holes," and by a novel MRI composite disease measure. CONCLUSIONS: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Oligoclonal bands in multiple sclerosis: clinical-pathologic correlation.

Although oligoclonal banding is a characteristic feature of MS spinal fluid, some patients do not show this abnormality. Four of 18 consecutive patients with autopsy-proven MS had no oligoclonal bands (OB) in CSF during life or at postmortem. Patients with OB had numerous plasma cells in meninges and plaques (confirmed in sections stained for cytoplasmic immunoglobulin). The four patients without bands had few or no identifiable plasma cells. Therefore, lack of OB correlates with both inactivity of plaques and absence of plasma cells in plaques or meninges. This is another form of heterogeneity in MS.

An open-trial evaluation of mitoxantrone in the treatment of progressive MS.

We treated 13 patients with progressive MS with mitoxantrone. All patients received a standard IV dose of mitoxantrone (8 mg/m2) every 3 weeks for a total of seven infusions, with dosage adjustments depending on the hematologic profile at the nadir. The treatment was well tolerated, with the most common side effect being mild nausea. Four of seven women developed transient secondary amenorrhea. The postenrollment clinical behavior of these patients was generally more favorable than during the 18 months prior to enrollment (only three of 13 patients developed an increase in the Expanded Disability Status Scale of more than 0.5 points), suggesting a possible treatment effect, but comparison with two historical control groups (both the active and placebo groups from the Canadian Cooperative Trial of Cyclophosphamide and Plasma Exchange) does not suggest that mitoxantrone was efficacious. Eight of 12 patients had evidence of MRI activity on 13 of 29 follow-up visits. This small, open-labeled pilot study did not provide strong support for proceeding with a randomized, controlled trial of this dosage regimen of mitoxantrone in patients with progressive MS.

IV immunoglobulin does not reverse established weakness in MS.

BACKGROUND: Immunoglobulin (Ig) administration induces remyelination in the Theiler's virus model of MS. METHODS: A randomized, double-blinded, placebo-controlled trial of IV immunoglobulin (IVIg) was performed in patients with MS who had persistent muscle weakness that had been stable for between 4 and 18 months to determine whether this would improve muscle strength (primary outcome: isometric muscle strength). Patients received either IVIg (0.4 g/kg) or placebo daily for 5 days, then single infusions every 2 weeks for 3 months (total, 11 infusions). Muscle groups identified by clinical measures to have unchanging significant weakness were the major targets for therapeutic response (targeted neurologic deficit [TND]). RESULTS: IVIg was well tolerated. An interim analysis after 67 patients were enrolled indicated no difference in the degree of change in strength between treatment groups in either the TND or non-TND muscle groups at 6 months, and the trial was terminated. There was no apparent benefit in relapse behavior or impairment measures during the 6-month observation period. Nor was there apparent benefit in either patients who remained clinically stable or in those with evidence of disease activity. Patients with active MS during the trial worsened in both TND and non-TND muscle groups. This worsening was seen regardless of whether the clinical manifestations of disease activity involved the TND muscle groups. CONCLUSIONS: IVIg does not reverse established weakness in MS. Measurements of isometric muscle strength were reliable (reproducible) indices of strength and may be sensitive, objective methods to document functional changes in impairment in future MS trials.

The Mayo Clinic-Canadian Cooperative trial of sulfasalazine in active multiple sclerosis.

OBJECTIVE: To determine whether sulfasalazine is better than placebo in slowing disability progression in MS. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 199 patients with active relapsing-remitting (n = 151) or progressive (n = 48) MS were evaluated at 3-month intervals for a minimum of 3 years (94% completed 3 years of follow-up; mean follow-up, 3.7 years). MRI studies were performed at 6-month intervals on a subset of 89 patients. RESULTS: Sulfasalazine failed to slow or prevent disability progression as measured by the primary outcome (confirmed worsening of the Expanded Disability Status Scale [EDSS] score by at least 1.0 point on two consecutive 3-month visits). Sulfasalazine influenced favorably a number of secondary outcomes during the first 18 months of the trial (e.g., annualized relapse rate, proportion of relapse-free patients; progressive subgroup only: rate of EDSS progression at 1 and 2 years, median time to EDSS progression) but these positive findings were not sustained into the second half of the trial. CONCLUSIONS: Sulfasalazine does not prevent EDSS score progression in the subset of MS patients studied by this protocol. Treatments may improve relapse-related outcomes in MS, at least temporarily, without providing sustained slowing of EDSS progression. Phase III MS trials should be of sufficient length to determine a meaningful impact on disease course.

A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis.

OBJECTIVE: To determine whether IV immunoglobulin (IVIg) reverses chronic visual impairment in MS patients with optic neuritis (ON). METHODS: In this double-blind, placebo-controlled Phase II trial, 55 patients with persistent acuity loss after ON were randomized to receive either IVIg 0.4 g/kg daily for 5 days followed by three single infusions monthly for 3 months, or placebo. RESULTS: The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled. Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up. Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR visual scores at 6 months (p = 0.766). Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable MS during the trial. CONCLUSIONS: IVIg administration does not reverse persistent visual loss from ON to a degree that merits general use.

Value of magnetic resonance imaging in assessing efficacy in clinical trials of multiple sclerosis therapies.

Magnetic resonance imaging (MRI) has become an important technique for monitoring the effectiveness of putative treatments for multiple sclerosis (MS) because of its high sensitivity, objectivity, and noninvasive nature. Its importance as a surrogate measure of disease, however, is an issue that is more difficult to validate than might seem to be the case. In this review, we describe the role of MRI in the assessment of putative therapies for MS. New magnetic resonance techniques and methods of image analyses aimed at better demonstrating the nature and extent of disease are discussed, and the role of MRI in published MS therapeutic trials is examined. MRI is a frequently used secondary outcome measure for putative treatment strategies for MS. Although it is sensitive to changes in the inflammatory component of the MS disease process, poor correlation has been noted between MRI findings and long-term patient outcome. There is a widespread expectation that new magnetic resonance techniques--such as fluid-attenuated inversion recovery, magnetization transfer imaging, and magnetic resonance spectroscopy--will ultimately be useful for characterization of pathologic changes within the MS lesion and more generally of the MS disease process. Whether magnetic resonance changes seen in experimental therapies predict the long-term clinical course of the disease remains to be determined.

Clinical outcome measures and rating scales in multiple sclerosis trials.

In this review, we analyzed clinical outcome measures used in multiple sclerosis (MS) clinical trials in which the primary goal is to slow or arrest progression of disease. In addition, we examined rating scales that quantify symptomatic complications of MS (for example, spasticity) and the current role of magnetic resonance imaging in MS treatment trials. Each proposed scale has advantages and deficiencies, and none meets all the criteria for an ideal outcome measure. The validity of trial design may be improved by using combinations of selected components of current scales as well as new instruments targeted to specific variables (such as motor strength). Symptom-specific rating scales are most appropriately used in trials of symptomatic therapeutic strategies for MS. Until serial magnetic resonance imaging changes are definitely known to predict long-term impairment and disability in patients with MS, clinical outcome measures will remain the primary means of assessing therapeutic efficacy in phase III clinical trials.

Rational clinical immunotherapy for multiple sclerosis.

In this article, we assess the roles and the efficacy of immunopharmacologic agents in the treatment of multiple sclerosis (MS) and other demyelinating disease syndromes. The initial clinical manifestations of demyelinating disease, immunotherapeutic goals, efficacy of individual agents, and specific immunopharmacologic recommendations are discussed. MS and other idiopathic demyelinating disease syndromes can be effectively managed with immunotherapy. Exacerbations are treatable, and the frequency and severity of exacerbations can be reduced. Although some agents have a minor effect on progression of disability, current approaches have not proved to have a major influence on treatment of progressive MS. Immunotherapy for inflammatory demyelinating disease necessitates a high degree of clinical certainty about the diagnosis. Because all available therapeutic agents have limitations and significant toxic effects, careful consideration is necessary before use. Treatment should be individualized on the basis of the clinical course of the disease and the degree of patient disability.