Predictive value of lesions for relapses in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Recent studies have suggested that enhancing lesions on contrast-enhanced T1-weighted MR images are predictive of impending exacerbations in cases of relapsing-remitting multiple sclerosis. We examined whether enhancing lesions, new enhancing lesions, and new hypointense lesions ("black holes") could accurately predict exacerbations in a cohort of 50 patients with relapsing-remitting multiple sclerosis within a time frame of up to 6 months. METHODS: Data were obtained from 50 patients with relapsing-remitting disease. All patients underwent monthly MR imaging and clinical examinations for a period of 12 months. Putative predictors of clinical relapse were defined from enhancing lesions, new enhancing lesions, and new black hole outcomes, and their operating characteristics were studied. RESULTS: Overall, the positive predictive values (PV+) of enhancing lesions, new enhancing lesions, or new black holes for an exacerbation did not exceed 0.25 and the negative predictive values (PV-) were all near 0.9. The best predictor for new enhancing lesions was the occurrence of new enhancing lesions in each of the previous 3 months (PV+: 0.79 [95% confidence interval, 0.651-0.900]; PV-: 0.83 [95% confidence interval, 0.751-0.887]). Similarly, new black holes were predicted best by the occurrence of new black holes in each of the previous 2 months (PV+: 0.54 [95% confidence interval: 0.372-0.697]; PV-: 0.85 [95% confidence interval, 0.790-0.896]). CONCLUSION: None of the MR markers could predict an impending relapse with any reasonable degree of precision. Rather, the absence of MR markers is associated with a more favorable clinical course (ie, fewer relapses).

New hypointense lesions on MRI in relapsing-remitting multiple sclerosis patients.

BACKGROUND: Preliminary observational studies with multiple sclerosis (MS) patients have reported strong correlations between an increase in hypointense lesion load (black holes) on T1-weighted spin echo images, and an increase in disability. OBJECTIVE: We assessed the relationship of hypointense lesions to the clinical course of disease among 50 relapsing-remitting MS patients in the controlled setting of a randomized clinical trial. METHODS: Fifty patients with relapsing-remitting disease were enrolled in a randomized double-blind two-arm (cladribine vs. placebo) clinical trial of 1-year duration. All patients had monthly clinical evaluations and MRIs over the course of the trial. Multivariate techniques were used to identify predictors of clinical severity from information on exacerbations, MRIs, baseline clinical parameters, and demographics. RESULTS: At baseline, clinical severity is weakly related to counts of black holes, with rank correlations between counts and clinical scores (EDSS and SNRS) of absolute magnitude 0.3. Rates of appearance of new black holes over the course of the trial are higher for patients with more severe disease at baseline (EDSS > or = 4) than for the less severe patients. Changes in clinical severity over the course of the trial are best predicted by baseline neurologic scores and numbers of exacerbations, with black holes adding no further improvement in prediction. CONCLUSIONS: Numbers of exacerbations seem more critical to short-term clinical outcomes in relapsing-remitting MS, as reflected by patients' clinical scores, rather than black holes. Various imaging methods and MRI indices capture complementary information relating to MS disease processes. The determination of which processes are affected by different drugs should lead to more effective treatment of MS patients.

Responsiveness of the Scripps neurologic rating scale during a multiple sclerosis clinical trial.

OBJECTIVE: The Scripps neurologic rating scale (SNRS) is a summary measure of individual components comprising a neurological examination, designed for use in multiple sclerosis (MS). Our objective is to evaluate the responsiveness of the SNRS, within the context of a 2-year, randomized, double-blind crossover study of the efficacy of cladribine for treatment of secondary progressive MS. METHODS: Effect sizes were determined for the SNRS and its components, separately for each treatment group (initial placebo, and initial cladribine) over both years of the clinical trial, using a standard random effects model. RESULTS: Individual components tended to show positive effect sizes (improvement) during periods of active therapy in both treatment groups, and negative effect sizes (deterioration) during periods of no active therapy. Summation indices derived from the individual components of the SNRS seemed somewhat more stable than the individual components. The two components mentation and mood, and bladder, bowel, or sexual dysfunction, were rather unresponsive in our clinical trial. CONCLUSIONS: Changes in the components of the SNRS over the course of our clinical trial were consistent between the two treatment groups. Most components were moderately responsive; and, the summary SNRS score appropriately summarized the moderate magnitudes of change evinced in the individual components.

Hypointense and hyperintense lesions on magnetic resonance imaging in secondary-progressive MS patients.

Cranial magnetic resonance imaging (MRI) is widely used to monitor disease activity in clinical trials in multiple sclerosis (MS). The purpose of this study is to examine lesion burden as determined from hypointense regions on postcontrast T1-weighted scans (or black holes), and lesion burden on conventional T2-weighted scans, from a cohort of secondary progressive MS patients who participated in a placebo-controlled, randomized, double-blind cross-over trial assessing the therapeutic efficacy of cladribine. T2 lesion volumes and black hole volumes are approximately normal distributed when log-transformed, and are highly correlated (adjusted R2 = 0.63). Changes in clinical scores could be predicted with a reasonable degree of precision from baseline scores and changes in T2 lesion volumes (adjusted R2 values 0.52-0.7). Stratification schemes for clinical trials should include the acute proportion of the disease (enhancing T1 lesions), degree of permanent damage (black holes), and T2 lesion volume.

A double-blind, placebo-controlled, randomized trial of cladribine in relapsing-remitting multiple sclerosis.

We conducted an 18-month, placebo-controlled, double-blind study to evaluate cladribine in the treatment of 52 patients with relapsing-remitting multiple sclerosis. Patients received either placebo or cladribine 0.07 mg/kg/day by subcutaneous injection for 5 consecutive days as six monthly courses for a total cumulative dose of 2.1 mg/kg. Analysis of results revealed a statistically significant favorable effect of cladribine on the joint frequency and severity of relapses and magnetic resonance imaging (MRI) findings. MRI-enhancing lesions were completely suppressed in the cladribine patients by the sixth month of treatment. Mild segmental herpes zoster occurred in two cladribine-treated patients and one patient receiving placebo. Otherwise, there were no side effects or adverse events. We conclude that cladribine shows promise as a treatment for relapsing-remitting multiple sclerosis.

Cladribine.

Cladribine is a novel drug that selectively depletes lymphocytes and may be able to destroy the activated immunocytes that damage the central nervous system in multiple sclerosis. Our initial controlled studies have shown a beneficial, although temporary, dose-related effect of cladribine on the course of chronic progressive multiple sclerosis. Peak improvement in median Scripps Neurological Rating Scale (SNRS) neurological performance scores, followed by gradual decline, occurred at month 14 after initiation of treatment with a 2.8 mg/kg total dose and at month 7 after initiation of treatment with a 1.4 mg/kg total dose. A marked decrease in the presence of enhanced magnetic resonance imaging lesions was observed at both dose levels. Adverse effects are also dose-related. Mild segmental herpes zoster or transient marrow suppression occurred in some patients treated at the higher total dose, whereas no problems of this kind were observed at the lower total dose. It is our hope that studies that are presently under way will establish cladribine as a practical therapeutic option for patients with all non-benign forms of multiple sclerosis.

Development of cladribine treatment in multiple sclerosis.

Cladribine is a new type of drug with properties of selective lymphocyte suppression that appear to favorably alter the clinical course of progressive multiple sclerosis (MS). The history of the development of cladribine treatment in chronic progressive MS is discussed, and the application of cladribine treatment to progressive multiple sclerosis in a double-blind, placebo crossover study is reviewed. Cladribine selectively targets both resting and dividing lymphocytes and may be able to destroy the activated lymphocytes that induce CNS demyelination, thus producing stabilization or improvement in chronic MS. Although the role of cladribine has not yet been fully defined, additional studies are underway to evaluate the efficacy and safety of cladribine in both progressive MS and relapsing-remitting MS.

A comparison of two neurologic scoring instruments for multiple sclerosis.

We examined the degree of association between two neurologic impairment scales, the Extended Disability Status Scale (EDSS) and the Scripps Neurologic Rating Scale (SNRS), with data from a randomized, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of cladribine as treatment for chronic progressive multiple sclerosis (MS). We found that the EDSS and SNRS were not strongly correlated within individual patients, contrary to expectation; moreover, in 9 of the 48 evaluable patients, the directions of their changes from baseline values were not mutually consistent. The scales were differentially sensitive to clinical changes over time, with the EDSS indicating a more abrupt, and the SNRS a more gradual, change in the clinical course of disease. The validity of different impairment scales, and their sensitivity to detect clinical changes, should be formally assessed in future clinical trials using these scales as outcome measures.

The treatment of chronic progressive multiple sclerosis with cladribine.

A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis. In the first year patients were given cladribine 0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or placebo. During the second year patients treated with placebo during the first year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per kg of body weight per day for 7 consecutive days in three successive monthly courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously with cladribine were crossed over to placebo. Analysis of the results revealed a favorable influence on the neurological performance scores, both in the Kurtze extended disability status and the Scripps neurological rating scale, and on MRI findings in patients treated with cladribine. In the first year the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received cladribine stabilized or even improved slightly. Toxicity and therapeutic response were dose-related.

Cladribine in treatment of chronic progressive multiple sclerosis.

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.

Marrow suppression produced by repeated doses of cladribine.

2-Chlorodeoxyadenosine (cladribine, Leustatin) is being used extensively in the treatment of hematologic malignancies, but relatively little is known regarding its toxicity to the normal marrow. Long-term serial hematologic observations have been made on 29 patients with multiple sclerosis undergoing experimental therapy with monthly courses of cladribine, each of which consisted of 0.087-0.1 mg/kg per day for 7 days. The characteristic hematologic responses of the patients consisted of acute transient monocytopenia, prolonged, profound lymphopenia especially of CD4-positive cells, and modest lowering of the granulocyte count and hemoglobin with development of long-lasting macrocytosis. Two patients developed severe aplastic anemia, requiring transfusion both of red cells and platelets. One of these had previously received extensive therapy with chlorambucil, while the other had received carbamazepine (Tegretol) and was ingesting phenytoin (Dilantin) at the time of cladribine therapy. Both patients recovered after several months of marrow suppression.

P300 in multiple sclerosis: a preliminary report.

The P300 component of the event-related brain potential (ERP) elicited with auditory stimuli and pattern-shift visual evoked potentials (VEPs) was obtained from 16 patients with multiple sclerosis (MS) and 16 matched control subjects. P300 latency was significantly longer and component amplitude relatively depressed in the MS patients compared to control subjects. The P100 potential of the VEP also was delayed for both full-field and half-field stimulus conditions in the patients compared to control subjects. The findings suggest that the P300 ERP may reflect the cognitive decline associated with MS.

Serial recordings of multimodality evoked potentials in multiple sclerosis: a four year follow-up study.

Pattern reversal visual, brain-stem auditory, and short latency median nerve somatosensory evoked potentials (EPs) were evaluated in a prospective study over 4 years in 20 patients with clinically definite sclerosis (MS). Standardized neurological examinations were done at regular intervals and correlated with EP findings. The highest incidence of EP abnormalities occurred in the visual system followed by the somatosensory and auditory systems. Clinical relapse was usually accompanied by EP deterioration, but clinical improvement often occurred without parallel EP recovery. EP changes were not always related to clinical symptoms and often took place during remission periods in the absence of clinical changes. There was no significant correlation between clinical and electrophysiological progression within any given sensory modality. The progression of clinical disability, however, showed a fairly good correlation with the overall progression of EP abnormalities. We conclude that EPs complement the neurological exam in the evaluation of MS and may have a place in the investigation of the effects of therapeutic agents on the neurological status in MS.

Evoked potentials in trigeminal neuralgia associated with multiple sclerosis.

A 49-year-old man with definite multiple sclerosis suffered an episode of right-sided trigeminal neuralgia (TN) of two weeks' duration, unaccompanied by any other clinical symptoms or signs of exacerbation. Serial evoked potentials, obtained before, during, and after TN, demonstrated developing abnormalities in brain-stem auditory evoked potentials from the right ear that disappeared in a delayed fashion after the clinical symptoms of TN had subsided. This rare combination of clinical and electrophysiologic abnormalities suggests a pontine demyelinating plaque involving the right trigeminal sensory root and the right lateral lemniscus.

Serum demyelinating factors in multiple sclerosis.

Sera from 21 patients with multiple sclerosis were applied to myelinated spinal cord cultures and evaluated for demyelinating activity. Samples were collected at various times when patients were on or off therapy with myelin basic protein or prednisone or both, and at various stages of disease. Five of 31 serum samples from 17 patients exhibited demyelinating activity when tested in a 40% concentration in tissue culture nutrient medium. Four of the 10 serum samples taken from patients with active or remitting multiple sclerosis (2 samples from the same patient) were demyelinative; 1 of 21 sera collected during stationary periods of disease was positive. There was no correlation between serum demyelinating activity and the presence or absence of treatment. Sera positive for demyelinating activity failed to inhibit myelin formation in initially unmyelinated cerebellar cultures.

Modulation of 5-fluorouracil toxicity by allopurinol in man.

Oxipurinol, the major metabolite of allopurinol, decreased the toxicity of 5-fluorouracil (5-FU) to human granulocyte colony-forming units in vitro by a factor of four. The ability of allopurinol to reduce 5-FU toxicity in vivo was studied in 23 advanced cancer patients during 42 courses of treatment. 5-FU was administered by continuous intravenous infusion for five days; allopurinol, 300 mg, po, every 8 hours was started 2 hours before and continued during and for 24 hours after 5-FU infusion. 5-FU was escalated from 1.5 to 2.25 g/m2/day on separate courses; the dose-limiting toxicity was mucositis which occurred at a level of 2.0 g/m2/day. At a 5-FU dose rate of greater than 2.0 g/m2/day 5-FU pharmacokinetics were nonlinear, reflecting saturation of catabolic pathways, and the steady-state 5-FU serum concentration was approximately 4 times that which was tolerable without allopurinol. At these concentrations of 5-FU oxipurinol significantly influenced the clearance of 5-FU. Thus concurrent allopurinol therapy permitted a doubling of the maximum tolerated dose of 5-FU and a four-fold increase in the tolerated concentration x time exposure to 5-FU.

Thoracic spinal cord tumor presenting with dysautonomic diarrhea.

A patient, presenting with incapacitating diarrhea of 1-month duration, developed orthostatic hypotension and progressive long tract central nervous system signs. No enteric disease was found to account for the diarrhea. An intramedullary midthoracic spinal cord tumor (ependymoma) was found. Diarrhea and hypotension resolved after local cord decompression and irradiation of the tumor. Dysmotility caused by interruption of thoracic sympathetic pathways to the gut was considered responsible for the diarrhea, and altered splanchnic hemodynamics for the hypotension. The regional autonomic neuroanatomy and the known effects of the autonomic nervous system upon bowel function and the splanchnic circulation explain the patient's symptoms.