Lawrence W. Myers

A health-related quality of life measure for multiple sclerosis.

The need for measures of health-related quality of life (HRQOL) for clinical effectiveness research and for quality of care research, particularly for chronic diseases, is increasingly recognized. We assessed a measure of HRQOL for people with multiple sclerosis, a chronic neurological condition. We used the RAND 36-Item Health Survey 1.0 (aka SF-36) as a generic core measure, to enable comparisons of HRQOL of patients with multiple sclerosis to those of other patient populations and to the general population. To enhance comparisons within groups of multiple sclerosis patients, these items were supplemented with 18 additional items in the areas of health distress (four items), sexual function (four items), satisfaction with sexual function (one item), overall quality of life (two items), cognitive function (four items), energy (one item), pain (one item), and social function (one item). The final measure, the Multiple Sclerosis Quality of Life (MSQOL)-54 instrument, contains 52 items distributed into 12 scales, and two single items. Internal consistency reliability estimates for the 12 multi-item scales ranged from 0.75 to 0.96 in a sample of 179 patients with multiple sclerosis. Test-retest intraclass correlation coefficients ranged from 0.66 to 0.96. Exploratory factor analysis confirmed two underlying dimensions of physical health and mental health. Construct validity was supported by significant associates between MSQOL-54 scales and degree of multiple sclerosis symptom severity in the prior year, level of ambulation, employment limitations due to health, admission to hospital in the previous year, and depressive symptoms.

Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

Criteria for the clinical diagnosis of multiple sclerosis.

No. 6 Criteria for the clinical diagnosis of multiple sclerosis AUGUSTUS S. ROSE, GEORGE W. ELLISON, LAWRENCE W. MYERS, and WALLACE W. TOURTELLOTTE Department of Neurology, Reed Neurological Research Center, UCLA School of Medicine, and the Veterans Administration Wadswofih Hospital Center, Los Angeles t is appropriate that a conference designed to I presen t r e sea rch in mul t ip l e s c l e ros i s have presentations concerning the clinical diagnosis of the disease. Medicine is not an exact science. Clinical and scientific investigations involving patients with multiple sclerosis have the additional difficulties of dealing with a disease of unknown cause and for which no specific objective laboratory tests have been described. Until the present, the only proof of the diagnosis of multiple sclerosis is derived from pathologic examination after death. Yet, with experience and clinical acumen, it is believed that by utilizing the clinical observations made on patients who came to autopsy in the past, the diagnosis can be made during life with reasonable accuracy, and cases can be categorized on the basis of probability. In the last 25 years clinical and research interests in multiple sclerosis have increased remarkably throughout the world. Early on, however, it became clear that results from various studies had to be viewed with doubt and caution because of the lack of precision in diagnosis and the failure on the part of some investigators to define the patient population under study adequately. These circumstances led to a number of proposals of patient classification, and it is believed that even though still somewhat imprecise, the clinical evaluations of patients with this disease have been greatly enhanced, especially in medical centers where there is active research. Multiple sclerosis is a disease of the human. Its pathology is located principally in the white matter of the central nervous system and consists of scattered lesions of myelin loss. In the majority of lesions the axons are preserved. Symptoms and signs are the result of interference in neuronal conduction. This interference in function may be acute and temporary, but eventually, in a large proportion of cases, becomes permanent and progressive. From good pathologic and epidemiologic studies it is considered that the disease multiple sclerosis is acquired in youth, particularly in areas of high risk, and that following the beginning of central nervous system pathology, there is a clinical quiescent period of varying duration before the onset of symptoms. First symptoms seldom begin before the age of 10 or after the age of 50. The initial symptoms may be mild and go unnoticed by the patient. Others have a rapid devastating downhill course, but the majority of patients are intermittently affected, with ultimate persisting and progressive disability. Because of the varying clinical manifestations and the differences in the prognosis in individual cases, the question has been raised as to whether multiple sclerosis should be considered a syndrome with a number of clinical forms, in which more than one acquired external agent may provoke the central nervous system process, rather than a single disease due to a single cause. At the present time, the evidence is not sufficient to make this determination. However, it is generally agreed that a significant component of the central nervous system disease process is due to an immunologic disorder. And it is felt that this process plays an important role in the variability of the clinical manifestations. Immune reactions may be influenced for better or worse by many internal and external events, each of which may be different from patient to patient and at different times. Such factors are almost impossible to define with accuracy. Furthermore, the overall confusion about the nature of the disease is added to by the fact that in many patients the administration of steroids and other means of suppres s ing the i m m u n o l o g i c r eac t ions br ing 20 Neurology, June 1976 Part 2 improvement in symptoms and signs, yet without changing the ultimate prognosis of the disease. The classical case of a young adult with relapsing and remitting symptoms and neurologic signs pointing to dissemination of central nervous system pathology offers the least problem in diagnosis, although the clinician must be alert to the possibility of coexisting disease. On the other hand, cases that begin with optic neuritis or some other single symptom followed by a long period without other symptoms, and those cases of late onset with only slowly progressive spasticity of the lower extremities, are difficult to classify. The existence of multiple sites of central nervous system disease is often less than clear. Also, patients with rapid progressive symptoms with diffuse involvement may be confused with and be difficult to separate from acute or subacute encephalomyelitis. Over the years and throughout the world the one laboratory test for which the greatest experience and validity has been found is the determination of the gamma globulin fraction of the cerebrospinal fluid total protein. A relative elevation of gamma globulin is found in from 60 to 80 percent of patients, with the greatest percentage being found among those patients in whom there is evidence for activity of the disease process. Tourtellotte’ points out that in multiple sclerosis patients IgG is chiefly synthesized in the central nervous system, and he considers that the finding of oligoclonal cerebrospinal fluid IgG may be strongly confirmatory of the diagnosis, Multiple sclerosis patients have been recognized for many years as having an unusual sensitivity to heat exposure. In many clinics it has become common practice to use this sensitivity to assist in diagnosis. Moist heat applied to the body, not necessarily sufficient to raise body temperature, will frequently cause temporary exaggeration of neurologic signs or produce reduction in visual acuity in patients with histories of optic neuritis, or the heat may cause abnormal neurologic signs that had disappeared to reappear. Although this reaction is not specific for multiple sclerosis, it is felt that it occurs almost exclusively in patients with central nervous system demyelination. The conceptual explanation is that heat in some manner changes the biochemical environment of demyelinated axons sufficient to temporarily reduce conduction. Following the widespread recognition of heat sensitivity in multiple sclerosis patients, physiologic studies undertaken in a number of laboratories demonstrated a disorder in evoked responses. When a “slowed” response is found similar to the results obtained in e s t ab l i shed cases , whether t he s t imu lus i s somatosensory, visual, auditory, or vestibular, it is considered that confirmation of demyelination has been demonstrated. This test procedure is of greatest value in patients in whom clinical signs are insufficient to establish more than one site of central nervous system pathology. However, because special equipment and an experienced technician are required, and because of the lack of proved specificity, there is doubt that this procedure should be generally accepted as a means of confirming the diagnosis. It is extremely helpful in those clinics where the expertise is available. An interesting newly observed abnormality of the retinae in multiple sclerosis patients was reported in 1974 by F r i sen and H o y t ? By the use of red-free ophthalmoscopic lighting, retinal striae involving the peripapillary region and located appropriately to explain small scotomata, are described. McDonald3 reports that these observations have been confirmed at the National Hospital, Queen’s Square, and at Moorfield’s Eye Hospital in London. The origin of the striae is uncertain, but it is felt that they reflect nerve fiber bundle degeneration, secondary to disease in the pregeniculate visual pathway. If these observations are found to be present in a large percentage of multiple sclerosis patients, the finding could become an important clinically observable sign that can be documented by retinal photography Over the years a number of criteria for the classification of multiple sclerosis patients have been proposed, each with the intent of separating patients on the basis of clinical qualities. The schema proposed by Allison and Mill& was widely used, yet was modified somewhat by McAlpine, Lumsden, and A c h e ~ o n . ~ McAlpine’s “definite multiple sclerosis” is similar to Allison’s ‘‘probable multiple sclerosis,” and McAlpine’s “probable multiple sclerosis” corresponds to Allison’s ‘‘early probable and latent multiple sclerosis.” The category of “possible multiple sclerosis” is the same in both proposals, including patients with progressive disability and those showing ‘‘insufficient evidence of multiple sclerosis. ” In the United States the schema developed by the panel of neurologists, headed by Schumacher and associates,6 has been most generally accepted. In this, the emphasis is placed on the category of ‘‘clinically definite multiple sclerosis. ’ ’ More recently, McDonald3 presented expanded criteria in which he includes: (1) clinically definite, (2) early probable and latent, (3) progressive possible, and (4) progressive probable cases. In discussing the matters of diagnosis and classification, McDonald emphasizes the pertinence of a number of ancillary, supportive test procedures, and considers that the evidences of activity of the disease process are important to include in differential considerations. In recognizing the many problems in diagnosis and in patient classification and in an effort to be as nearly precise as is reasonably possible, our UCLA-VA Wadsworth Hospital Groups have established the three categories into which all patients under study are placed: (I) Clinically definite multiple sclerosis, (11) Probable multiple sclerosis, and (111) Possible mult

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

A comparison of health-related quality of life in patients with epilepsy, diabetes and multiple sclerosis

The purpose of this investigation was to compare self-reported health-related quality of life (HRQOL) in epilepsy compared to another neurological condition or a non-neurological chronic illness. Patients with epilepsy (N = 271), multiple sclerosis (N = 85) and diabetes (N = 555) completed a generic measure of HRQOL (RAND 36-Item Health Survey 1.0 (SF-36)), and the eight SF-36 scale scores were compared across groups, adjusting for differences in sociodemographic characteristics and co-morbid medical conditions. Patients with multiple sclerosis reported significantly worse HRQOL compared to both the epilepsy and diabetes groups (who did not differ from one another) on the Physical Functioning, Role Limitations-Physical, Energy, and Social Function scales. Patients with epilepsy and multiple sclerosis did not differ from one another but reported significantly lower HRQOL scores than the diabetes group on the Emotional Well-Being and Role Limitations-Emotional scales. However, the epilepsy group reported better health perceptions compared to the diabetes and multiple sclerosis patients. Generic measures of HRQOL appear useful in identifying some effects of neurological disease, but disease-targeted supplements may be required to more clearly identify the impact of epilepsy on quality of life.

Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis : results from the 15-year analysis of the US prospective open-label study of glatiramer acetate

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of ‘Withdrawn’ patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received ≥ 1 GA dose since 1991; ‘Ongoing’ patients (n=108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to ∼1 relapse/5 years; median time to ≥ 1 EDSS point increase was 8.8 years; mean EDSS change was 0.739±1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.509±1.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.249±1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

A placebo-controlled, randomized, double-masked, variable dosage, clinical trial of azathioprine with and without methylprednisolone in multiple sclerosis

Ninety-eight patients with multiple sclerosis (MS) in the chronic progression phase entered a 3-year clinical trial to determine if azathioprine (AZ) alone or with adrenal cortical steroids stabilizes the course of MS. In group AM, the patients took AZ throughout and methylprednisolone (MP) for the first 36 weeks. Group AP received AZ and placebo instead of MP. Group PP took placebos for both drugs. We adjusted the AZ to maintain the total white blood cell count within 3,000 to 4,000/mm3; we gave the MP in a fixed dose “pulse” and alternate-day regimen. The “intent-to-treat” groups had no statistically significant differences in the rates of progression among the 3 treatments. Subgroup analysis suggests that patients in the AM group who completed treatment exactly according to protocol did statistically significantly better than the placebo recipients using the sum of Standard Neurological Examination scores, slightly better using the quantitative neuro-performance tests, but no better using Mickeys Illness Severity Scores or Kurtzkes Disability Status Scale. Also, the AZ-treated groups had half the relapse rate of the placebo-treated group. Adverse reactions to AZ accounted for most withdrawals. Hematologic and hepatic abnormalities were significantly associated with AZ, but serious non-MS abnormalities were uncommon and were equally distributed among the 3 groups. Addition of MP to the AZ slightly improved the efficacy of the treatment, but also increased the adverse effects. The benefits of AZ with or without steroids did not outweigh the risks, and therefore we do not recommend this treatment for patients with chronic progressive MS.

Anti-ganglioside antibodies in multiple sclerosis☆

Serological activity against several purified brain gangliosides has been demonstrated in sera of a proportion of multiple sclerosis patients, but not in normal individuals. The activity was determined by the capacity of the sera to bring about complement-dependent lysis of liposomes containing the respective ganglioside in their lipid bilayer. An apparent correlation is indicated between the severity of the disease and the extent of liposome lysis. Cerebrospinal fluid of the patients did not induce lysis, probably due to low antibody concentration.

In vitro study of mediators of inflammation in multiple sclerosis

Prostaglandin E levels have previously been demonstrated to be elevated in multiple sclerosis (MS). We have further investigated other products of activated macrophages related to inflammation. We report here on prostaglandin E and its relationship to interleukin 1, tumor necrosis factor, and leukotriene B4 produced by macrophages from blood and cerebrospinal fluid of MS patients and controlsin vitro. Interleukin and tumor necrosis factor are elevated significantly after stimulation in MS, while leukotriene B4 production by blood macrophages is depressed compared to other neurological disease and normal healthy controls. In 40% of MS patients tested, peripheral blood macrophages spontaneously produced elevated levels of interleukin 1. All mediators of inflammation are produced in increased amounts by MS cerebrospinal fluid leukocytes after stimulation. Macrophages from MS blood are not as sensitive as controls to nonsteroidal inhibitors specific for lipoxygenase or cyclo-oxygenase pathways. Positive correlations of elevations in production of such mediators of inflammation as prostaglandin E, interleukin 1, and tumor necrosis factor in MS were significant. Elevated production of these mediators in combination with insensitivity to inhibitors of inflammation suggests a role for activated macrophages in the demyelination process.