George W. Ellison

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.

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

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.

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.

Evoked potentials predict the clinical changes in a multiple sclerosis drug study

Visual, brainstem auditory, and median nerve somatosensory evoked potential (EP) tests were performed annually during a 3-year, double-blind, placebo-controlled study of azathioprine with or without steroids in chronic progressive MS. Treatment-related visual and somatosensory EP changes became statistically different 1 year before corresponding differences were seen in the Standard Neurological Examination scores. The statistical significance of EP changes was substantially greater than seen for changes in other clinical scales. The degree of significance was increased by using EP latency values, rather than simple criteria for change. EPs are sensitive, objective measurements useful in MS therapeutic trials.

A humoral response to oligodendrocyte-specific protein in MS A potential molecular mimic

Objective: To determine the antibody response to oligodendrocyte-specific protein (OSP) in patients with MS. Background: OSP is a recently identified CNS-specific myelin protein that is abundant and therefore a candidate autoantigen in MS. Methods: The presence of anti-OSP antibodies was determined using Western blot analysis, peptide blots, and ELISA in patients with MS and in other neurologic and normal control subjects. Results: Using Western blot analysis, seven patients with relapsing–remitting MS (RRMS) were found to contain anti-OSP antibodies in their CSF that were not present in control subjects. Peptide mapping determined that the antibody response was directed to a seven aa peptide (OSP 114-120), which has 71% homology with several common pathogenic proteins. Using OSP 114-120 as antigen, ELISAs were performed on CSF from 85 MS and 51 control patients. Eighty percent of the samples from RRMS patients followed at the University of California at Los Angeles had an ELISA reading above 0.55 optical density units, whereas all 20 control CSF samples had values less than 0.55 U. Similar results were found in specimens from an outside research bank. ELISAs performed on CSF using homologous viral peptides as antigen showed a close correlation with anti-OSP 114-120 ELISA readings, and in some, the readings were higher than those using OSP peptides. Conclusions: There is a specific humoral response directed against a region of OSP in RRMS patients that cross-reacts with several common viral peptides. This suggests a possible role for molecular mimicry in the development of MS.

Management of multiple sclerosis across managed care and fee-for-service systems.

Objective: To measure and compare care for adults with MS across managed care and fee-for-service (FFS) health systems. Methods: The authors sampled adults with MS having physician visits over a 2-year period from a group model health maintenance organization (HMO) in southern California, from a midwestern independent practice association (IPA) model managed care plan, and from the FFS portion of the practices of a random sample of southern California neurologists. The authors mailed surveys to subjects in mid-1996; 930 of 1,164 (80%) of those eligible responded. The authors measured sociodemographic and clinical characteristics, management of recent changes in mobility, bladder control, and fatigue, use of a disease-modifying agent, assessment of general health symptoms and issues, and unmet information needs. The authors adjusted comparisons between systems for comorbidity, disease severity, and disease type. Results: The groups differed on most sociodemographic and clinical characteristics. There were few differences in symptom management; differences that did exist tended toward more referrals or treatment for the FFS group. Access to the disease-modifying agent available at the time of the survey did not differ across systems, although patients’ perceptions of the rationale for not using the drug did vary. General health issues and symptoms were more often assessed in the FFS and IPA systems than in the HMO, but improvement was needed across all three systems of care. There were substantial unmet information needs in all groups and especially high ones in the FFS and HMO samples. Conclusions: Strategies to improve care for people with MS should be developed and evaluated, particularly in areas like symptom assessment and meeting patient information needs. Where variations in service delivery exist, longitudinal studies are also needed to evaluate the potential impact on outcomes and to evaluate reasons for variation.

Mobility impairments and use of preventive services in women with multiple sclerosis : observational study

Use of preventive health services is affected by factors such as patient demographics, clinical characteristics, type of provider, and type of healthcare system.1 Although people with multiple sclerosis may have impaired mobility, their lifespans are similar to age matched population controls. They therefore need standard preventive services to prevent early mortality. We evaluated the relation between mobility and use of preventive services in women with multiple sclerosis. In 1996, we sent questionnaires to 1164 adults with multiple sclerosis who had received outpatient care in 1993 or 1994 from one of three systems of health care (two forms of managed care and fee for service insurance) in two regions of the United States.2 The overall response rate was 80% (930/1164). We report here survey analyses from the 713 women respondents. We collected self reported rates of cervical smear testing, mammography, and breast examination (if over age 50), blood pressure checks, cholesterol screening, and physician …

A review of systemic nonspecific immunosuppressive treatment of multiple sclerosis

This article is a critical review of the literature about the effects of systemic immunosuppression on patients with multiple sclerosis. Azathioprine (or 6-mercaptopurine), chlorambucil, cyclophosphamide, levamisole, melphalan, podophyllin and other drugs by themselves and in combination therapies with adrenocortical steroids, thoracic duct drainage, and antilymphocyte sera or globulins are discussed. A decrease in frequency of relapses, rate of progression, cerebrospinal fluid gamma globulin and oligoclones, and in cerebrospinal fluid pleocytosis can be achieved, at least temporarily, by certain treatments. Lack of appropriate controls makes it difficult to evaluate these results. Therefore, immunosuppressive therapy of multiple sclerosis should be considered highly experimental. Systemic immunosuppression is difficult to achieve and maintain, has a high incidence of side effects, and the long-term consequences are not well established. More studies of drug combinations, with stratification of patients and with follow-up observations for at least 5 years, will be necessary before firm conclusions can be reached. Controlled studies of cyclophosphamide or azathioprine might be started now but other modalities also might be used in exploratory or pilot studies. These studies will require a significant investment by patients, biomedical personnel, and funding agencies, and should not be entered into casually.