THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON

The Design and Analysis of Experiments

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use.

/pdf/diagnostic-criteria-for-multiple-sclerosis-2010-revisions-to-24iph50480.pdf

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

Several schemes for the diagnosis and clinical classification of multiple sclerosis (MS) have been advanced [l}. The best known is that published by Schumacher et alC31. The criteria for this scheme were established in order to select patients for participation in therapeutic trials, and pertain only to what might be called definite MS. No provision was made for incorporating supportive laboratory data into the diagnostic criteria. As no reliable specific laboratory test for the diagnosis of MS has been discovered, the diagnosis remains a clinical one, and there is still a need for clinical diagnostic criteria. However, several laboratory and clinical procedures have been developed within the last decade which aid greatly in demonstrating neurological dysfunction attributable to lesions, and even the lesions themselves. One problem with the various published diagnostic classifications is their discrepant terminology: what is considered “probable” in one is called “definite” in another. Another problem is that all the proposed schemes require much subjective judgment, a difficulty which cannot be completely overcome but can be diminished by adding to the clinical evaluation the results of laboratory, neuroimaging, neuropsychological, and neurophysiological procedures. Today there is a need for more exact criteria than existed earlier in order to conduct therapeutic trials in multicenter programs, to compare epidemiological surveys, to evaluate new diagnostic procedures, and to estimate the activity of the disease process in MS. Method and Procedure

New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

https://www.onlinelibrary.wiley.com/doi/epdf/10.1002/ana.1032

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

• Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.

The Fatigue Severity Scale: Application to Patients With Multiple Sclerosis and Systemic Lupus Erythematosus

Multiple sclerosis has become a focus of growing interest to neurologists, general physicians, and the public. The disorder has an uneven but worldwide distribution and is present in approximately 30 to 60 people per 100,000 in the temperate zones of the world. Though some of these individuals remain unaffected by serious disability, in the majority the disease leads to crippling and ultimately premature death. To the public a special appeal lies in the frequent occurrence of multiple sclerosis in the young adult, often with disruption of early family life. To date no satisfactory treatment for the amelioration or cure of the disease has been discovered. Since its etiology and pathogenesis have eluded detection, it is not surprising that therapeutic attempts have been empiric and often unscientific. Reports of benefit from various types of therapy based on uncontrolled observations have led to unwarranted and occasionally widespread application of methods whose value remained unsubstantiated. In recent years criticisms have been made of the lack of adequate controls in trials of therapy. The difficulties inherent in judging the effects of therapy have been stressed.', * These are: (1) Lack of precision in diagnosis. (2) The erratic and unpredictable course of the disease with periods of spontaneous remission of symptoms. (3) Lack of a direct method for investigating activity of the disease. (4) The existence of only crude parameters for quantitating and recording the clinical course of the disease. (5) The irreversibility of gliosis and its masking effect on disease activity elsewhere in the nervous system. (6) Psychological disturbances, including hysterical tendencies, in some patients. (7) Problems of keeping large groups of patients under standard conditions of therapy or control for long periods (necessary because of the chronicity and erratic nature of the disease). Attempts to apply some degree of scientific control to therapeutic investigations in multiple sclerosis, however, have been made r e ~ e n t l y . ~ ~ Because of the prevalence of poorly controlled therapy reports, the National Institute of Neurological Diseases and Blindness provided financial support for a Symposium on the Evaluation of Drug Therapy in Neurologic and Sensory Diseases* which was held at the University of Wisconsin in May, 1960. Ten panels composed of investigators, clinicians, and statisticians met to consider the problem of experimental trials of therapy in various areas of nervous system disease. The results of the discussions were subsequently published.6 The conclusions reached by the Panel on Multiple Sclerosis comprised essentially a statement of the problems that needed study and solution to permit the design of a protocol for sound experimental trials of therapy. Thus, they formed merely a point of departure for future study. As an outgrowth of the initial considerations of the Panel on Multiple Sclerosis, a continuing panel was formed which held a series of workshops on the problem.

Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis.

The problems encountered in evaluating the effectiveness of treatment methods in multiple sclerosis are well recognized They result in large part from the nature of the disease, which is characterized by a variable course and many different clinical manifestations It has been estimated that approximately twothirds of multiple sclerosis patients experience a remission of symptoms at some time during their illness Many forms of treatment have been proposed with claims of beneficial results for patients at all stages of the disease Yet, most of these regimens are generally believed to be useless If the empirical search for an effective treatment for multiple sclerosis is to have any chance of success, it is apparent that a reliable method of accurate assessment must be developed

In 1960, a symposium concerned with the evaluation of drug therapy in neurological and sensory diseases recognized the many serious difficulties involved in clinical trials of therapy in multiple sclerosis including those pertaining to the conduct of cooperative studies1 In the months following that symposium, an Ad Hoc committee agreed upon certain diagnostic criteria, scoring systems and principles of design for a suitable protocol for such clinical trials2 The work of the Ad Hoc committee provided the basis for a subsequently designed protocol for a cooperative study utilizing ACTH vs placebo in the treatment of multiple sclerosis patients in acute exacerbations A group of neurologists representing ten university treatment centers undertook a cooperative study utilizing this protocol beginning in April 1965 This preliminary report, based on observations of the first 135 cases entered, pre sents the characteristics of the study, demonstrates that adequate randomization of patients can be obtained in this disease and describes means for reasonably accurate evaluation of the many clinical changes seen in multiple sclerosis patients under treatment Because the study is …

Cooperative study in the evaluation of therapy in multiple sclerosis; ACTH vs placebo in acute exacerbations

No extant protocol for an experimental trial of therapy in multiple sclerosis provides a reliable tool for the determination of therapeutic efficacy. Quantitative evaluations of clinical phenomena do not reflect the true activity of the underlying disease, and summative scoring of neurologic dysfunction is unreliable. Comparisons in treatment trials should utilize data only from subjects with substantive changes or no changes. Evaluation of experimental treatment of acute exacerbations is unreliable and less important than that aimed at eradication or prevention. Knowledge of etiology and pathogenesis remains the best potential source of effective therapy. Suggestions are made for conducting trials of empiric methods along simpler lines with high powers of resolution. Serious reservations should be retained concerning the wisdom of further expenditure of time, energy, or funds for experimental trials of therapy in multiple sclerosis patterned after protocols utilized to date.

Critique of experimental trials of therapy in multiple sclerosis.

Virus antibody levels were determined for multiple sclerosis patients and matched controls from three different locations. For rubeola, several different antigen preparations were used. Measles antibody titers were significantly elevated in multiple sclerosis patients in Washington, DC, increased in the patients in Minneapolis, and somewhat elevated in the patients in Vermont. In the Vermont series, the trend for high measles antibody levels only became apparent when sibling controls were excluded from the analysis. Antibody levels for respiratory syncytial virus, adenovirus, mumps, and varicella were also increased among multiple sclerosis patients in individual groups, but this was not consistent for all three groups.

https://jamanetwork.com/journals/NEUR/articlepdf/570556/archneur_24_6_002.pdf

Virus antibodies and multiple sclerosis.

1. Instrumentation and technique for microsurgical reconstruction of small arteries are described. 2. Two cases are reported in each of which an obstruction was removed from the middle cerebral artery for early hemiplegia. 3. The work presented is of a preliminary nature. No conclusions can be drawn as to ultimate value. Further clinical trial seems justified.

George A. Schumacher

Papers

Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis.

Cooperative study in the evaluation of therapy in multiple sclerosis; ACTH vs placebo in acute exacerbations

Critique of experimental trials of therapy in multiple sclerosis.

Virus antibodies and multiple sclerosis.

Microsurgery as an aid to middle cerebral artery endarterectomy.