Augustus S. Rose

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

Transient ischemic strokes: A report of a study of anticoagulant therapy

THE TERM “transient ischemic stroke” or “transient cerebral ischemic attack is used to designate neurological disturbances of brief duration due to focal cerebral ischemia caused by, or related to, occlusive vascular disease. The brief duration or transiency is a key issue. In this report, we include only patients whose symptoms cleared completely within a few minutes or a few hours and who were neurologically normal within twenty-four hours. Many conditions besides transient disturbances of cerebral circulation may produce similar symptomatology. These must be carefully excluded. Concepts of pathogenesis and pathophysiology are frequently implied or assumed in discussions. They are important but are difficult to elucidate and interpret. For this reason, the term transient cerebral ischemic attack is used in this report as a descriptive diagnostic grouping based on clinical findings.

An assessment of the reliability of three methods used in evaluating the status of multiple sclerosis patients

Abstract The reliability of three different evaluation methods used in a cooperative clinical trial of the efficacy of ACTH in multiple sclerosis patients was evaluated in a uniformity study that used an efficient statistical design requiring only 10 patients and 5 examiners. The methods were the standard neurologic examination, a scoring system for functional grades and disability status, and a 7-day symptom score. Each patient was examined only 3 times at the beginning of the study and 3 more times 6 days later. No significant differences among the 5 examiners were observed on 82 of the 87 items used to measure neurologic function. With the exception of 1 variable, there were no significant differences among the average values of the sequence of the 3 examinations, nor among the average increments of change in the numerical scores between the first and second trials. In an additional examination in which all 5 examiners simultaneously evaluated 3 patients 1 at a time, it was found that the 5 examiners observed uniformly in all of the neurologic tests. The results of this study indicate that, by and large, the three evaluation methods appear to be reliable in the evaluation of neurologic status when used in a cooperative clinical trial where several investigators contribute data. Furthermore, investigations of reliability in cooperative studies can be performed with the use of efficient statistical designs such as the incomplete Latin-square design.

THE AMINO ACID COMPOSITION OF CENTRAL AND PERIPHERAL NERVE NEUROKERATIN

THE WORD ‘neurokeratin’ was coined by EWALD and KUHNE (1877) to describe the myelin protein resistant to digestion with gastric and pancreatic juices. It has remained a subject of interest ever since. There have been several investigations of its elemental and amino acid conipostion (ARGIRIS, 1907; NELSON, 1916; BLOCK, 1932, 1951). Traditionally neurokeratin has been characterized by its resistance to proteolytic enzymes (usually pepsin or trypsin) and its insolubility in organic solvents and dilute acids and bases. FOLCH and LEES (1951) showed that the chloroform-methanol soluble proteolipids of nervous tissue, which they discovered, are also trypsin and pepsin resistant. Furthermore, LEBARON and FOLCH (1956) and FOLCH and LEBARON (1959) demonstrated that after removal of the proteolipids with chloroform-methanol there still exists a trypsin-resistant protein (TRPR) in the insoluble residue. This TRPR has phosphorus, inositol, and peptides bound to it and these ‘phosphatido-peptides’ can be removed from the protein by treatment with chloroform-methanol-HCI (200: 100: 1, by vol.). It was clearly established then by these investigations that neurokeratin prepared by the traditional methods is a mixture of proteolipid protein and TRPR. The question thus arises as to whether the protein moieties of proteolipid and TRPR are similar or not. The earlier amino acid analyses of neurokeratin (BLOCK, 1951) provide no answer since they were made on neurokeratin prepared by the methods in use before the discovery of proteolipids. The amino acids of bovine proteolipid protein from white matter were analysed by FOLCH and LEES (1951). WOLFGRAM and ROSE (1961) repeated the analysis of the proteolipid from this tissue and also determined the amino acid composition of the proteoIipids of human CNS white matter and human and bovine intradural spinal roots. It was pointed out that the proteolipids from these diverse sources have remarkably similar amino acid patterns. TRPR is a satisfactory term to describe the non-proteolipid protein of the CNS resistant to proteolytic enzymes. However, in the peripheral nervous system, TRPR is misleading in that collagen is also a TRPR (FOLCH, LEES and CARR, 1958; WOLFCRAM and ROSE, 1961). For this reason we propose to designate our fractions as neurokeratin, objectionable as the word may be, and to redefine it as the chloroformmethanol insoluble, trypsin-resistant protein of nervous tissue freed of collagen and phosphatido-peptides, E X P E R I M E N T A L Most of the methods used have been described previously (WOLFCRAM and ROSE, 1961). All of the experiments reported here were done on bovine centrum ovale white matter or bovine intradural

Chemical basis of the Marchi method for degenerating myelin.

THE MARCHI stain for demonstrating degenerating myelin is an empirical method, the fundamental chemistry of which is not well understood. The method depends upon the ability of formalin-fixed degenerating myelin to reduce osmium tetroxide in the presence of an oxidizing agent. Although normal myelin is unstained, the method is not specific for degenerating myelin because neutral fat also stains by this method.1 In spite of the usefulness of the technic, relatively little has been done to elucidate its chemistry. In a series of recent studies on this problem, Wolman233~4-5 has concluded that the responsible factor in the degenerating myelin may be a breakdown product of an acidic polysaccharide. The present study concerns the solubility of the Marchi material in some organic solvents and in water.

THE TEACHING OF UNDERGRADUATE NEUROLOGY. A SURVEY BASED ON A VISIT TO 26 MEDICAL SCHOOLS.

MEDICAL PHACTICE and medical education have undergone and are undergoing significant changes. In the decade of the 1950s, emphasis was placed on graduate training and the expansion of research. The curricula in medical schools are being altered to accommodate new knowledge and to ensure that students are properly prepared for the practice of modern medicine. Many medical schools have made changes, some minor and some major, and at other schools curricular changes are under study. Training programs in clinical neurology have expanded, and research in basic neurology has received great support and widespread attention. Yet the specialty of neurology remains considerably undermanned. Since the undergraduate student body in medical school is the reservoir from which recruits for any branch of medicine are chiefly obtained and in view of the changes in medical school curricula, it seemed appropriate to review the methods and techniques of undergraduate teaching of neurology. Accordingly, a personal survey was undertaken during the academic year 1962-63. This was made possible by a partial sabbatical leave from university duties and through the support of the Commonwealth Fund of New York. This paper records information obtained from the survey. I t presents an evaluation of the experience derived from interviews with faculties of 26 medical schools and conferences with 277 students from these schools.

American neurology: What is its present status?

THE HONOR OF PRESENTING the presidential address to the American Academy of Neurology is a privilege which comes to but a few. It is with humble spirit and genuine appreciation that I appear before you today. And I assure you that I am aware of the rare opportunity and the not inconsiderable responsibility which this occasion affords. I am conscious also of the fact that I enjoy a certain advantage over those of you who will follow me to the rostrum-for this essay has not had to pass through the scrupulous filtering of the Scientific Program Committee! This is the thirteenth annual meeting of the Academy. We are young by comparison to some other societies in medicine. However, there is no doubt that we have survived a turbulent youth and entered into a well modulated maturity. Born during the period of postwar scientific awakening, this organization sprung into being as if by spontaneous general demand, and immediately it began to exert an influence far out of proportion to that which might have been expected. The individuals who made up its initial core claim no unusual assets individually, yet, collectively, they were able to ignite and supply the dynamic force for a powerful change in orientation for the specialty of neurology. Without doubt, we were a product of the times, and it would be unrealistic not to realize that enthusiasm and drive alone could have accomplished little if the profession, the people, and the Congress were not ready to respond and to render support. Verve and vigor are healthy traits of youth, and in them the Academy may take just pride; yet, on coming of age, we acquire the responsibilities of maturity, and we are now confronted with the serious challenge of maintaining stability, holding the dynamic spirit, and continuing to exert influence for the best interest of neurology. The experience of serving as President and of participating for several additional years in the administrative affairs of the Academy is sobering and chastening, and, although it does not qualify one to be a sage or prophet, it