Diagnostic criteria for multiple sclerosis.

In 1972 ~ and 19852 the Committee on Hearing and Equilibrium of the American Academy of Otolaryngolog3~-Head and Neck Surgery published recommended guidelines for reporting the results of treatment of Meniere's disease. These reports have proved very beneficial to efforts to understand this disorder and its treatment. With advancing knowledge it has become evident that the reporting guidelines could be refined further. In undertaking this review, the Committee established several guiding principles. We wished to establish a distinction between the recording of results and the analysis and interpretation of results. Insofar as is possible, we wanted to retain and integrate the methods recommended in the 1972 and 1985 reports. We wanted guidelines to be \"upwardly compatible\" in the sense of computer software, so that existing data could not only be conserved but analyzed in new ways. Reporting methods should be clearly stated, straightforward to apply, as simple as possible, and usable in a wide range of settings, from multicenter university studies to reviews of personal experience by individual private practitioners. Specialized test equipment should not be required. Methods should facilitate statistical evaluation and comparison of results among studies. The guidelines should encourage reports to reflect disease severity in a meaningful manner.

Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Meniere's disease*

We report a natural history study of 216 patients with primary progressive (PP)- multiple sclerosis defined by at least 1 year of exacerbation-free progression at onset. This represents 19.8% of a largely population-based patient cohort having a mean longitudinal follow-up of 23 years. This subgroup of PP-multiple sclerosis patients had a mean age of onset of 38.5 years, with females predominating by a ratio of 1.3:1.0. The rate of deterioration from disease onset was substantially more rapid than for relapsing-remitting multiple sclerosis, with a median time to disability status score (DSS) 6 and DSS 8 of 8 and 18 years, respectively. Forty-nine percent of patients were followed through to death. Examination of the early disease course revealed two groups with adverse prognostic profiles. Firstly, a shorter time to reach DSS 3 from onset of PP-multiple sclerosis significantly adversely influenced time to DSS 8. Second, involvement of three or more neurological systems at onset resulted in a median time to DSS 10 of 13.5 years in contrast to PP-multiple sclerosis patients with one system involved at onset where median time to death from multiple sclerosis was 33.2 years. However, age, gender and type of neurological system involved at onset appeared to have little influence on prognosis. Life expectancy, cause of mortality and familial history profile were similar in PP-multiple sclerosis and non-PP-multiple sclerosis (all other multiple sclerosis patients from the total population). From clinical onset, rate of progression was faster in the PP-multiple sclerosis group than in the secondary progressive (SP)-multiple sclerosis group. When the rates of progression from onset of the progressive phase to DSS 6, 8 and 10 were compared, SP-multiple sclerosis had a more rapid progressive phase. A substantial minority (28%) of the PP-multiple sclerosis cohort had a distinct relapse even decades after onset of progressive deterioration. These studies establish natural history outcomes for the subgroup of multiple sclerosis patients with primary progressive disease.

The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis.

Background and Methods. The use of corticosteroids to treat optic neuritis is controversial. At 15 clinical centers, we randomly assigned 457 patients with acute optic neuritis to receive oral prednisone (1 mg per kilogram of body weight per day) for 14 days; intravenous methylprednisolone (1 g per day) for 3 days, followed by oral prednisone (1 mg per kilogram per day) for 11 days; or oral placebo for 14 days. Visual function was assessed over a six-month follow-up period. Results. Visual function recovered faster in the group receiving intravenous methylprednisolone than in the placebo group; this was particularly true for the reversal of visual-field defects (P = 0.0001). Although the differences between the groups decreased with time, at six months the group that received intravenous methylprednisolone still had slightly better visual fields (P = 0.054), contrast sensitivity (P = 0.026), and color vision (P = 0.033) but not better visual acuity (P = 0.66). The outcome in the oral-prednisone group did ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199202273260901

A Randomized, Controlled Trial of Corticosteroids in the Treatment of Acute Optic Neuritis

Kuru was the first chronic degenerative disease of man shown to be a slow virus infection, with incubation periods measured in years and with a progressive accumulative pathology always leading to death. This established that virus infections of man could, after long delay, produce chronic degenerative disease and disease with apparent heredofamilial patterns of occurrence, and with none of the inflammatory responses regularly associated with viral infections. Soon thereafter, several other progressive degenerative diseases of the brain were likewise attributed to slow virus infections (see Tables 1 and 2). These include delayed and slow measles encephalitis, now usually called subacute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy (PML), and transmissible virus dementias usually of the Creutzfeldt-Jakob disease (CJD) type. Thus, slow virus infections, first recognized in animals, became recognized as a real problem in human medicine. Kuru has led us, however, to a more exciting frontier in microbiology than only the demonstration of a new mechanism of pathogenesis of infectious disease, namely the recognition of a new group of viruses possessing unconventional physical and chemical properties and biological behavior far different from those of any other group of microorganisms. However, these viruses still demonstrate sufficiently classical behavior of other infectious microbial agents for us to retain, perhaps with misgivings, the title of “viruses”. It is about these unconventional viruses that I would further elaborate. The group consists of viruses causing four known natural diseases: two of man, kuru and CJD, and two of animals, scrapie in sheep and goats, and transmissible mink encephalopathy (TME) (Table 1). The remarkable unconventional properties of these viruses are summarized in Tables 3 and 4. Because only primate hosts have been available as indicators for the viruses

https://science.sciencemag.org/content/sci/197/4307/943.full.pdf

Unconventional viruses and the origin and disappearance of kuru.

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

Criteria for the clinical diagnosis of multiple sclerosis

Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report.

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

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.

Augustus S. Rose

Papers

Criteria for the clinical diagnosis of multiple sclerosis

Cooperative study in the evaluation of therapy in multiple sclerosis. ACTH vs. placebo--final report.

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

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

Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo in acute exacerbation.