John F. Kurtzke

NEUROLOGIC IMPAIRMENT IN MULTIPLE SCLEROSIS AND THE DISABILITY STATUS SCALE

Scales to measure disability in multiple sclerosis have been rather numerous. One system used includes the delineation of overall neurologic dysfunction according to a Disability Status Scale which is scored on a 0 to 10 basis, with 0 being normal, the numbers rising in proportion to severity of involvement, and 10 used for death due to MS. The other part of this system is the assessment of dysfunction according to Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel and Bladder, Visual, Cerebral, and Other functions, each one save the last being graded 0 to 5 or 0 to 6 according to severity of involvement. Based on some 2000 examinations over the first 20 years or so of illness in 572 male MS patients, the overall frequency of involvement according to the functional systems was Pyramidal 80 per cent, Cerebellar 72 per cent, Brain Stem 69 per cent, Sensory 52 per cent, Bowel & Bladder 33 per cent, Visual 31 per cent, Cerebral (mood) 16 per cent, Cerebral (mentation) 5 per cent, and Other 21 per cent. Seizures were present in 1.4 per cent. When symptoms referable to pyramidal and cerebellar dysfunction were distributed by limbs involved, there was a tendency toward symmetry of involvement with the lowers much more often affected than the uppers. Sensory complaints were equally common for each limb or combination of limbs, but sensory findings on exam showed the same pattern as the motor and coordination complaints. When correlated with the Disability Status Scale, each of the functional systems showed not only increasing frequency but also increasing severity of involvement as overall disability increased. Involvement in each functional system was significantly correlated with involvement in each of the others, save for the Cerebral‐Sensory pair, and the highest correlations for each functional system were with the Disability Status Scale. Accordingly, it is concluded that as groups of MS patients worsen, they worsen in all areas. Therefore, any measure which will reflect even a part of this worsening will appear to be a valid estimate for the course of disease in groups of patients, and all of the published scales designed to evaluate disability in MS meet this criterion. Whether one system is more “correct” than another is not amenable to proof, and the choice would seem to depend more on factors such as familiarity and ease of application of the system rather than on its intrinsic merits.

Geography in multiple sclerosis.

SummaryBoth mortality and morbidity data indicate quite clearly that multiple sclerosis is a geographically-related disease, and thus MS can be thought of as an acquired environmental (exogenous) illness. High frequency parts of the world for MS are Europe between 65° and 45° north latitude, northern United States and southern Canada, New Zealand, and southern Australia. These regions are bounded by medium frequency MS regions: in Europe to the north, east, and south; in America for southern U.S.; and the remainder of Australia. Latin America, Asia and Africa are essentially of low frequency from present data. Latitude is not a sufficient criterion: at 40° north latitude, MS is high in America, medium in Europe, and low in Asia.All high and medium risk areas therefore are in Europe or European colonies; thus MS is the white mans burden spread from western Europe. Within the U.S., MS is less common among Negroes, Japanese, and possibly Amerindians than in whites regardless of geography. Migration studies among risk areas indicate that migrants keep much of the risk of their birthplace, but also that overall the risk is decreased by high-to-low migration, and probably increased by low-to-high. For the former, it seems that adolescence is the age critical for retention of birthplace risk. Some preliminary data on a possible epidemic of MS are also presented.All the epidemiologic information would be most easily explained if MS were an infectious (?viral) illness with prolonged latency. The proof of this though must come from the laboratory.ZusammenfassungDie Daten über Mortalität und Vorkommen der Multiplen Sklerose zeigen eindeutig, daß es sich um eine Krankheit mit einer bestimmten geographischen Verbreitung handelt, und daß die Multiple Sklerose als eine erworbene, (exogene) umweltbedingte Krankheit angesehen werden muß. Gebiete mit hoher Frequenz der Multiplen Sklerose liegen in Europa zwischen dem 65. und 45. Breitengrad, in den nördlichen Vereinigten Staaten, Südkanada, Neuseeland und Südaustralien. An diese Regionen grenzen solche mit einer mittleren MS-Frequenz, in Europa nördlich, östlich und südlich, in Amerika gilt das für die südlichen Vereinigten Staaten und es gilt für den Rest von Australien. Lateinamerika, Asien und Afrika zeigen im wesentlichen nach den heutigen Untersuchungen eine niedrige Frequenz. Aber der Breitengrad ist nicht genug: auf dem 40. Breitengrad nördlich ist die Multiple Sklerose in Amerika sehr häufig, mittelhäufig in Europa und niedrig in Asien.Alle Gebiete hohen und mittleren Risikos liegen deswegen in Europa oder in den europäischen Kolonien. Die Multiple Sklerose ist also die Bürde des weißen Mannes, die sich von Westeuropa aus ausgebreitet hat. Innerhalb der Vereinigten Staaten ist Multiple Sklerose seltener bei den Negern und Japanern und wahrscheinlich auch bei den amerikanischen Indianern als bei den Weißen, unabhängig von der Geographie. Untersuchungen des Einflusses der Wanderung von Risikogegenden aus zeigen, daß die Wanderer das Risiko ihrer Geburtsländer mit sich bringen, daß aber im großen und ganzen das Risiko abnimmt, wenn die Wanderung von risikoreichen zu risikoniedrigen Gebieten erfolgt ist, und daß das Risiko zunimmt, wenn die Wanderung in umgekehrter Richtung erfolgt. Bei der ersteren scheint es, daß die Adoleszenz das kritische Alter für die Beibehaltung des Risikos des Geburtslandes darstellt. Es werden vorläufige Daten einer möglichen MS-Epidemie vorgestellt. Alle epidemiologischen Unterlagen werden am leichtesten erklärbar, wenn die Multiple Sklerose eine infektiöse (Virus?) Krankheit mit langer Latenz wäre. Der Nachweis dafür muß allerdings durch Laboratoriumsuntersuchungen erbracht werden.

STUDIES ON THE NATURAL HISTORY OF MULTIPLE SCLEROSIS: 1. Design and Diagnosis

After a century of investigative effort the etiology of multiple sclerosis (MS) remains unknown and no specific therapy is available. Variability in course as well as possible multiplicity of cause suggest the need for more careful studies of natural history. Epidemiologic studies of the disease have produced evidence that incidence depends on geographic and climatic factors, but these relationships have not been specific enough to stimulate investigation on more fundamental levels. Such studies have been hampered by difficulties in acquiring series of adequate size and representativeness and in making parallel, concurrent observations on suitable controls. The U S . veteran population is an exceptional resource ( 3 ) for epidemiologic investigations, since it comprises an enumerable population, well-indexed at many points of medical interest. Its potential for longterm follow-up is better than that of any comparably large segment of the U.S. population. For investigations of multiple sclerosis there are other advantages as well. Since men with known multiple sclerosis were ineligible for military service in World War I1 ( 1 2 ) , those so diagnosed during service provide a sample of the disease in its earlier phases. Such a sample cannot be reliably constructed outside a complete medical care program such as the armed services provided. A t entry into service, before multiple sclerosis was diagnosed, extensive

STUDIES ON THE NATURAL HISTORY OF MULTIPLE SCLEROSIS 6. Clinical and Laboratory Findings at First Diagnosis

Signs, symptoms, and laboratory findings were presented to describe an early bout of multiple sclerosis (MS). Data were derived from U.S. Army hospitalizations during the World War II period. For 293 men (group A), there had been previous bouts before the one for which they were hospitalized in the Army, whereas for 234 men (group B), this Army hospital bout was the onset bout. Median duration of this Army diagnostic bout was 2 months from onset to neurologic examination. Signs found at neurologic examination were classified into 8 functional systems: pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, cerebral, and miscellaneous; symptoms were categorized into 8 equivalent groups. Over‐all dysfunction was graded according to the Disability Status Scale. There was a moderate degree of concordance between signs and symptoms of each type. In every aspect save one, the group A and group B cases were indistinguishable; visual dysfunction was somewhat more prevalent in group A. Involvement at examination was most common in pyramidal (85 %), cerebellar (77 %), brain stem (73 %), and sensory (55 %); less common were bowel and bladder (23%), visual (34%), cerebral (mostly mood change) (21 %), and miscellaneous signs (15 %). Each functional system tended to correlate with over‐all disability in both frequency and severity of involvement. When symptoms were distributed by limbs affected, motor and coordination complaints showed a predilection for lower limbs and a tendency to symmetry, whereas sensory complaints were almost equally common in each body part. Cerebrospinal fluid findings were in accord with those of most series. There was no relationship of any or all CSF abnormalities with total duration of illness, duration of the bout, over‐all disability, or type or severity of any functional system, except for a possible correlation between pyramidal signs and abnormalities of colloidal gold curve, and pyramidal signs and any abnormality of CSF. These data, in addition to detailing an early bout of MS in a nationwide sample of males, also provide the bases for our later efforts to predict the course of illness for the persons affected.

STUDIES ON NATURAL HISTORY OF MULTIPLE SCLEROSIS

The early manifestations of multiple sclerosis (hSS) are seldom directly observed, and their characterization therefore has been open to some question because of the inevitable dependence upon the patient’s memory of events often years past. Furthermore, being drawn from hospital or clinic files, most series may well be overweighted with severe cases. In contrast, the experience of a screened military population provided with complete medical care would seem to afford a better opportunity to describe the onset of hfS as it occurs in the general (male) population. A diagnosis of ASS was cause for rejection from service. When on active duty, any symptomatology interfering with military activities led to early hospitalization. Whenever there was a suspicion of MS, neurologic evaluation followed, since this diagnosis was grounds for medical discharge from service. For these reasons, we have been seeking information on the natural history of MS on the basis of the U. S. Army experience in World War 11. The general design of the study (Nagler et al. 1966), an assessment of optic neuritis ( K u r l a n d et al. 1966), and the epidemiologic features (Beebe et al. 1967) have thus far been published. In this paper, the first on the

Studies on the natural history of multiple sclerosis. 2. The progression of optic neuritis to multiple sclerosis.

Optic neuritis may be defined as involvement of the optic nerve by toxic, metabolic, infectious, hereditary, or dcmyelinating processes. In a young adult, optic neuritis is often considered a forerunner of multiple sclerosis if no specific cause can be identified. Optic neuritis is divisible into retrobulbar neuritis and optic papillitis, depending on the site of involvement as inferred from the ophthalmoscopic appearance. The annual incidence of optic neuritis has been estiniatcd at 4 to 5 per 100,000 population ( 1 3 , 1 8 ) , a rate several times greatcr than the incidence of multiple sclerosis in the United States (18). The present investigation is part of a study of the natural history of multiple sclerosis based upon the experience of men in the U S . Army in World War I1 (22) in which geographic or climatic influences on the progression of multiple sclerosis were to be evaluated. The mcn with optic neuritis were chosen since visual impairment during military service almost always lcads to a medical evaluation. Early in the investigation, however, it became clear that the great majority of men with optic neuritis were not considered to have multiple sclerosis according to subsequent Veterans Administration records. The study was thcrcfore redirected to the question of the likelihood of multiple sclerosis developing after an attack of optic neuritis in young adult males.

FURTHER FEATURES OF THE FENNOSCANDIAN FOCUS OF MULTIPLE SCLEROSIS

Reassessment of the distribution of multiple sclerosis with the methodology employed in previous work provides strong evidence for a single focus of high‐frequency MS in Norway. This focus occupies the eastern mountain plains area of Southern Norway and extends to the coast on both south and east, as well as northward to encompass the entire waist of Norway up to some 64° north latitude. The distributions are very similar for both cumulative death rates (1951–65) and for disability‐pensioned cases (1966), when assessed according to residence within the 104 small units comprising Norway, a number which represents the lower limit of unit size for the method used. In combination with the previously described distributions of MS within small units of Sweden and intermediate‐sized units of Finland, the Norwegian data provide even stronger evidence for the existence of a single Fennoscandian focus of high‐frequency MS, extending from the southern mountain plains of Norway eastward across the inland lake area of southern Sweden, across the Bay of Bothnia to south‐western Finland, and thence back to Sweden at Umeå. The combination of separate studies is thought valid in the light of the strong correlations between distributions of MS covering different generations of patients in Denmark, Switzerland, and Norway. The slope of the regression line for these three lands is about the same, and is such as to raise the possibility of the diffusion of MS over time in these countries.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF MULTIPLE SCLEROSIS

The criteria of the Schumacher committee appear to be the most practical set of requirements for the clinical diagnosis of multiple sclerosis. Multiplicity in both time and space are essential for this disease. A combination of optic nerve involvement, long‐tract signs and evidence of brain‐stem dysfunction is a constellation which is most likely to be due to multiple sclerosis in young individuals. Even here though, other disorders need be kept in mind: Lebers optic atrophy, heredofamilial spinocerebellar degenerations, nutritional disorders, ischemic and inflammatory vascular disease. When the eye is not involved, one need also consider Behçets disease and other chronic meningoencephalitides. Regardless what the course of illness has been, a lack of spatial dissemination within the central nervous system precludes a diagnosis of MS. Brain stem or spinal cord disorders are notorious for causing disturbances suspicious of multiple lesions when in fact a single local lesion is operative. Early development of dementia or seizures, or the presence of extrapyramidal signs, stupor, aphasia, or focal atrophy with fasciculations is in each instance most unusual in MS.

Tremor in progressive supranuclear palsy

ABSTRACT— Reports of tremor in progressive supranuclear palsy (PSP) have been infrequent; some authors indicate that tremor is never seen in PSP. Five patients with PSP and tremor are presented. Our series of cases and those reviewed in the literature suggest that tremor occurs in 12–16% of PSP cases. The rest tremor observed in 3 of our cases differed from the “pill‐rolling” and “parkinsonian tremor” described in previously reported cases by being slower in rate (3 per second or less). This slow rest tremor is rarely seen in Parkinsons disease (4–6 per second). Our experience suggests that, contrary to previous opinions, tremor may be the presenting complaint and a prominent finding in PSP and the presence or absence of tremor is of no value in the differential diagnosis of PSP from Parkinsons disease.

Some epidemiological trends in multiple sclerosis

Abstract For the last 25 years multiple sclerosis (MS) has been one of the most intensively studied of all the diseases of the human nervous system. What is the geographic distribution of MS cases, how is the incidence of the disease affected by age, sex or race? The answers to questions such as these are not just of clinical interest, they also hold clues as to the etiological factors involved.