Schriftenreihe N eurologie

Neurology Series 20

Herausgeber
H. 1. Bauer, Gattingen . G. Baumgartner, Zurich· A. N. Davison,
London· H. Ganshirt, Heidelberg . P. Vogel, Heidelberg

Beirat
H.Caspers, Munster· H.Hager, GieBen· M.Mumenthaler, Bern
A. Pentschew, Baltimore· G. Pilleri, Bern· G. Quadbeck, Heidelberg
F.Seitelberger, Wien· W.Tannis, Kaln
Sigrid Poser

Multiple Sclerosis
An Analysis of 812 Cases by Means of
Electronic Data Processing

With 28 Figures

Springer-Verlag
Berlin Heidelberg New York 1978
Privatdozentin Dr. Sigrid Poser
Neurologische Klinik und Poliklinik der Universitat Gottingen
Robert-Koch-StraBe 40, D-3400 Gottingen

ISBN-13: 978-3-642-87570-0 e-ISBN-13: 978-3-642-87568-7

001: 10.1007/978-3-642-87568-7

Library of Congress Cataloging in Publication Data. Poser, Sigrid, 1941- Multiple sclerosis. (Neurology series; 20)
Bibliography: p. Includes index. 1. MUltiple sclerosis-Cases, clinical reports, statistics-Data processing.
I. Title. II. Series: Schriftenreihe Neurologie; 20. RC377.P67 616.8'34'09 78-2266
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© by Springer-Verlag Berlin· Heidelberg 1978.
Softcover reprint of the hardcover 18t edition 1978
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Foreword

The value of prospective long-term studies on the features and course of

multiple sclerosis is determined by the reliability with which relevant infor-
mation is documented. This involves two basic problems: I) The docu-
mentation system used must be detailed enough to provide adequate data
on the essential features and course of the disease in a given case; on the
other hand, it must not be so complicated and cumbersome as to preclude
its use in the routine care of MS patients. 2) Since no system can fully
anticipate new problems and scientific approaches that may become impor-
tant at some future time, the system must be open to provide the possi-
bility of adding and correlating the data of special research studies with the .
basic data.
These considerations led to the development of the basic documentation
system described here and employed for the analysis of clinical data in
this monograph. The work was carried out with the help of the Deutsche
Forschungsgemeinscha/t as a part of its research program on multiple
sclerosis and related demyelinating disease. A basic documentation pool
including the data of more than 2 000 patients has been accumulated in
the last six years. The system has been put to practical use in a number of
epidemiologic surveys completed or under way, in following up the cases
in an epidemiologic observation area in South Lower Saxony, and in
studies on spasticity, cerebrospinal fluid findings, clinical forms and neuro-
physiological aspects of MS.
The author deserves great credit for developing and improving the optical
mark reader sheets and for her decisive work in the organization and main-
tenance of the system now in use.
Documentation programs are laborious, time-consuming and, over long
stretches of the work, not endowed with the glamour that makes experi-
mental approaches and laboratory studies based on intriguing hypotheses
so fascinating. MS, as a disease of only the human species, cannot be fully
comprehended in its etiology and pathogenesis, however, unless reliable
data on the features and the course of the disease are accumulated in pro-
spective studies, with sufficiently large data banks available to make possible
VI

the selection of comparable cases for investigations focussed on special

problems. This monograph by Dr. Sigrid Poser testifies to the diligence and
continuity with which such basic work has been accomplished and is being
continued.

February 1978 Prof. Dr. H. J. Bauer

Director, Neurological Department
University of G6ttingen
Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 The Need for a New Documentation System . . . . . . . . . . . . . . . . . . . 2
1.2 Current Methods of Documentation in General Neurology ......... . 4
1.3 Documentation of Special Neurologic Diseases . . . . . . . . . . . . . . . . . 4

2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1 Different Forms of Documentation . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1.1 Punched Cards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1.2 Modern Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2 Choice of Documentation Method for Multiple Sclerosis .......... . 9
2.2.1 Development of the Documentation Sheet for Multiple Sclerosis .... . 10
2.2.2 Handling of the Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.3 Quality Control of the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.4 Management of the Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.4.1 The Process of Registration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.4.2 Description of the Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.4.3 Access to the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l2
2.4.4 Correction of Errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.5 Analysis of the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.6 Distribution of the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.7 The New Set of Documentation Sheets . . . . . . . . . . . . . . . . . . . . . . 16
2.8 Statistical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.8.1 Significance Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.8.2 Graphic Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3. Results .......................................... . 19
3.1 Size of the Study .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ., 20
3.2 Comments on the Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2.1 Analysis of Errors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2.2 The Precision of Recording . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.2.3 Free Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.2.4 Validity of the System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.3 Documentation of Disease Course .. . . . . . . . . . . . . . . . . . . . . . . . .. 25
3.4 Analysis of All Examinations Performed . . . . . . . . . . . . . . . . . . . . . . 25
3.5 Analysis of First Examinations ... . . . . . . . . . . . . . . . . . . . . . . . . .. 26
VIII

3.5.1 Month of Onset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 27

3.5.2 Age at Onset, Present Age, and Differences Between Males and Females. 27
3.5.3 Disturbances of the Functional Systems ... . . . . . . . . . . . . . . . . . .. 29
3.5.4 Selection of Certain Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 31
3.5.5 Statistical Analysis of Symptoms .......................... 32
3.6 Correlations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 35
3.6.1 Correlation Between Mental Changes and Other Disturbances . . . . . . .. 35
3.6.2 Duration of Disease and Symptoms . . . . . . . . . . . . . . . . . . . . . . . .. 37
3.6.3 Duration of Disease and Performance ....................... 39
3.6.4 Age at Onset and Performance ............................ 40
3.6.5 Disease Course and Performance .. . . . . . . . . . . . . . . . . . . . . . . . .. 43
3.6.6 Analysis of Bouts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 46
3.7 Diagnostic Classification ................................ 47
3.8 Laboratory Results ................................... 48
3.8.1 CSF Findings ....................................... 48
3.8.2 Serologic Studies ...................................... 49
3.9 Different Samples .................................... 49
3.9.1 The Epidemiologic Study ............................... 49
3.9.2 Subgroups ......................................... 50
4. Discussion 53
4.1 Clinical Questions .................................... 54
4.1.1 Prognosis .......................................... 54
4.1.2 The Problem of Diagnosis ............................... 62
4.1.3 Statistics on Signs and Symptoms ..................... . . . .. 63
4.1.4 Follow-Up Examinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63
4.2 Critical Comments on the Method . . . . . . . . . . . . . . . . . . . . . . . . .. 63
4.3 The Contribution of the New Documentation System to MS Research .. 66

s. Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 67
5.1 Neuropathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 68
5.2 Virology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 68
5.3 Immunology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 70
5.4 Relevance of CSF Findings .............................. 71
5.5 Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 71
5.6 The Standardized Medical Record ....................... . .. 72

Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73
References .............................................. 75
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
1. Introduction
2

Abbreviations

MS Multiple Sclerosis
CSF Cerebro-Spinal Fluid
FRG Federal Republic of Germany
DFG Deutsche Forschungsgemeinschaft (German Research Society)
GDI Grunddokumentationsbogen I (Basic Documentation Sheet I)
GD II Grunddokumentationsbogen II (Basic Documentation Sheet II)

1.1 The Need for a New Documentation System

The etiology of multiple sclerosis (MS or disseminated encephalomyelitis)

is still unknown. A causal therapy is therefore not possible, and the limited
success of symptomatic treatment is felt by the individual patient all too
often. These therapeutic limitations have wide social consequences, because
MS runs a chronic course affecting mainly young people, and because it is
one of the most common neurologic diseases.
The prevalence of MS in central Europe (see McAlpine et aI., 1972) is
approximately 50 patients per 100,000 inhabitants. An epidemiologic study
in Lower Saxony yielded a rate of 36.8/100,000 inhabitants (Firnhaber,
1969). Thus, the number of MS patients in the Federal Republic of Ger-
many (FRG) could be 22,000 or more. A proportion of cases are probably
missed because of diagnostic difficulties, particularly in early and atypical
cases (Kappeli et aI., 1972, v. BUren et aI., 1972). However, Schrader's (1974)
figure of more than 100,000 MS patients for the FRG was not based on
systematic investigations and could be an overestimate.
Although social and medical care for MS patients has been inadequate in
the past and still needs much improvement (Heier, 1973), there has been an
interest in the etiology and pathogenesis of the disease for years. A broad
spectrum of scientific methods have been applied, and a variety of hypoth-
eses presented. Nowadays, the idea of a slow virus infection prevails; some
authors discuss the additional role of immunologic factors (see Bauer, 1970).
With increasing specialization in research methods, it has become increas-
ingly difficult to relate the clinical symptomatology of MS to scientific
data. It is possible that the term "MS" represents a syndrome rather than
a disease. The form, duration, intensity, localization, and time course of
MS vary considerably. These complications have to be kept in mind in the
interpretation of laboratory results and in clinical trials.
The correlation of laboratory findings with clinical data presents prob-
lems. The majority of patients are treated in hospitals where both the inter-
 3

est in and facilities for scientific work are limited. Conversely, institutions
and university hospitals have special facilities and staff but usually only
a limited number of patients.
The documentation of clinical findings varies from hospital to hospital.
As a result, the correlation of research findings to symptomatology has al-
ways been limited to small groups (Bradshaw, 1964; Vymazal et aI., 1966;
H. Strotker, 1968; S. Strotker, 1969; Schwartz et aI., 1970; Castaigne et aI.,
1971;Stenuit, 1972;Baderetal., 1973; Jersild et aI., 1973b;Olssonetal.,
1973; Salmi et aI., 1973; Schuller et aI., 1973; Tichy et aI., 1973; Frick et
aI., 1974).
In clinical studies the number of patients is usually too small for useful
statistical analysis. For instance, it is still not known whether or not the
age at disease onset has an influence on the prognosis of MS.
In 1970 a program "Etiology and Pathogenesis of Multiple Sclerosis and
Related Diseases" was started as a Schwerpunktprogramm (Priority pro-
gram) of the Deutsche Forschungsgemeinscha!t (DFG). The main purpose
was to relate laboratory results to clinical data on a large scale. A standard-
ized documentation system was planned for the collecting of clinical data,
and an electronic data processing program for subsequent storage and anal-
ysis. The data should finally be available to all members of the project
(17 hospitals, as well as research groups in virology, immunology, morphol-
ogy, epidemiology, biochemistry, documentation, and histocompatibility):
The first step was therefore to find a suitable documentation system.
Numerical data are not difficult to record in a standardized form: however,
case histories and clinical data present problems (Ehlers et aI., 1975).
Traditional medical records are usually incomplete and often imprecise.
Systematic analysis of such records is difficult, if not impossible (Immich,
1964; Jenkins, 1966; 0011, 1968; Kroner, 1969; Wagner 1969; Feinstein,
1970; Gordon, 1970; Wersig et aI., 1971). It is evident that documentation
of clinical data, the main topic of this paper, must be revised if further
research is to be productive.
Roser et ai. called for standardized clinical data as early as 1841. This
idea was not followed up until Bleuler complained in 1919 of the insuffi-
ciency of medical records in his book Das autistisch-undisziplinierte Den-
ken in der Medizin und seine tlberwindung (Overcoming Autistic, Undisci-
plined Thinking in Medicine).
At about the same time, Kraepelin (1919) developed a new system of re-
cording clinical data on a Ziihlkarte (a precursor of punching documents).
He registered not only the personal data of each patient but also the etio-
logy, pathogenesis, and course of the disease. It has taken a long time for
this system to be generally accepted, and it is still being developed.
4

1.2 Current Methods of Documentation in General Neurology

Standardized recording techniques have already been applied in the follow-

ing fields of neurology: Electroencephalography (Metcalf et aI., 1960;
Doose et aI., 1962; Bochnik et al., 1964; Oberhoffer, 1967; Helmchen et
aI., 1968; Baust, 1971; Penin et aI., 1972), echoencephalography (Galicich
et aI., 1971), neuroradiology (Korein et aI., 1965, 1966; Kricheff et aI.,
1970), brain scanning (Heiss et aI., 1970), electromyography (Baust, 1971,
Micheloyannakis et aI., 1974), and neurootology (Claussen, 1973).
These techniques have made possible analysis by electronic data process-
ing in these fields.
Metcalf et ai. (1960) and Doose et ai. (1962) used the punch card system
to correlate EEG findings with clinical data. Oberhoffer (1967) introduced
the optical mark reader documentation system into neurology for the same
purpose. Penin et ai. (1972) continued along this line, and Patzold et ai.
(1973) and Haller et ai. (1973) were the first to publish results obtained
this way.
Moiseeva (1967) worked on a systematic classification of reflexes with a
view to computerized diagnosis and decision-making in the future. In 1969
Schmitt published his experiences with electronic data processing in the
Bad Homburg Neurologic Hospital, but did not mention the documenta-
tion of his neurologic findings. Baust developed a new system of medical
recording in neurology with an on-line computer terminal (Baust, 1971,
1973). The work of v. Albert (1973) and Patzold et aI. (1975) on an opti-
cal mark reader documentation system is still in progress. Vastola et al.
(1973) recommended the use of a computer for screening ambulatory neu-
rologic patients.

1.3 Documentation of Special Neurologic Diseases

Standardized documentation systems exist mainly for those neurologic

diseases in which diagnosis and case control are based on clinical data rath-
er than on laboratory findings. This applies to MS as well as to Parkinson's
disease. Standardized registration of patients with parkinsonism is well
established (Fairman et aI., 1956; Canter et aI., 1961; Webster, 1968).
The first documentation systems for MS were developed in the context
of therapeutic studies (Arkin et aI., 1950; Alexander, 1951). Details of signs
and symptoms were omitted in favor of information about disability. This
method was extended by Kurztke (1961, 1965) and applied to a large-scale
study on the influence of ACTH on acute bouts of MS by Tourtellotte et
ai. (1965) and Kuzma et ai. (1965).
 5

This tendency to concentrate on disability was shown by other authors

with a view to giving a prognosis (McAlpine et al., 1952; Thygesen, 1953;
Hyllested, 1956; Bauer et aI., 1963; Broman et aI., 1965; Fog, 1965a;
Pedersen, 1965; Gilland, 1965; Cendrowski, 1971). Usually, a mixed group
of patients were examined. Retrospective analysis of the duration and course
of their disease together with their present disability gave a general prognos-
tic index. Fog et ai. (1970) determined the individual prognosis for 73 pa-
tients by analyzing their case histories. Kurtzke et al. (1968, 1969) followed
up the performance of American veterans over longer periods of time.
However, in addition to the disadvantage of bias of selection, in this study
grading of the disability was done in retrospect, based on medical records
and not on a specially designed examination.
A standardized system for the documentation of signs and symptoms of
MS has not yet been developed 1. One of the early descriptions of the disease
was by Charcot in 1868, and MS symptoms have appeared in medical re-
cords since then. These records were the source of numerous statistical anal-
yses (E. MUller, 1904; Berger, 1905; Bramwell, 1905, 1917; Bohmig, 1925;
Obstander, 1926; Marburg, 1932; Sallstrom, 1942; Lazarte, 1950; MacLean
etal., 1951;AbbetaI., 1956;Papac, 1957; Morsier, 1971). The value of
retrospective studies of this kind is limited; records are often incomplete
and sometimes illegible, various diagnostic criteria are applied, and defini-
tions used for the description of signs and symptoms are not always given.
A few authors (R. MUller, 1949; Leibowitz et aI., 1964a, b; Panelius, 1969)
have based their statistical analyses of clinical findings on specially designed
examinations of patients.
The course of events is particularly important in chronic disease, which is
characterized by bouts and remissions. Since data taken from traditional
medical records and the patients' own recollections are often inaccurate,
the only way to get reliable information is to keep standardized records
from the very onset of the disease. This is difficult to achieve and requires
good communication and cooperation with physicians, who might be more
positively motivated if shown the advantages of such a system (Proppe,
1960).
The concept of the DFG's program on MS was to approach questions of
etiology and pathogenesis with a wide range of well-documented data. It
was hoped that this large-scale computerized analysis might reveal new in-
formation about the disease. This paper describes the development and use
of a standardized documentation system for clinical MS data, which was
simple enough for multicenter use, and yet sufficiently detailed for scien-
tific analyses and correlations.

1 Simultaneously with the system presented here, Fog et al. (1976) developed a detailed
punched card documentation system.
2. Methods
8

2.1 Different Forms of Documentation

2.1.1 Punched Cards

Punching documents were developed from the Ziihlkarte. The available data
are written on these punching documents in coded form and then transfer-
red to punched cards by punch operators. The punched card is one of the
most frequently used devices for reading data in fields where information is
basically numerical (for instance, laboratory results). All nonnumerical data
must be coded before the punching process, a disadvantage that can be elim-
inated in other systems (see below). The registration of personal patient
data (name, sex, date of birth, marital status, residence) on punching doc-
uments presents no real difficulties because the items of data are well de-
fined. Problems arise with the documentation of diagnoses. A standard
classification system does not exist. For instance, WHO's international key
for diagnoses is not generally accepted in the field of neurology. Individual
codes are used (Seitz, 1973), which makes standardized documentation
difficult. In the field of psychiatry the international code is in general use
in Germany (Helmchen, 1974), and a common system of recording patients'
personal data and diagnoses is possible (Eckmann et aI., 1973).
A standardized system of recording clinical findings on punching docu-
ments has been used only in a few hospitals (Hosemann, 1946; Proppe et
aI., 1953; Ehlers, 1967b). A few multicenter studies have been made in the
context of smaller, easily defined problems (Dold, 1970).

2.1.2 Modern Methods

The newly developed methods of recording and processing data facilitate

large-scale documentation. The advantage of the optical mark reader system
(Ehlers, 1967a) is that data can be recorded without coding, Le., time is
saved, and coding and punching errors are avoided. Boxes are already
printed on forms, each box associated with a particular sign or symptom
and marked with a pencil or left open. The pencil marks are then detected
by an optical reader. (Photo cells detect the different reflections of light:
see ruM 1968.) The reader is used off line (Le., without direct access to the
computer), simply for storing information on punched cards or tape; or it
is used on line as a direct input device. Computerized plausibility controls
allow detection and rejection of incorrectly or incompletely marked sheets
A wide range of data can be recorded on a single sheet (Ehlers, 1967a;
Ehlers et aI., 1968).
 9

In some fields standardized data have to be supplemented by free text.

This free text can be recorded on the same sheet, but it has to be punched
onto cards later. The simplicity of the off line procedure of optical mark
reading makes it suitable for multicenter studies. Individual groups do not
need computer facilities; processing can be done centrally. However, this
centralization has the disadvantage that delays are encountered in the han-
dling of incorrectly marked sheets. This can be particularly troublesome in
intensive patient care.
The optical mark reader system is now used in numerous fields of medi-
cine (Poser et aI., 1974b). However, it is important to remember that well-
designed questions and precise definitions are required if the system is to
be successful. Two groups of psychiatrists succeeded in designing an optical
mark reader documentation system for multicenter use (see Angst et aI.,
1969; Spitzer et aI., 1971). The system stood up well in several therapeutic
trials (Berner et aI., 1971; Angst et al., 1971; Bente et aI., 1974). It allows
the recording of data from the patient's case history as well as physical and
mental findings.
Optical mark reader systems have already been used for recording case
histories in other fields of medicine (internal medicine: Giere et aI., 1972;
surgery: Grund-Krehl, 1973). Several attempts have been made to tailor
questions about case history to each individual patient by using a computer-
aided questionnaire. This modem method has also been suggested for phys-
ical examinations (Reichertz, 1973).

2.2 Choice of Documentation Method for Multiple Sclerosis

A first approach to standardized documentation of MS patients was made

in the Department of Neurology of G6ttingen University. Between 1963
and 1968 data from 625 inpatients were recorded on punching documents
(Bauer et aI., 1978). The form was developed in connection with the Ger-
man Ministry of Labor's study on the feasibility of rehabilitation for MS
patients already receiving compensation. In this investigation 22 of 80 items
concerned working capacity; neurologic findings were recorded briefly in
terms of disability only.
The present attempt to correlate clinical and laboratory data required
more detailed documentation of neurologic signs and symptoms. As men-
tioned above, the optical mark reader system was considered suitable for
this purpose. It soon became evident to us that we should consider only
those signs and symptoms most frequently observed in MS.
The recording of all available neurologic findings had proved to be time
consuming and tiresome (Poser et aI., 1976a). Thus, the first aim here was
10

to design a single documentation sheet containing the data most relevant to

the research groups concerned.

2.2.1 Development of the Documentation Sheet for Multiple Sclerosis

A preliminary sheet was used in a pilot study (Poser, 1974). After discus-
sion with the participating physicians about the difficulties that arose, mod-
ifications were made in the sheet. The standard examination was not fol-
lowed exactly; and it became evident, for example, that reflexes were in-
conveniently placed on the sheet, and that there were too many details
about sensory signs and symptoms.
The final documentation sheet (see Fig. 1 inside back cover) was divided
into three main parts:
1. Personal data of the patient and hospital identification.
2. Case history, CSF findings, diagnostic classification, complicating and
unrelated diseases.
3. Present neurologic findings.
A survey of the main items is given on Figure 2.

--
---
Date of
r-
Hos- Identification - Number

pital of the Patient

Examination

Personal Data

'inr@ia/@d ni.~".@.

Date of Onset Free Text

Motor Functions
Cranial Nerves

Reflexes Sensory
Brainstem
Findings
Mental State
Performance

Gait SvnoDsis

Coordination
Free Text Fig. 2. Layout of the main items
Tremor on the documentation sheet
 11

The first part was arranged in a similar way to sheets already being used
in other hospitals of Gottingen University. This made sharing of a common
plausibility program possible.
Part 2 gave the date of birth and time of onset of the first symptoms (left
side); and the course of the disease, a summary of CSF findings, diagnostic
classification, and complicating and unrelated diseases (right side). Quanti-
tative details of the CSF findings would have taken too much space and
were therefore omitted on this first sheet.
The arrangement of clinical findings on the lower part of the form fol-
lowed the usual pattern of a neurologic examination. A summary of clin-
ical findings was given at the end. Additional data could be written as free
text in the lower right hand comer.
A form-filling guide was added to each sheet. This contained technical in-
structions and explanations of abbreviations as well as definitions of terms
used on the sheet.

2.2.2 Handling of the Sheet

Members of participating hospitals and institutions met during the first

workshop of the DFG-Schwerpunktprogramm in December 1971 in order
to become familiar with the new system. The documentation procedure
was demonstrated during examination of a patient. Since January 1972,
seventeen hospitals have joined in the program. A central secretary's office
was responsible for the organization and coordination of the program.
Monthly reports were made on the state of the data-pool and on problems
arising.

2.3 Quality Control of the Data

Analysis of errors is particularly important in medical documentation

(Proppe et at, 1956; Immich, 1964; Wagner, 1964; Nacke et at, 1964). In
the present study plausibility programs were used to prevent the storage
of incomplete data; incorrectly or incompletely marked sheets were auto-
matically rejected. Examination and documentation of the same patient by
different physicians was used in a test for validity. Each of 25 patients was
examined in the Neurology Department of Gottingen University by two or
more physicians within a 2-day period. The results of these 65 examina-
tions were compared with the help of a computer program and the differ-
ences analyzed (see Sect. 3.2.4).
A number of patients were examined repeatedly by the same physician
over a longer period. However, it was not possible to test the reliability of
these data, since the signs and symptoms of MS can change rapidly.
12

2.4 Management of the Fonns

2.4.1 The Process of Registration
Incoming sheets were registered in the central office. An index card con-
taining personal data, the date of examination, and the name of the exam-
ining physician was set up for each patient, who was given a number. The
forms were then sent to the computing center. The information was auto-
matically transferred from the documentation sheet to three punched cards
by an IBM optical mark reader 1232 and then transferred onto a magnetic
tape and fed into a Siemens 4004/35 computer.

2.4.2 Description of the Program

A computer program is a sequence of instructions that enables the computer
to solve specific, usually repetitive tasks. Lange et a1. (1972) developed a
universal program, MARBEL, for plausibility control and storage of data on
optical mark reader sheets. By means of a program written by Mr. Wegener
and Mr. Brauns, EDP Department, G6ttingen, MARBEL was adapted to
our problem. The plausibility controls had to be individually defined for
each item (see Poser, 1974). A detailed description of the program for data
analysis is given in an earlier paper (Poser et aI., 1974b).

2.4.3 Access to the Data

Each user of the system was able to select data which interested him. The
field num bers corresponding to the particular items were transferred to a
punching document (see Fig. 3) and then were transferred manually from

Fig. 3. Punching document on which the field numbers are filled in.
135, age at onset 15,15 years
16,16 years etc.
4>15, course of disease 1, remitting
2, remitting and progressive
3, progressive from onset
4>4>9, sex of patient 1, male
2, female
138-149
152 } cIi'
mca1 sIgns
.
2, present
117 or symptoms
4>26, clinical diagnosis 1, definite
2, probable
3, possible
4>74, ability to WOrk) 1, normal see Fig. 4
2, slightly disturbed
3, severely disturbed
4>77, ability to walk 4, lost
1 .... _ _ ....

AblochSchemcl:ABNert~1 Progo.-rA_NElJG.RlJjlEUAUS ."

1....
. 1 - ....--... ........... _ J~QS 0tWm 20.2.74

FREI

~f;;~~r~Jjglrlilii!md~E~.A~ 1152h 1,..12

" I ' I I I I - I ,I. I I I I - I -t-f ~ J-o-+- I "-
I::-I: t t· I ~ I h l~h'I Il I _ I I I I i I I , I ---t--"-
I I·
1_- .-. , .--
~
1-· .~-- 1:-::- H=r=tL~I : 1-:: 11 -: I : I: I l~=tl l: ~
'- I ~

E~-j . ~.· l - ~1-" r~-l~ 1:::l~I=' :ttPFfflIlll~1! FEA Zero .. .(f

1- .... -- . - -
-.tEEf~ .. I
E.. Counting Of Items
I---
O.. Selection Of Alternative
"! -:-- ~ - ... _. _...... .. ~ -!.. ... ""'- - t - : ' ~'" ... .. ~ -+'
Items
.
.--t--.---+--.
I :.:
I ~' I,;'I.~ :::~:_ ,c-l-l ~'aft
'~ . ..~-l1~ ,_ :: ~~ 1An
.. _' . - l ~'~ r-il
~ t- U.. Combination Of Items
....t., - - t o - - - • •• ~.. • '. ~...... . • ·'f-.f "1 ' 1- 1 t ot I I I .....
/' " " .' ~;jl!. ".i11 ul'1. .16:,,-•• h," X11,';n Bh~ ijl)l!3~f; Jili£\h~ h' ~4 l.liOi.~dI!!1 . ~:~tl4!.~ 41Ws{:t:~'!d:; P.1W·~~ It.3i ~lk:itLa.ln H ~M~~'t ' "I.., '7 ., •• f ,'4 w
14

the punching document to punched cards and then fed into the computer
for analysis. The results were printed out as shown in Figure 4. These print-
outs gave the field numbers, together with the number of patients exhibi-
ting the particular feature. Further analysis of the results (calculation of
mean values, standard deviation, and percentages) was performed on a
Hewlett-Packard 9820 desk-computer.

2.4.4 Correction of Errors

The mark reader sheets were returned to the central office. Forms accepted
by the computer were filed; incompletely or incorrectly marked sheets
were returned to the physicians, together with a list of particular errors
made. Corrected sheets were returned via the central office to the EDP De-
partment.

2.5 Analysis of the Data

Patients were registered according to the above-mentioned sheet until

July 1973. The file was then closed and a pair of new forms was introduced
(see Sect. 2.7). The computer program enabled us to group the patients
according to sex, age at onset, month of onset, duration and course of dis-
ease, disability, working ability, probability of diagnosis, CSF findings, and
individual signs and symptoms. Different signs and symptoms could then
be correlated with various groups and subgroups.
A selection of patients for special investigations or therapeutic procedures
was also possible. The relationship between certain symptoms and the
course of the disease could be determined by comparing different groups
of patients. The program allowed selection of patients for future tests for
correlation between laboratory results and clinical findings. Clinical data of
a particular patient could not be obtained in text form from the original
closed file. However, a print-out is already in use in the new two-sheet sys-
tem (see Sects. 5.6 and 2.7).

2.6 Distribution of the Data

Initially, only the author and programer handled the data directly. They
then had continuous access to the data while checking and correcting the
program. Other members of the project had indirect access to the data;
 15

EVALUATION OPTICAL MARK R~AOER FOR"1 01 - ~EUROLOGY - 0212A/IC)74 PAGE

PUNCHED CARD CONTENT

013515135161351713518135191 '3520 1352113 5221352313 524

PArt ENT NO.

0000019
0000021
0000035
0000051
0000094
0000108
0000124
0000161
0000115
0000280
0000331
0000353
DOD040X
OQOQ41X
0000485
0000531
0000582
0000590
OOOOb39
DODOllX
0000728
0000752
00007bO
0000817
000085X
0000892
0000949

+
EVALUATION OPTICAL "IAtl..K QEADER FOR"! 01 - ~EUlH1l0GY - 021281lQ1't

FI ELf) \35 FLEtt" 13S FIELD 135 cI'=lO 135 flU!) \15 FTELO 135 FIH1) l1o; t:tHI) l'35 F IE'lD 1" FIn/) 135
VAllJE 15 VAlUr: 16 VALIJE 17 VALUE I ' V.6.lUE 19 I/AlUI720 V~LUE 21 VA.LUE 22 VA.lUF ?1 VHUt: 2'_

NO OF CASES r;oUNTt;=D 312

OF THESE APPLICABLE HE~E 21B

~lG:IITFICANCE Of THE F I ElO NU'lBER, Sf E KEY LIST

EVAlUATI ON OPT I CAL MI\RK READER FORM 01 - NFURrJlOGY - 0212 HI 1974 Pl\r;~

PUNCHED CARD CONTENT

E0151 0152 0153 0091 \1092 13g2 1392 1402 1432 1452 1462 1472 14q2 15') 1 14q2

FIELD f)l') FIELD 015 F IELO 015 FIELD 009 FI ELD 000 FIELD 13" FI !::LD \30 fInn 140 FIFI.D 143 ;:y fLf) 14'
VALUE 1 VALUE 2 VALUE 3 VALUE 1 VALUE 7 VALUE 1 VALUI: 2 Vo\.LUf 2 VlolIJ": 2 V~lll~ 2

[23 79 16 66 152 III 150 174 177 ')')1

FIElO 14. FIElO 147 F [::LO 14a F I'::LD 1'2 FHllJ 14 0

VALUE 2 VALUE 2 VALUE 2 VAlU~ 1 VAlUE

150 17 43 101 132 "In Of" r: ~ )~<:; r:'):p.JT;:11 >1'

PUNCHEI) CARD CO".lfENT

ELL11 0261 0262 ::>263 0741 014l 0143 0144 0111007120

FIELrl ll1 FtEL!) 026 FIELD 07.6 FIELD n" FIHD 014 FIHn'174 FI':LI1 074 FJI:'Vl'174 FIFI.Il orr JOfl'"ll) r)77
vALUE 1 VALUr: 1 VALUE 2 VALUE "3 VALUE 1 VALtJE V~L'J!:"3 VI},LIJ~ 4 VAlU:: 10 VII.LUr" ?')

50 49 21 40

"Ill flF r ~<:; r:s C JUNT F'1 ?1q

Fig. 4. Computer print-out of the data that had been requested on the punching docu-
ment (for the meanings of field numbers, see Fig. 3)
16

they could send in a request for a particular analysis and later receive the
results in a computer print-out in tabulated form. All participants have di-
rect access to the new open file.

2.7 The New Set of Documentation Sheets

An extended version of the documentation system was introduced in 1973

and the data stored in a new file. The basic documentation sheet I (Grund-
dokumentationsbogen 1== GD I; see Fig. 5 inside back cover) was elaborated
by a commitee 2 after frequent discussions with the participating clinicians
and research-workers. The additional section is largely devoted to the pre-
ceding course of the disease (Poser et aI., 1973b).
The second part Grunddokumentationsbogen II (GD II; see Fig. 6 inside
back cover) was designed in cooperation with H. Hauptvogei. Graphic rep-
resentation of the body facilitates the recording of clinical findings. The
most important definitions are printed on the back of both sheets. The orig-
inal sheets are sent to the BDP Department; a copy of each sheet is filed in
the medical record.
The personal data of patients are recorded on a separate form, the Stamm-
datenbogen (see Fig. 7 inside back cover). Plausibility controls for this new
set of sheets were defined for each item as before. In the new sheets it is
possible to indicate that details from the previous history are unknown by
marking "yes" and "no" simultaneously (see instruction in the upper right-
hand corner of Fig. 5).

2.8 Statistical Methods

2.8.1 Significance Tests

Frequency distributions were compared using 2-I-tests (Kullback et aI.,

1951). Unlike the Chi-square-test, they provide for analysis of contingency
tables with small numbers (Sachs, 1968, p. 475 ff.). The coefficient of con-
striction was calculated using the method of Lienert (1973). It is similar to
the correlation coefficient and can vary between 0 and ± 1. The age at onset

2 H. Angstwurm, Mtinchen; W. Grtininger, Wtirzburg; H. Hauptvogel, G6ttingen;

U. Patzold, Hannover; S. Poser, G6ttingen; D. Przuntek, Wtirzburg; W. Weinrich, Han-
nover.
 17

and duration of the disease were each given as the mean ± the standard devi-
ation.
Analysis of variance revealed that not all numerical data were normally
distributed, whereupon distribution-free significance tests were used.
Wilcoxon's rank test was used for comparison of two independent samples,
the H-test of Kruskal and Wallis for comparison of more than two indepen-
dent samples (Sachs, 1968, pp. 302-306). The null hypothesis was as-
sumed to be wrong if p < 0.05. These significance tests were performed on
a PDP 12 computer (Digital Equipment Maynard, USA).

2.8.2 Graphic Presentation

When symptoms or disability were to be considered graphically as func-

tions of time, a weighted mean was used (averages taken over 5-year peri-
ods). Short-term irregularities were thereby eliminated (Pfanzagl, 1966).
3. Results
20

3.1 Size of the Study

In this study, 1125 examinations of 947 patients were recorded from No-
vember 1, 1971 until July 19, 1973. Thirty-two physicians in 17 hospitals
participated. When the data file was closed in August 1973, only 990 exam-
inations of 812 patients were available for analysis. The other 135 sheets
were still being corrected. The latest results are based on 831 patients (state
offile in January 1974). For practical reasons it was not always possible to
include all 812 patients in all tests (see details below).

3.2 Comments on the Method

3.2.1 Analysis of Errors

Details on the frequency of errors during different periods of time cannot

be given; the optical mark reader rejected sheets that were incompletely
or incorrectly marked. The sheets were returned to the physician; unfor-
tunately, statistics on this procedure were not collected. Before the plausi-
bility program was working, the quality of the marking was checked man-
ually. During this period the rate of errors fell from 30 to a final level of
10-15 per 100 sheets.
At the end of the study, when the plausibility program was used, it was
found that 4 out of 47 sheets were not correctly marked. The following
errors were made:
1. Incorrect registration of patient identification numbers.
2. Contradiction in the description of symptoms by marking "no distur-
bance" and "sensory symptoms present" in the same field.
3. Misunderstanding of the definitions given.
4. Simple omission and incomplete erasing
A particularly frequent source of error was omission of zeros at the end of
a number, whereupon a special reminder was printed on the new sheets (see
Fig. 5, upper right-hand comer). Sensory signs and symptoms and distur-
bances of cranial nerves were sometimes completely ignored, perhaps be-
cause these fields were easily overlooked. There were sometimes inconsis-
tencies between the summary at the end and the main body containing
more detailed information. Refusals were often the result of technical prob-
lems, e.g., if the surface of the paper was damaged by erasing or if a mark
was not sufficiently clear.
The plausibility controls were not general enough to check all types of
data. There was not always enough room to record "no", "yes", or "un-
 21

known" for each item separately. For example, control over micturition,
bowel function, sexual function, and circulatory and trophic regulations
had to be considered together as vegetative disturbances (see Fig. I, lower
right-hand part). If one of these symptoms was marked, there was no way
to check whether the examiner had asked for any of the others. For in-
stance, sexual disturbances were often not discussed at all. They were ap-
parently more common in men than in women (see below), although it is
possible that more men than women talk about this problem spontaneously.

3.2.2 The Precision of Recording

The quality of recording varied between the two extremes shown in Fig-
ures 8 and 9. The items were marked by crossing the boxes with a ball-
point pen on the sheet of Figure 8; in this form the sheet could not be read
at all. The neat record seen on Figure 9 was made by a physician working in
a busy hospital for MS patients. She participated in this survey regularly and
had the least number of errors despite a considerable work load. Some doc-
tors could be recognized by their specific and recurring pattern of errors.
The number and kind of errors thus seem to depend on the individual phy-
sician.

3.2.3 Free Text

Free text was added frequently; in the beginning, 35% of the sheets con-
tained additional findings, later 30%. Usually, the free text included CSF
findings or comments on other diseases. Technical comments appeared in
10% of the sheets at the beginning and in 3% later.
Documentation difficulties were often found in the Romberg and Gang
(gait) fields; unfortunately, the sheet did not allow for a "not possible to
examine" comment. It was also difficult to record slight differences in re-
flexes, in spasticity, or in disturbances not directly related to MS. All these
objections were considered in the planning of the new set of sheets.

3.2.4 Validity of the System

Twenty-five patients were examined by two or more physicians within two

days: 13 patients twice, 9 patients three times, 2 patients four times and
I patient five times. The results of these 65 examinations were compared
with the aid of a computer 3.

3 Program written by Mr. Kerscher, EDP-Department, Gottingen University.

 22

UllVllllTiUWll1
aom.SEI '=
IEUIOLOllSCBE Will

6.6 C
c
- --
64
<=> ~
2
<=> <=>• , ? I •
•, •, b 0
,
c:.." ' -= 6.
, b• .., b =p
c::::I

•
~

,
<=> , 3
<=>
0
= b = •
c:-
=:>
" l
<:::::>
3
==> ~ 6 =
, c...o
A

e
= •
<==
8
<:::::I .6 , • => c;.,
= I • 5
t:....l

~ ~~ 6 ,
= 6
~
(I'! NO'll
<:::::>
0
;c:::J C:::I • ~ =:>
5

g"g,. 6 1
<=
1IoQ, b b .6 b G
6 .!!:db ~
b "= b b .6:"
~~~~~­
~ ~ '" 1_
bcl=b:,b b
6c':!,~~ ~~
bbbbb-- b6b b
~ ~ ~. ~ . ~~~~~
~ 2!!:, ~. bbbb~

--
KI.IHISCltIR SIEFUNg ~ ~

==
~=

==
=
.'1I9no
===
...

=
---
" c-..

=== ===:> r;:(:J =

Fig. 8. Example of a sheet that could not be read by the computer

 23

UllVIlIllTiTllUll1
60mlGEI
lEU OtolllC EIUIlI
0F6 I Dr. F1sch....Iosch-Stlf!ung
=
= -....

.-.. ~ =
=
Liquor: 21.7.67,.. 16/3 Zellen, Ges.-=
EiweiB 20 mg%, ues.~lobul1ne 21 mg%=
Maatixkurve normal.
LINISCHI!:A BEfUND

Vaaale Hypotonie. -
SOP 11.8.67: 13/3 Zellen, Ges.-
EiweiB 34 mg%.
Andere Erkrankungen: vasale Hypo-
tonie. G-J:seit Jahren Magen- und
Gallebeschwerden.1968 Gallenstein-
operation. Verletzungafolgen:1943
Granatsplitterverletzung li.Obersche~

Fig. 9. Example of a neatly marked sheet

24

Figure 10 shows an example of three examinations of one patient given

by different physicians. Each number indicates how many of the three
physicians marked that particular part of the sheet. Thus, the number 3
means that there was perfect agreement, whereas the numbers 2 and 1 in-
dicate disagreement. The number of discrepancies increased, as is to be ex-
pected, with increasing frequency of a disturbance and with more refined
grading of a sign or symptom (see Fig. 11).

PH .NO : OO(l080

o 1 2 3 4 5 6 7 8 9

PER50~AL DATA

3 2 COUR5r=
':PISODE
CSF
CLINICAL DIAGN[]$15
COMPLICATIONS DUE Tn ~s
OTHER-
F IRST APPEAR.A~CE -Dt S~ASFS

_u Cl1NICU FINDt~GS .""1<

MUTIL I TV OISTURI3"'NCE DISORDERS 01= CI{Af'IIiAl NERV!;~ 1\"11) BO"'lN~T"''''
, 3 3 C~A"lIAl ~p::~vrs
3 3 , ? I
3 1 2 2 1 3 I I
3 12 21 3
REFLEXES DISTU"l:BA,~CES OF S17NSITIVITY
3 3
3 3
2 I
2 I
,
3 , I 2
2 I 3 8Q.AI"lST!:~

2 I , I
I 2 3
I 2 3 2 I
PERFORMANCE STATUS 1 c::p,,: ~R.AI
,
,
I I

3
•••• * ***i<**,***"'**
PA 11>.1
VEGETATIVE- ,
GAIT sy~npSI s
3 3 2 I
DIFFICUlTI.:'S IN FIlL!~Jt; FnR~ 1
conROI~A.TION .............. -t:*.". It • •' ~ "' ..... *'" *" *~"'.l'
2 ,
2 3

TREMOR
3 3 I

Fig. 10. Summary of three examinations of one patient given by three physicians.
3, item marked by all three physicians
2, item marked by two of the three physicians
1, item marked by one of the physicians

It is known that discrepancies of this kind can often be prevented by

dearly defining the criteria to be applied (Fletcher, 1963; Gill et aI., 1973).
These multiple examinations, made early in the project, enabled us, after
discussions with the physicians concerned, to design a suitable glossary.
This was printed on the back of the new sheets, so that the physicians did
not need to refer to a separate glossary. Unfortunately, it was not possible
to repeat the multiple examination check after the glossary was in use.
 ..................--......-=-
2S

~12~J ~~'1 ~20:'~,4M

<...:..>

SO/cl-81
...,.J

2et/el21
17% 4
50~ 12%(6} ::
--
~=

2"Al CUO/,U %i9J =

~Ic
-
~l l ~17J c:.... _
=>

~ I~ =
=
=
Jo/d6J
V~)
=
.J
24'/0(5)
3°/~
==
~.4b 1 ~

= 23%[SI.} w.':: . . 0%151

.,=
'-10~ =
---
<-.. -- c= I:-

22%[27) 2%111
~~~ ~=
-
t ..:l

m[5~ = 20% 158)

'T4~
T4
=
2'2 =:0
C-.j
=
c=
= 5~ [;if:»
1 20;'o [06&1
--
=
, 5% (4 BJ 8%(431
. ~
2%'(5'1)
c:::::::::I c......,;..
L-
= 'aOIo14
t:::::::I

Fig. 11. Discrepancies among different examiners given as a percentage of 6S multiple

examinations. Frequency of occurrence of the item in the whole group (N = 812) is
given in brackets

3.3 Documentation of Disease Course

The data of the 178 follow-up examinations were not analyzed by the com-
puter. It became evident that the clinical findings could not be recorded in
sufficient detail, because variations were usually small during the course of
this project. It therefore did not seem worthwhile comparing the repeated
examinations by computer.

3.4 Analysis of All Examinations Performed

Some of the data here refer to all examinations performed, as did those of
Kurtzke (1970). The frequency of cranial nerve disturbances and bulbar
symptoms refer to 990 examinations of 812 patients in our project; a com-
26

parison with the data of Kurtzke is shown in Table I. Repeated examina-

tions of a patient with a rare symptom can give misleading statistical results;
the value of analyzing all examinations is therefore limited. Discrepancies
among data from different samples are perhaps to be expected if repeated
examinations are included.

Table 1. Brain stem symptoms in MS. Data from all examinations (N = 990) compared
with the Army series of Kurtzke (1970)

Pool Army series

N =990 N = 1999
(%)
Diplopia 195 (20%) 19.1
Altered facial sensation 60 (6%) 4.6
Jaw weakness 2 (0%) 0.3
Facial weakness 103 (10%) 2.6
Dysarthria 256 (26%) 19.9
Dysphagia 51 (5%) 4.4
Bulbar palsy 8 0%) 0.8
Vertigo 91 (9%) 4.7

3.S Analysis of First Examinations

The data presented in the following sections refer to the documentation of

812 examinations on sheet No. I. Altogether, 812 patients with definite,
probable, or possible diagnosis of MS were included, irrespective of the
duration and previous course of the disease. Different kinds of hospitals
participated: special hospitals for MS patients, neurology departments of
general and university hospitals, and two outpatient departments. There
was, therefore, a wide range of symptoms and of severity of MS. The num-
ber of patients recorded in a particular hospital depended on the availabil-
ity and motivation of the staff. It was therefore possible that the selection
of patients was biased.
In an attempt to test for possible bias, 226 patients from the epidemio-
logic area of Lower Saxony were examined and compared with the main
group of 812 patients. In the epidemiologic study all known patients were
recorded. It was hoped that the control group of 226 patients was typical,
i.e., not biased itself.
 27

3.5.1 Month of Onset

In a retrospective study, Wuthrich et ai. (1968) and Rudin (1968) found

that onset of MS was significantly less likely during the summer and autumn
months. In our sample, too, the first bouts were less likely to occur in sum-
mer and in autumn (see Fig. 12; the precise onset was known in only 472
cases). However, deviation from the expected number of bouts was not
significant. Other authors (Limburg, 1950; Poskanzer et aI., 1966; Panelius,
1969) confirm our fmding. The difference found by Caselmann (1968) was
not significant when we reassessed his data by means of the 2-I-test.

50

1.0
~
~,~:
I I

.t! 30 Deviation
~'"
From The
Expected
20
~ Value

'l5 10
!
§
:i!: Jan. Febr. Marrh April /VIay June July Aug. Sept. Oct. Nov. Dec.

Fig. 12. Occurrence of first bouts related to the time of year

3.5.2 Age at Onset, Present Age, and Differences Between Males and Females

The present age of patients and age at disease onset are shown on Figure 13
and 14. The present age was compared to the age distribution of males and
females of the normal population in 1971 (Statistisches lahrbuch). The
deviations observed between MS patients and the normal population reflect
that first, MS is a rare disease in children; secondly, that MS patients do not
usually reach old age. In Figure 14 the age at onset is given for the whole
sample as well as for males and females separately; there were no signi-
ficant differences between the two groups. The mean age at onset was
31.1 years, but the scatter was slightly higher for females than for males
(see Table 2). The lower age at onset for females mentioned in the litera-
ture (see Discussion) was not confirmed in our study.
The disease lasted longer in females than in males. The significant differ-
ence of 1.3 years could be responsible for the differences found between
the frequency of pareses (77% for females, 67% for males, p = 0.0034) and
limb ataxias (84% for females, 78% for males, p = 0.0305). However, sen-
28

.- -. Female Population

./-.,. -
Of The FRG

~.
f ~
Female Patients N=520

\ Aj'
~ ~' ,_.~... •.• 4
• . . .L : "....... . ,. . .

,...,...'. .'..... \ .../ ......\;}\'

". ............. \ .......... ..

c:
~ i"'~ ....,.
~ 300 " ,
.!:! ~ 15 'J '- :'
::. tJ , •
e .. '
~ 200 at 10
-!! Cl
E TOO ~ 5
at ~
<:
a 15 25 35 45 55 65 Years

If--IC Male Population of the FRG

- - . Male Patients

<>
<>
400
~
~
c: 300 15
..
VI
0

"" ~
200 10 <=
"*~ ~
-!!
~

15 25 35 45 55 65 Years
b
Fig. 13. (a) Present age of female MS patients compared with that in the normal female
population. (b) Present age of male MS patients compared with that in the normal male
population

sory signs and symptoms depend on disease duration only slightly, so that
differences found between men and women cannot be explained in this
way (see Sect. 3.6.2).
Disturbances of sexual function were recorded in 5% of the women and
23% of the men (p < 0.0001). However, as mentioned above, in the plau-
sibility control we did not check whether this item was specifically asked
for, and it is possible that men are more likely than women to complain
of sexual disturbances spontaneously. Bladder infections occurred more
frequently in females than in males, possibly for anatomic reasons. No sig-
nificant differences between men and women were found either in the re-
maining signs and symptoms or in performance.
The preponderance of females having MS (64% females, 36% males) in
our study confirms the findings of other authors (McIntyre et aI., 1943;
 29

70

- Whole Material N= 812

60
-2- Females N=520
-t- Males N=292

50

~o

!!c:
.!!
i;
.... 30
....
'a

.Q
E
::.
~ 20

Fig. 14. Age of MS patients at disease onset

Alexander et aI., 1958; H. R. MUller, 1961 and 1966; Stazio et aI., 1964;
Panelius, 1969; Gudmundsson, 1971; Dassel, 1973; Lhermitte et aI., 1973).
However, the actual ratios varied (see Table 15).

3.5.3 Disturbances of the Functional Systems

Disturbances of different functional systems are summarized and compared

with the findings of R. MUller (1949) and Kurtzke (1961) in Table 3. The
only striking difference among the three sets of findings concerns mental
changes. We found cerebral signs or symptoms in 56% of the patients,
Kurtzke in 20%. R. MUller did not give the corresponding figure; however,
he found dementia in 28% of his patients (4% in our sample; see Sect. 4.1.3).
30

Table 2. Symptomatology in MS compared for men and women (N = 812)

n. s. = not significant

Men Women Level of

N=292 N = 520 significance
(36%) (64%)

Age at onset (years) 31.1 ±8.5 31.1 ± 9.95 n. s.

Duration of disease (years) 7.8 ± 7.2 9.1 ± 8.3 p=0.017
. / Remitting 133 (46%) 212 (41%)}
Course " Rem. + progressive 117 (40%) 207(40%) n. s.
Progr. from onset 42 (14%) 101 (19%)
Paresis of lim bs 197 (67%) 401 (77%) p = 0.0034
Spasticity 182 (62%) 340 (65%) n. s.
Hyperreflexia 273 (93%) 482 (93%) n. s.
Sensory disturbances 222 (76%) 429 (83%) p = 0.0261
Ataxia of lim bs 227 (78%) 436 (84%) p = 0.0305
Ataxic gait 129 (44%) 217(42%) n. s.
Urinary dysfunct. 135 (46%) 264 (51%) n. s.
Sexual dysfunct. 66 (23%) 27 (5%) p < 0.0001
Visual disturb. 180 (62%) 311 (60%) n. s.
Diplopia 69 (24%) 99 (19%) n. s.
Brainstem symptoms 191 (65%) 305 (59%) n. s.
Euphoria 72 (25%) 120 (23%) n. s.
Depression 29 (10%) 65 (13%) n. s.
) Nonn.1 29 (10%) 56(11%»)
Ability Slightly dist. 114 (39%) 195 (38%)
n. s.
to work Severely dist. 78 (27%) 129 (25%)
Lost 71 (24%) 139 (27%)
51 (17%) 93 (18%) )
) Nonnru
Ability Sligh tly dist. 112 (38%) 176 (34%)
n. s.
to walk Severely dist. 67 (23%) 117(23%)
Lost 62 (21%) 134 (26%)
Infection of urinary tract 39 (13%) 102(20%) p = 0.0204

Table 3. Signs and symptoms in the pool material compared with the series of R. MUller
and J. F. Kurtzke
? = no comparable data

R. MUller J. F. Kurtzke
Pool (1949) (1961 )
Signs and Symptoms N = 812 N = 582 N =408

Pyramidal tract dysfunct. 757 (93%) ? 93%

Paresis of lim bs 598 (74%) 436 (75%) ?
Impairment of coordination ? ? 87%
Balance disturb. 343 (42%) 287 (49%) ?
Sensory disturb. 651 (80%) ? 65%
Figure-writing ? 359(81%) ?
Bowel and bladder dysfunct. 413 (51%) ? 53%
Bladder sympt. 399 (49%) 290 (50%) ?
Bowel complaints 158 (19%) 145 (25%) ?
Visual impairment 289 (36%) ? 40%
(N = 93)
 31

Table 3 (continued)

R. Milller I. F. Kurtzke
Pool (1949) (1961 )
Signs and Symptoms N = 812 N= 582 N= 408

Other cranial nervejbrainstem

disturb. (excl. trigeminal 562 (69%) 382 (66%) 81%
involvement)
Cerebral signs and symptoms 451 (56%) ? 20%
(N = 93)
Euphoria 192 (24%) 102 (18%) ?
Dementia 35 (4%) 164(28%) ?

3.5.4 Selection of Certain Groups

3.5.4.1 Therapeutic Procedures

Patients with spasticity were selected for special therapy. Their motor per-
formance was assessed on a special mark reader sheet and appropiate treat-
ment given (Lowitzsch, 1973). Patients with a severe tremor were selected
for another special therapy. Riechert (1973) suggested that stereotactic
operations should be considered for patients whose main symptom was an
incapacitating tremor of the arms. We found 51 patients to be suitable can-
didates for stereotactic surgery (26 right-sided, 25 left-sided tremor). Each
of these patients showed intention tremor of one arm, full power or only
slight paresis of the same arm, and full dependence on help for washing,
eating, and dressing.

3.5.4.2 Patients with Epileptic Seizures

The frequency of epileptic fits in patients with MS is reported to vary be-
tween 1% and 6% (Hopf et aI., 1970). In the present study 9 out of 812
patients had seizures. With the help of extra, more detailed, medical records
from the various hospitals it was possible to analyze the occurrence of epi-
lepsy with MS (Ritter et aI., 1974). In four cases epilepsy appeared first and
MS years later; in three cases this was reversed. In two cases only one of
the diagnoses was satisfactorily clear-cut. The prevalence rate of epilepsy
is 0.5%-5%, that of MS 0.05% for a normal population. Thus, there does not
appear to be a syntropism of the two syndromes.

3.5.4.3 Familial Cases

Although the incidence of MS among immediate relatives of MS patients is
known to be 15 to 20 times that normally expected (see McAlpine et aI.,
32

1972), the role of heredity remains unclear. Bertrams et al. (1972) and
Jersild et al. (1972, 1973a) found a correlation between a certain pattern
of histocompatibility antigens and MS. This supported the concept that
genetic factors might be involved. Investigations of the histocompatibility
antigens of ''MS families" should be particularly interesting in this context.
Analysis of the genetic background of four pairs of twins (one identical
and three nonidentical) and 39 other familial cases is in progress (Zander et
at, 1976).

3.5.5 Statistical Analysis of Symptoms

The statistics on signs and symptoms of MS that are currently available are
mostly based on retrospective data or on small samples. The value of a cer-
tain symptom or of a pattern of symptoms in the diagnosis of a disease can
only be assessed after long-term analysis of a large sample (Griesser, 1965).
It is also necessary to study other diseases with similar symptoms, partic-
ularly in the context of a planned, computer-assisted diagnosis.
The frequency of disturbances of motor performance, of reflexes, of
sensory functions, and of coordination is given in Table 4. Separate analy-

Table 4. Symptoms in MS (N =812)

Total Upper limbs Lower limbs

Spasticity 522 (64%) 254 (31%) 507(62%)

Paresis 598 (74%) 289 (36%) 578 (71%)
Atrophy 94 (12%) 39 (5%) 78 (10%)
Hyperreflexia 755 (93%) 568 (70%) 724 (89%)
Ataxia of limbs 663 (82%) 340 (42%) 424 (52%)
Tremor 114 (14%) 93 (11%) 44 (5%)
Involuntary spasms 156 (19%) 9 (1%) 154 (19%)
Sensory disturb. 651 (80%) 340 (42%) 582 (72%)

sis of arms and legs showed the well-known preponderance of disturbances

in the lower extremities.
Table 5 shows the exact location of pareses in our survey and in those of
R. Milller (1949) and Kurtzke (1970). The different kinds of sensory signs
and symptoms and their combinations are shown in Figure 15; disturbances
of cranial nerves and brainstem symptoms are seen in Figure 16 and in
Table 6. Dysphoric and depressive patients are combined into one group in
a graphic representation of mental changes in Figure 17. Out of 812 pa-
tients, 451 showed signs of mental impairment, predominantly an affective
disorder (382 patients). Of these, 192 were recorded to be euphoric, 190
depressive-dysphoric. The pattern of other mental changes in combination
with euphoria or depression is shown in Figure 17.
 33

Table 5. Pattern of motor symptoms by limbs involved (3 series compared)

Pool Miiller (1949) Kurtzke (1970)

Limb involvement N =812 N = 582 N = 2019

None 214(26%) 211 (36.1%) 37.7%

One upper 19 (2%) 7 (1.2%) 3.6%
One lower 102 (13%) 30 (5.2%) 7.8%
Two upper 1 (1%) I (0.2%) 0.9%
Two lower 207 (25%) 176 (30.2%) 22.8%
Two upper-lower 49 (6%) 21 (3.6%) 9.7%
Three 94 (12%) 64 (11.0%) 4.0%
Four 126 (16%) 73 (12.5%) 13.4%

N=812 Superficial
Sensation
Sensory Disturbances
present in N=651

Fig. IS. Sensory signs

and symptoms and their
combinations in MS pa-
tients

NYSTAGMUS
present in N = '38

Fig. 16. Different forms of nystagmus

and their combinations in MS patients.
~ = vertical. -- = horizontal. (\ = rotary.
(=-\ =jellylike
34

Table 6. Involvement of cranial nerves and brainstem in MS (N = 812)

No. of nerve
involved

j Vision impaired
Amaurosis
291 (36%)
23 (3%)

<
Scotomas 56 (7%)
temporal 311(38%)
II 491 (60%) ~ Atrophy
~ total 92 (11%)
~ Papillitis 40 (5%)
Periphlebitis 8 (1%)
____ Diplopia 74 (9%)
III 9602%) ___ Disturb. of pupillary
28 (3%)
reactions
IV 17 (2%)
Hypaesthesia 29 (4%)
~ Pain/paraesth. 41 (5%)
V 10102%)
~ Corneal reflex -l- 73 (9%)
Jaw weakness 2 « 1%)
VI 9702%)
____ Peripheral palsy 23 (3%)
VII 9001%)
------Central palsy 67 (8%)
____ Hearing loss 52 (6%)
VIII 127 0 6%) ______
Vertigo 8500%)
____ Scanning 159 (20%)--26 (30/<)
Speech 222 (27%) _____ Disarticulated 8500%)- . 0
Aphasia 2 0%)
Dysphagia 38 (5%)
Disorder of
respiration
2 « 1%)
Bulbar palsy 7 0%)
Triad of Charcot 8901%)

EUPHORIA DEPRESSIVE SYNDROME

N:192 N:190 D without other
mental disturbances

II1II with dementia

~ with loss of interest

. . with apathy

o with labile affect

Fig. 17. Combination of euphoria and depressive syndrome with other mental distur-
bances in MS patients
 35

The difference between left- and right-sided reflex-abnormalities and

pareses found by Morsier (1971) could not be confirmed in our study (see
Fig. 18). A difference between left- and right-sided symptoms was only
registered in dysdiadochokinesis (p = 0.0011); the higher left-sided frequen-
cy could easily be due to the clumsiness of the left hand in right-handed
people.

65 5":

right "
67
":9 VB
11
71 left

Ataxia ":22
DysdiadoctJokinesis
362 ":30
slight" ...... slight 169
192 severe' ParesIs ... severe
25 3":
31 Atrophy 31
501 Reflex- Disturbances 529
181, slight" S .....- slight 162
n severe - pastlclty " severe
'------"'.
19

287
211
61
586
176
17":
Ataxia 365
Involu~tary Spasms 132 Fig. 18. Regional distribution of
Ankle-Jerk dist. 753
Babinski- Sign. 507 symptoms (N = 812)

3.6 Correlations

3.6.1 Correlation between Mental Changes and Other Disturbances

Psychopathologic phenomena are particularly difficult to record. Those

related to MS in the literature vary widely, depending on the sample exam-
ined and on the method applied. The simplified classification scheme on
our sheet does not allow a detailed analysis. Six categories of mental distur-
bances were defined according to Payk (1973). Correlation with other pa-
rameters (see Table 7) showed that patients with any kind of mental changes
had a longer and more severe course of MS than patients without mental
impairment. Patients with intellectual deterioration and disturbances of
 II-)
C\

Table 7. Mental disturbances in relation to other symptoms and to clinical characters in MS

Course
N Severe Ataxia of Ataxic Miction Com- Age at Duration
paresis limbs gait disorder pletely onset of disease Rem. Rem.
----1---- Progr.
helpless and from
progr. onset

No mental
impair- 342 56 (16%) 240 (70%) 122 (36%) 120 (35%) 3 (1%) 30.7 ± 9.5 6.7 ± 7.7 205 91 46
ment (60%) (27%) (13%)
Euphoria 192 84 (44%) 179 (93%) 92 (48%) 111 (58%) 13 (7%) 30.8 ± 9.0 9.9 ± 7.3 46 104 42
(24%) (54%) (22%)
Depressive 183 73 (40%) 162 (89%) 86 (47%) 114 (62%) 15 (8%) 31.6 ± 9.5 9.7 ± 7.9 60 84 39
syndrom (33%) (46%) (21%)
Labile 110 40 (36%) 97 (88%) 58 (53%) 69 (63%) 8 (7%) 31.2 ± 9.9 9.4±8.1 41 52 17
affect (37%) (47%) (15%)
Dementia 169 88 (52%) 156 (92%) 76 (45%) 117 (69%) 19(11%) 31.6 ± 9.1 10.7±8.0 35 89 45
(21%) (53%) (27%)
Disturb. of
conscious- 6 3 (50%) 6 (100%) 5 (83%) 6 (100%) 1 (17%) 28.8 ± 11.7 11.8 ± 6.4 0 5 1
ness (83%) (17%)

p < 0.0001 p < 0.0001 p =0.0023 p < 0.0001 < 0.0001 ~ot signif- p< 0.01 p < 0.0001
p lcant
 37

consciousness were found to be those most seriously ill. According to some

authors, euphoria is typical for the cerebellar form of the disease. Unlike
Poeck (1973), we (Poser et aI., 1974a) found from our data that the state-
ment "The Person who shakes can laugh" is a clinical impression rather
than a proven correlation.

3.6.2 Duration of Disease and Symptoms

The influence of the duration of the disease on different signs and symp-
toms is seen in Figures 19-21. With increasing duration of the disease,
patients were more likely to develop spasticity, pareses, disturbances of
micturition (with bladder infections as a sequel), and euphoria. The same
was true for ataxia (not included in the figures). Regarding affective dis-
orders, it can be assumed that euphoria becomes increasingly frequent as a
result of a build-up of organic lesions. On the other hand, depression, as a
reactive disorder, is relatively independent of the duration of the disease
(see Fig. 21).

100
N=812
1/-
90 .......... -., ,'.',
•
/
" , 0 '
'.-.~
0 __1
, ~/
?
80 /\ ......... _.-.-.-. :~. ~ \'.
I '."" ......... / ........ --....... --./
I /
70 ~._.e'
I ,. .......... __ ..........
...... 0 _ . ' ..........

.-_.I' ........ Spnsory Disturbancps

,,"
50 - Paresis
e.·e Spasticity
,,
I
30
....
o
I
5 /0 15 20 >20

DUration of DispOsP (Years)

Fig. 19. Frequency of sensory disturbances, paresis, and spasticity in relation to the
duration of MS (averages taken over 5-year periods)
38

70
N= 812
//..A
60

50

.t!
c: "'0
~
'"
"- 30
'Q
,.-_ ............ --........ . .
.' -'--'-1/--
~ ,. - .....
20

, . " ,'III
~ ..... -.-.- .... Infection of urinary tract

10
- .'
o 5 10 15 20 > 20

Duration of Disease (Years)

Fig. 20. Frequency of micturition disorders and of bladder infections in relation to the
duration of MS (averages taken over 5-year periods)

'I, of Patients

,,
N= 812
,
. ,
, "
:r..
,'" .... .
I

30 .
"....' "'III'
,
'. " '. Euphoria

. .... "
-

.
'III,;'
20 ,•
I', "
I
I
I
I
~
~ Depression

o 5 10 15 20 > 20

Duration of Disease (years)

Fig. 21. Frequency of euphoria and depression in relation to the duration of MS (aver-
ages taken over 5-year periods)
 39

3.6.3 Duration of Disease and Performance

Single signs and symptoms are only of limited value in predicting the over-
all performance of a patient. In our study the degree of disability was there-
fore assessed by the ability to work and to walk. As seen in Figure 22, the

60'1.

50'/• ..........
....•
~~~;..............
~O'l.
O;.j.~
....•
-

20'1.

"-----
________________ __________________ __ _________

5 10 15 20 > 20

Duration Of Disease (Years)

Fig. 22. Ability to work in relation to the duration of MS in 812 MS patients (averages
taken over 5-year periods)

number of patients still able to work decreased with increasing duration of

the disease, and the number of patients with severely disturbed working
ability or complete loss thereof increased. However, after 20 years duration
of MS, about 30% of the patients were still not seriously restricted in their
ability to work. The ability to work is not only limited by physical handi-
caps (mainly spastic pareses, ataxia, and bladder disturbances; see Bauer et
al., 1963); it also depends on the sex of the patient, on his profession, on
the tolerance of his employer, on future prospects, and on the local employ-
ment situation.
The ability to walk, which is not influenced by these factors, tended simi-
larly to decrease with increasing duration of the disease. The particular kind
of ambulatory disturbance does not seem to be important. As shown in
Table 8, patients with cerebellar ataxia, spinal ataxia, or gait disturbance
due to spastic paresis are equally incapacitated.
40

Table 8. Different kinds of gait disturbances in correlation to the ability to work

n. s. = not significant

Gait distur- Ability to Ability to Ability to Ability to

bance due to N work nor- work slight- work se- work lost
mal ly dist. verely dist.

Cerebellar ataxia N=227 6 (3%) 77 (34%) 84 (37%) 60 (26%)

Spinal ataxia N = 181 6 (3%) 79 (44%) S4 (30%) 42 (23%)
Paresis/Spasticity N=404 13 (3%) 174 (43%) 131 (32%) 86 (21%)

Level of signif-
icance n. s. n. s. n. s. n. s.

The correlation between the ability to work and the ability to walk was
analyzed by the coefficient of constriction, which assumed a value of 0.38,
suggesting that 38% of the ability to work depends on the ability to walk.
In the following sections each statement on prognosis is made on the basis
of the ability to work and the ability to walk.

3.6.4 Age at Onset and Performance

Several authors have attempted to identify groups of patients with a par-

ticularly benign or malignant course. R. Muller (1949, 1951) and Leibo-
witz et al. (1964a, b, 1970, 1973) found that the age at onset of disease
did influence the prognosis. The patients in our sample were grouped accord-
ing to their age at onset to test this idea. Comparison of the groups showed
differences in the frequency of occurrence of single signs and symptoms
(spasticity, bulbar symptoms), but no important differences in the ability
to work or to walk (see Table 9).
Since the duration of the disease was sometimes related to the age at
onset, various grouping procedures were used in an attempt to eliminate
the influence of disease duration. Patients with different ages at onset but
similar duration of MS were compared (see Fig. 23). It was found that the
ability to work und to walk did not depend on age at onset, except in 1
out of the 16 groups (original data; see Poser, 1974). After calculating the
mean age at onset for patients with a particular sign or degree of disability,
no significant deviation from the mean age at onset of the total sample
(31.1 years) could be found (see Table 10).
 41

Table 9. Comparison of clinical parameters in patients with different ages at onset

Age at onset 15-24 25-34 35-44 45-65 Level of sign.

N 218 316 186 84
Mean duration of dis-
ease (in years) 10.3 ±9.1 9.3±8.0 7.5 ±6.6 4.7±4.4 p<O.OOI*

S .......-Females 152 (70%) 183 (58%) 118 (63%) 61 (73%)}

eX-Males 66 (30%) 133 (42%) 68 (37%) 23 (27%) p = 0.0118**
/Remitting 123 (56%) 130 (41%) 65 (35%) 22 (26%)}
Course-Rem. + progr. 79 (36%) 138 (44%) 73 (39%) 31 (37%)
"Progr. from p < 0.0001 **
16 (7%) 48 (15%) 48 (26%) 31 (37%)
onset
/Definite 159 (73%) 202 (64%) 109 (59%) 33 (39%)}
Diagnosis- Probable 49 (22%) 87 (28%) 66 (35%) 36 (43%) p < 0.0001 **
"Possible 8 (4%) 24 (8%) 10 (5%) 14 (17%)
Paresis of limbs 159 (73%) 222 (70%) 146(78%) 65 (77%) p = 0.1816
Spasticity 121 (56%) 210 (66%) 130 (70%) 55 (65%) p=0.0153
Sensory disturbances 177(81%) 254 (80%) 151 (81%) 70 (83%) p = 0.9437
Coordinationdist. 201 (92%) 282 (89%) 176 (95%) 79 (94%) p=0.1431
Micturition dist. 107 (49%) 152 (48%) 99 (53%) 36 (43%) p = 0.5566
Visual impairment 150(69%) 199 (63%) 93 (50%) 42 (50%) p = 0.0004
Diplopia 77 (35%) 124 (39%) 74 (40%) 34(40%) p = 0.7403
Other cranial nerve
43 (20%) 71 (22%) 44 (24%) 10(12%) p=0.1031
dist.
Bulbar symptoms 132(61%) 198 (63%) 121 (65%) 38 (45%) p=0.0169

I
Euphoria 50 (23%) 81 (26%) 42 (23%) 17 (20%) p = 0.7082
Depress. syndrome 63 (29%) 91 (29%) 64 (34%) 24 (29%) p = 0.5566
Ability to work: Normal 27 (12%) 36(11%) 16 (9%)
6 (7%)
Slightly dist. 80 (37%) 124 (39%) 64 (34%) 37 (44%) = 0 5549**
Severely dist. 62 (28%) 73 (23%) 51 (27%) 21 (25%) p .
Lost 49 (22%) 83 (26%) 54 (29%) 20 (24%)
Ability to walk: Normal 48 (22%) 60 (19%) 25 (13%) 10(12%)}
Slightly dist. 67(31%) 115 (36%) 68 (37%) 35 (42%) p = 0.1483**
Severely dist.
103 (47%) 141 (45%) 93 (50%) 39 (46%)
or lost

* H-test according to Kruskal and Wallis.

** k X m-field-2I-test.
 .,. of Pati.nts

..0
60
50
4> '0
'" D
~
20
~
10

50
..... 40
I 30
~ 20
10

50
...... 40
I 30
'"
N
20
10

...
N

~ 50
40
0;
§ 30
'0
Jl
. 20
10

~ 15

o normol 0
Ability to worI<
slightly dlSl . ~ severely drs!.. los t

Fig. 23. Ability to work in patients of different age at onset and with similar duration
ofMS

Table 10. Mean age at onset of patients with a given symptomatology

Disturbance N Mean age at onset

in years

Spasticity /paresis 669 30.6 ± 11.4

Severe paresis 251 31.3± 9.4
Ataxia of limbs 660 30.5 ± 10.5
Ataxic gait 343 30.6 ± 9.1
Sensory dist. 651 31.2± 9.5
Micturition dist. 399 31.1± 9.4
Impairment of vision 491 29.3 ± 9.8
Diplopia 168 30.8 ± 8.5
Ability to walk: Slightly dist. 288 31.8 ± 9.1
Severely dist. 184 32.2 ± 10.2
Lost 196 30.8 ± 9.3
Ability to work: Slightly dist. 309 31.1 ± 9.6
Severely dist. 207 31.3 ± 9.7
Lost 210 31.8 ± 9.4
 43

3.6.5 Disease Course and Perfonnance

The patients were divided into three groups according to the course of the
disease: (1) Patients with bouts and full remissions, (2) Patients with tran-
sition into a chronic-progressive stage after a phase of bouts and remissions,
and (3) Patients with a chronic-progressive course from the beginning. The
frequency of certain parameters was found to be different in the three
groups (see Table II). The lower incidence of disturbances in group I (re-
mitting course) could perhaps be the result of a shorter duration of the
disease or a lower age at onset. Grouping patients according to the duration
of their disease revealed significant differences again among the three groups
(see Fig. 24).

Table 11. Comparison of clinical parameters in patients with different course of MS

Course Remitting Rem. and Progr. from Level of sig-

progr. onset nificance
N =345 N= 324 N = 143

Mean age at onset

28.6 ± 8.9 31.2 ± 8.8 36.8 ± 9.8 P < 0.001
(in years)
Mean duration of
6.1 ± 7.2 11.7±8.0 8.0 ± 6.8 p < 0.001
disease (in years)
/Females 212 (61%) 207 (64%) 101 (71%)} p = 0.1493
Sex ___ Males 133 (39%) 117 (36%) 42 (29%)
/Definite 190 (55%) 248 (77%) 72 (50%)}
Diagnosis" Probable 121 (35%) 64 (20%) 54 (38%) p < 0.0001
Possible 30 (9%) 10 (3%) 16 (11%)
Paresis 182 (53%) 290(90%) 126 (88%) p < 0.0001
Spasticity 147 (43%) 263 (81%) 112 (78%) p < 0.0001
Sensory dist. 266 (77%) 269 (83%) 116(81%) n. s.
Ataxia of limbs 245 (71%) 291 (90%) 124 (87%) p< 0.0001
Ataxic gait 128 (37%) 161 (50%) 37 (26%) p< 0.0001
Micturition dist. 103 (30%) 219 (68%) 77 (54%) p< 0.0001
Impairment of vision 184 (53%) 225 (69%) 82 (57%) p = 0.0002
Other cranial nerve dist. 117 (34%) 135 (42%) 59(41%) n. s.

I
Bulbar symptoms 179 (52%) 229 (71%) 88 (62%) p < 0.0001
Mental dist. 140 (41%) 233 (72%) 97 (68%) P < 0.0001
Ability to walk: normal 138 (40%) 3 (1%)
3 (2%)
Slightly dist. 132 (38%) 104(32%) 52 (36%)
< 0.0001

I
p
Severely dist. 42 (12%) 100 (31 %) 42 (29%)
Lost 33 (10%) 117 (36%) 46 (32%)
Ability to work: normal 78 (23%) 5 (2%)
(I %)
Slightly dist. 172 (50%) 90 (28%) 472 (33%)
Severely dist. 53 (15%) 108 (33%) 46 (32%)
p < 0.0001
Lost 42 (12%) 120 (37%) 48 (34%)
44

'/0 Of Patients

so

I·E 30
20
~ 10

5 -9 10 -14 1015

60

t
50
40
• 3D
~ 20
::;
·E 10
~

o -4 5 -g 10 -14 = 15

S - 9 10 -14 ~15
Duration of dISease (years I

Ab,lity to war k

o normal 0 slightly dist. severely dis!. lost

Fig. 24. Ability to work in patients with different course but with similar duration of MS

To test for the possible influence of age at onset, each of the three groups
of patients was divided into eight subgroups (onset before or after the age
of 30 and duration of disease up to 4,9, 14 or more years). A significant
difference in favor of patients with lower age at onset was found in one
group only (see Table 12; group 1, duration of disease 10-14 years). The
difference found in another group (group 2: duration of disease 0-4 years),
however, was in favor of patients with higher age at onset. No clear differ-
ences were found in the remaining ten groups when patients with the same
course and duration but with different age at onset were compared. Patients
of similar age at onset and with similar duration, but with different course
of disease, differed significantly in their performance (for levels of signifi-
cance, see Poser, 1974).
 45

Table 12. Comparison of ability to work and walk in patients with different course of
MS (grouping according to age at onset and duration of disease; for level of significance,
see Poser, 1974)

Remitting Rem. and progr. Progr. from onset

N=~
802
Age at onse N < 30 > 30 < 30 > 30 < 30 > 30
Duration of
disease 315 94 92 23 44 10 52
0-4 years
Ability to
work:
Normal 25 (27%) 22 (24%) 0 2 (5%) 0 1 (2%)
Slightly dist. 48(51%) 43 (47%) 1 (4%) 26 (59%) 6 (60%) 27 (52%)
Severely dist. 11 (12%) 16 (17%) 14 (61%) 7 (16%) 2 (20%) 15 (29%)
Lost 10 (11%) 11(12%) 8 (35%) 9 (20%) 2 (20%) 9 (17%)
Ability to
walk:
Normal 47 (50%) 40 (43%) 1 (4%) 2 (5%) 0 1 (2%)
Slightly dist. 30 (32%) 33 (36%) 4 (17%) 27 (61%) 6 (60%) 27 (52%)
Severely dist. 11 (12%) 12(13%) 10 (43%) 8 (18%) 2 (20%) 15 (29%)
Lost 6 (6%) 7 (8%) 8 (35%) 7 (16%) 2 (20%) 9 (17%)
Duration of
disease 196 55 22 38 47 8 26
5-9 years
Ability to
work:
Normal 14 (25%) 5 (23%) 0 1 (2%) 0 1 (4%)
Sligh tly dist. 30 (55%) 10 (45%) 5 (13%) 14 (30%) 4 (50%) 6 (23%)
Severely dist. 7 (13%) 4 (18%) 22 (58%) 14 (30%) 2 (25%) 11 (42%)
Lost 4 (7%) 3 (14%) 11 (29%) 18 (38%) 2 (25%) 8 (31%)
Ability to
walk:
Normal 24 (44%) 7 (32%) 0 0 0 1 (4%)
Slightly dist. 20 (36%) 9 (41%) 7 (18%) 18 (38%) 4 (50%) 7 (27%)
Severely dist. 6 (11%) 2 (9%) 16 (42%) 13 (28%) 2 (25%) 9 (35%)
Lost 5 (9%) 4 (18%) 15 (39%) 16 (34%) 2 (25%) 9 (35%)
Duration of
disease 116 25 14 21 36 4 16
10-14 years
Ability to
work:
Normal 8 (32%) 1 (7%) 1 (5%) 0 0 0
Slightly dist. 12(48%) 5 (36%) 6 (29%) 7 (19%) 0 3 (19%)
Severely dist. 3 (12%) 3 (21%) 8 (38%) 16 (44%) 2 (50%) 5 (31%)
Lost 2 (8%) 5 (36%) 6 (29%) 13 (36%) 2 (50%) 8 (50%)
Ability to
walk:
Normal 12(48%) 2 (14%) 0 0 0 0
Slightly dist. 11 (44%) 6 (43%) 6 (29%) 12 (33%) 0 5 (31%)
Severely dist. 0 5 (36%) 7 (33%) 11 (31%) 2 (50%) 6 (38%)
Lost 2 (8%) 1 (7%) 8 (38%) 13 (36%) 2 (50%) 5 (31%)
46

Table 12 (continued)

N=~e Remitting Rem. and progr. Progr. from onset

802
Age at onset N < 30 > 30 < 30 > 30 < 30 > 30

Duration of
disease 175 30 7 68 43 12 15
;:;, 15 years
Ability to
work:
Normal 3 (10%) 0 0 I (2%) 0 0
Slightly dist. 14 (47%) 6 (86%) 23 (34%) 8 (19%) 0 I (7%)
Severely dist. 8 (27%) 0 20 (29%) 8 (19%) 4 (33%) 5 (33%)
Lost 5 (17%) I (14%) 25 (37%) 26 (60%) 8 (67%) 9 (60%)
Ability to
walk:
Normal 3 (10%) 2 (29%) 0 0 0 I (7%)
Slightly dist. 15 (50%) 5 (71%) 21 (31%) 8 (19%) 1 (8%) 2 (13%)
Severely dist. 6 (20%) 0 19 (28%) 15 (35% 4 (33%) 2 (13%)
Lost 6 (20%) 0 28 (41%) 20 (47%) 7 (58%) 10(67%)

The influence of duration of the disease was eliminated by the grouping

procedure. Consequently, differences in the ability to work and to walk
seen in patients with different disease courses could not be explained by
different duration or by different age at onset of MS.
Grouping patients according to the course and duration of the disease in
1 year steps (see Fig. 25) confirmed the above findings that the disease
course has an important influence on prognosis. Most patients with bouts
and remissions were not severely disabled, even after a long disease dura-
tion; whereas patients with a transition into a chronic-progressive course
developed considerable disability during the first 5 years, and not much
change was seen afterward. Patients with a chronic-progressive course from
the beginning showed steadily progressing disability throughout the years.

3.6.6 Analysis of Bouts

In patients with transition into a progressive course, a mean of 2.9 ± 2.5

bouts occured, in comparison to 2.6 ± 2.1 bouts in patients without pro-
gression. The timing of individual bouts was not entered on the sheet, so
it was impossible to conclude from this analysis how many bouts occur
on an average, before patients enter the progressive stage. Similarly, the
influence of bouts on prognosis could not be evaluated, because the rela-
tion of bouts to loss of performance was not registered on the sheet.
 47

remitting
(N=3'5)
remitt.•progressive 70%
Ability To Work Normal (N=32') 60% Ability To Work Severely Disturbed
progr. from onset 50 %
'0% (N=I'3) '0%
30%
20%
10%

o 5 10 IS 20

~ Ability To Work Slightly

\ Disturbed 90 % Ability To Work Lost
80%
70% \ 70%
60% 60%
50% 50%
"~.~.
'0% .~.
'0%
".
30% 30% ~""

20% '~"""""""'\I" 20 .'. .r'·· ,., .~.::'.

10%
II
10o~
"
\.i..
~ 'e.e-.-·-·
........... •
.~.-.-.~...
/-"
't~.·
"

° 5 10 IS 20 >20
° 5 10 15 20

Duration Of Disease (Years) Duration Of Disease (Years)

Fig, 25. The relation of the ability to work and the course of MS to the duration of MS
(averages taken over 5-year periods, N = 812)

3.7 Diagnostic Classification

The clinical diagnosis was classified as "definite" in 510 patients, as "prob-

able" in 239, and as "possible" in 56 cases (it was unknown in 7 cases). The
different frequency of some parameters in the three diagnostic groups
(definite, probable, possible) found earlier in a smaller sample (Poser et aI.,
1973a) was confirmed in this study. It is difficult to decide whether possible
cases should be included in statistics on MS or not. Leibowitz et a1. (1973)
suggested that exclusion of the possible cases would lead to a biased sample,
whereas Kurtzke et a1. (1969) have the opposite view. Since we particularly
wanted to reexamine the statement of Leibowitz et a1. (who did include
possible cases), that the age at onset has an important influence on prog-
nosis, the possible cases were included in our study, too.
48

3.8 Laboratory Results

3.8.1 CSF Findings

A lumbar puncture was performed on 435 out of 812 patients during the
present investigation. Abnormalities were found in 367 patients (84%). The
frequency of occurrence of pathologic CSF findings is given for the whole
sample as well as for the three groups showing different courses in Fig-
ure 26. More CSF examinations were made and the frequency of pleocytosis
was higher in patients with bouts and remissions. The value of this finding
is limited for two reasons: Firstly, a lumbar puncture was not done in all
patients; secondly, the present documentation sheet only allowed for a
rather crude classification.
It would be possible to record quantitative CSF findings on a special
optical mark reader sheet like that of Hauptvogel and Poser (1974), so that
direct correlation with clinical symptomatology could be made. In the con-

Course of disease

80
o
Ii
70

60

50
• PIOgI!SSM! from orset

30

20

10

Cell Count Protei n PathaL COlloidal Jmmunoglobul in G

> 4 mm' :> 50 rng% Curve .tevat<.>d

Fig. 26. CSF findings in patients with different course of MS

 49

text of these CSF findings, the current documentation sheet was only used
to select patients for reexamination; for example, in 1973 a search was made
for patients with signs of acute disease in their CSF during the preceding
year, and 217 patients were found.

3.8.2 Serologic Studies

In 1972 an infectious agent related to group-l parainfluenza virus was iso-

lated from the cultured brain cells of two MS cases (ter Meulen et a1.). A
study of specific immune reactions of other patients was planned in an
attempt to relate this virus to MS. Serologic studies in two groups of pa-
tients were started: first, patients in this survey who had signs of acute dis-
ease in the CSF during the preceding year (see Sect. 3.8.1); secondly, pa-
tients from the epidemiologic area of Lower Saxony. The patients of this
second group were examined, the findings recorded on the new documen-
tation sheets, and a blood sample was taken. They were interviewed about
social factors and previous infections. A control group consisted of normal
siblings or close friends not more than three years older or younger than
the patients. So far, 226 patients and 21 controls have been screened in the
same way.

3.9 Different Samples

3.9.1 The Epidemiologic Study

A manual analysis was made of clinical data from the patients in Lower
Saxony. These data comprised age at onset, duration of disease, sex, course
of disease, diagnostic classification, ability to walk, and a disability scale.
We could not include any more parameters, because no computer program
for the new documentation sheets was then available.
A comparison with the data of the 812 patients was made. Patients from
the epidemiologic area had a longer disease duration (see Table 13) but
were less restricted in their ability to walk. The interpretation of this dif-
ference can only be tentative; one would expect there to be more patients
with a benign course in the epidemiologic study. Some of these patients
had not seen a doctor for many years and came only on request for an
examination. These patients might account for the higher proportion of
"possible" cases in the epidemiologic sample (see Table 13).
A test like that in Section 3.6.4 was made to see whether or not the age
at onset, duration, and course of disease had an influence on the progno-
50

Table 13. Comparison of patients from the documentation pool and from the epide-
miologic area in respect to clinical parameters. n. s. = not significant

Pool Epidemiol. Level of

study significance
N =812 N=226

n. s., no dif.
Mean age at onset (years) 31.1 ± 9.5 31.8 ± 9.4
in distrib.
Mean duration of dis. (years) 8.7 ± 7.9 13.0 ± 9.4 p < 0.0001
/Males 292 (36%) 80 (35%)}
Sex_Females n. s.
520 (64%) 146 (65%)
/Remitting 345 (42%) 97(43%) }
Course ........... Rem. and progr. 324 (40%) 99 (44%) n. s.
Progr. from onset 143 (18%) 30 (13%)
/Definite 510(63%) 145 (64%) }
Diagnosis ........... Probable 239 (29%) 50 (22%) p = 0.0086
Possible 56 (7%) 28 (12%)

Ability
Normal
Slightly dist.
144 (18%)
288 (35%)
56 (25%)
60 (27%)
1
p = 0.0306
to walk Severely dist. 184 (23%) 54 (24%)
Lost 196 (24%) 56 (25%)

sis. The ability to walk and the disability scale (Kurtzke, 1961) were used
as measures of performance. Similar results were obtained from the presum-
ably selection-free sample of patients from Lower Saxony as well as from
the patients in the present study (for the original data, see Poser, 1974).
These results can be summarized as follows:
1. The degree of disability depends on the course of MS.
2. With longer duration of the disease, patients with a remitting course are
less disabled than patients with the progressive form.
3. The age at onset in itself has no influence on the prognosis.

3.9.2 Subgroups

The locations of hospitals participating in the program can be seen in Fig-

ure 27. They were grouped according to available facilities: firstly, univer-
sity hospitals (1, 4,5,6,10,12,13,15); secondly, neurology departments
of general hospitals (8, 9, 11, 14, 16, 17); and thirdly, special hospitals for
MS patients (2,3, 7). Selected items from these three groups are shown in
Table 14. The majority of patients in special hospitals had a chronic-pro-
gressive course; 74% of them were unable to work or were severely handi-
 51

Fig. 27. Geographic distribution of hospitals par-

ticipating in the documentation program

~ Epidemiologic area of
lower Saxony

Table 14. Clinical parameters compared for patients from different institutions
(N=831)

University Neurol. depart. Special instit.

hospitals of gen. hosp. for MS patients
N =421 N = 221 N = 189

/Females 271 (64%) 137 (62%) 122(65%)

Sex __ Males 150(36%) 84 (38%) 67 (35%)
Mean duration of disease
7.1 ± 6.8 11.0 ± 10.0 11.2 ± 6.9
(in years)
/Remitting 214 (51%) 100 (45%) 25 (13%)
Course-Rem. and progr. 146 (35%) 80 (36%) 116(61%)
'-.;". Progr. from onset 61 (14%) 41 (19%) 48 (25%)
/Definite 258 (61%) 142 (64%) 150 (79%)
Diagnosis - Probable 132(31%) 68(31%) 33 (17%)
'-..... Possible 31 (7%) 11 (5%) 6 (3%)
Normal 67 (16%) 20 (9%) o
Ability Slightly dist. 190 (45%) 65 (29%) 49 (26%)
to work Severely dist. 94 (22%) 44 (20%) 75 (40%)
Lost 70 (17%) 92 (42%) 65 (34%)
Normal 102 (24%) 33 (15%) 3 (2%)
Ability Slightly dist. 171 (41%) 61 (28%) 58(31%)
to walk Severely dist. 96 (23%) 59 (27%) 57 (30%)
Lost 52(12%) 68(31%) 71 (38%)
Completely helpless 7 (2%) 23 (10%) 12 (6%)
52

capped. In the neurology departments 62% of the patients were unable to

work or were severely handicapped; the greatest proportion of completely
helpless patients were seen in these departments.
Patients in university hospitals were usually less disabled than patients
from the other institutions. Cases with remitting course without progression
and possible cases were more often admitted to university hospitals. But a
few patients with chronic progression and clinically definite diagnosis were
also hospitalized there. This latter group could probably be better treated
in special hospitals. There has long been a need for aftercare facilities (Bauer
et aI., 1965), particularly for MS patients (Heier, 1973).
4. Discussion
54

4.1 Clinical Questions

4.1.1 Prognosis

For neurologists concerned with MS in clinical practice, the question of

prognosis inevitably arises. The physician's attitude toward the disease can
have a strong influence on the patient indirectly, if not directly. Individual
personal experience concerning prognosis is often limited. Opinions are
often contradictory in the literature. The data gathered with our documen-
tation system have made it possible to reexamine this problem. The present
status and the previous course of the disease were analyzed in a large num-
ber of cases; individual follow-up examinations were not included.
Prospective studies naturally give the most reliable statements on progno-
sis, since all patients are studied from the very beginning of their disease.
However, this method presents particular problems in analyzing MS. Many
patients do not see a doctor when the first slight and transient symptoms
appear. In addition, misdiagnoses often occur in the beginning (Sallstrom,
1942; Kolb, 1950; v. Buren et aI., 1972; Kappeli et aI., 1972). These early
stages are not only important for diagnostic reasons; McAlpine (1964) was
able to show that patients who were hospitalized during the early phase
actually had a more benign course of the disease later. He wrote: "The
period of rest in the early active stage of the disease, the advice given as to
future mode of living, and the stress laid on rest in bed during a relapse
may have played a part in modifying the course of the disease".
Early drug treatment might also influence the subsequent course of the
disease. In particular, an immunosuppressive therapy can reduce the fre-
quency of bouts, although it has no influence on preexisting progression
(Frick et aI., 1971; Groninger et aI., 1973).
The prospective method has not yet been used in a large representative
sample of MS patients. Kurtzke et a1. (1968, 1969) followed up 527 US
Veterans, including 234 early-onset cases, but it is doubtful whether his
sample is representative. First, only young males were recorded; and second-
ly, the data were not obtained in a standardized form, but reconstructed
from traditional records. It will be several years before the results of the de-
tailed prospective study on 93 patients by Broman et a1. (1972) are avail-
able. Thygesen (1949) and McAlpine (1961, 1964) reported on early cases;
however, a systematic follow-up was not made. Because large scale prospec-
tive studies are so difficult to carry out in MS, other methods have been
used to gather information on disease course and prognosis.
Several authors followed up a sample of patients over many years. In most
cases the numbers were small, and the patients did not participate in the
study from the disease onset (Mcintyre et aI., 1943; Millar, 1949; Allison,
 ss
1950; Panelius, 1969; Fog et al., 1970). Alexander et al. (1958) used a
quantitative scoring system with standardized definitions to register the
course of 554 patients. This study was designed from a therapeutic point
of view; therefore the average time of observation (3 years) was too short
to give a long-term prognosis. A variety of retrospective studies have ap-
peared in the literature. The results concerning factors which influence
prognosis often differ. This could perhaps be expected, because the selec-
tion of patients, the methods of registration, and the criteria applied in diag-
nosis and prognosis vary widely.
A survey of the most important studies is given in Table 15. Number and
selection of patients, method of recording, criteria applied for prognosis,
and the results obtained are included. In addition, statistical analyses are
mentioned, for they seem to be important. For example, Thygesen (1949)
suggested that the course of MS is more favorable in patients with late dis-
ease onset. However, statistical analysis of his data shows no significant
difference in ability to work among patients of different age at onset (2-1-
test applied to the data of his Table 6).
There was possibly no respresentative sample in our study. Not all inpa-
tients from the participating hospitals could be included (see Sect. 3.5), and
outpatients were recorded in only 2 of the 17 institutions. The registration
of all patients in a certain area should result in a relatively unbiased sample,
because no internal selection is made, but such registration requires organi-
zation and effort. Firnhaber (1969) received help in registration from all
family doctors, internists, ophthalmologists and neurologists in a defined
area. He then examined all the MS patients personally.
Preliminary results from 226 patients (those from Firnhaber's study, to-
gether with those from new patients) in the epidemiologic area were given
in Section 3.9.1 and compared with the corresponding data in our main
study of 812 patients in Table 13. No deviations were found regarding sex
ratio, age at onset, and desease course. The differences in disease duration,
in diagnostic classification, and in the ability to walk seem to indicate that
the percentage of patients with a benign course is higher in the epidemio-
logic group (see Sect. 3.9.1). The prognosis is apparently better in the epi-
demiologic group than in our group of patients, which is the type of group
normally studied.

4.1.1.1 Age at Onset and PrognosiS

R. Muller made a detailed study in 1949 and found that patients with lower
age at onset of their disease have a better prognosis. He also found that pa-
tients with progressive bouts do worse than patients with remittent bouts.
He did not attempt to correlate age at onset with disease course. However,
Leibowitz et al. (1964a, b, 1973), who confirmed the findings of MUller,
56

Table 15. Survey of the literature on the prognosis of MS

Author Place Year Sample N 'i' <5 Method of

Investigation
Brain London 1936 3 different 171 ? ? Retrosp. data coli.
samples
Henner et al. Prague 1939 Outpat. and 178 95 83 Retrosp. data coli.
inpat.
Mcintyre et al. Cincinnati/ 1943 ? 55 34 21 Follow-up study
USA
Millar Belfast 1949 Outpat. and 91 41 50 Retrosp. and
inpat. reexam.
R. Miiller Stockholm 1949 Outp. and inp. 810 453 357 Retrosp. and
from dif. instit. reexam.
Thygesen Copenhagen 1949 Inpat. only 110 59% 41% Retrosp. and
prosp. data coil.
Carter et al. New York 1950 Dead inpat. 46 22 24 Retrosp. data coil.
from autopsy cases
Kolb Baltimore 1950 Inpat. only 176 45% 51% Retrosp. and reex.
of a group
Lazarte Rochester 1950 Pat. from the 342 173 169 Retrosp. data colI.
Mayo Clinic
Allison Belfast 1950 Pat. from epid. 40 25 15 Follow-up study
area
McLean et al. Rochester 1951 Pat. from the Mayo 418 226 192 Retrosp. data coli.
Clin. (remit. course)
McAlpine et al. London 1952 Mainly inpat. 840 65% 35% Retrosp. and fol-
low-up
Abb et al. Wiirzburg 1956 Inpat. 1725 51% 49% Retrosp. and
reexamin.
Alexander Boston 1958 ? 554 352 202 Follow-up study
et al.
Hyllested Denmark 1961 Pat. dead from 854 452 402 Retrosp. data
MS coli.
H. R. Miiller Switzerland 1961 Pat. dead from 111 73 38 Retrosp. data
1966 MS colI.
Bauer et al. Hamburg 1963 War-veterans 797 14% 86% Retrosp. and
1965 and inpat. reexam.
Stazio et al. Winnipeg 1964 Pat. from epid. 128 88 40 Retrosp. and
area reexam.
Leibowitz Israel 1964 All pat. from 266 141 125 Retrosp. and
et al. 1973 Israel reexam.
Poeck et al. Freiburg 1964 Inpat. 220 130 65 Retrosp. and reex.
of 17 pat.
Kurtzke et al. Washington 1968 US-veterans 527 527 Follow-up from
1969 med. records
Panelius Finland 1969 Pat. from epid. 146 90 56 Retrosp. and
area reexam.
Fog et al. Copenhagen 1970 Outpat. and 73 39 34 Follow-up study
inpat.
Riser et al. Toulouse 1971 Inpat. 203 108 95 Retrosp. and fol-
low-up
Gudmundsson Iceland 1971 All pat. from 104 63 41 Retrosp. and
Iceland reexam.
Dassel Netherlands 1973 Pat. dead from 3788 2121 1667 Mortality sta-
MS 1950-58 tistics
Lhermitte Paris 1973 Inpat. 245 69% 31% Follow-up study

Poser Germany 1974 Inpat. and 812 520 292 Retrosp. and
outpat. reexam.
 57

Criterion Stat. Sex Age at onset Infl. of Course

applied anal. Infl. ? Quality Infl.? Quality symptoms Infl.? Quality
At onset Later
Duration of dis., No ? Yes Old Yes Yes Yes ?
disability better
Ability to walk No Yes Cjl Worse Yes Old Yes ? ?
better
Our. of dis., No ? ? Yes Rapid progr.
symptomatol. unfavorable
Our. of dis. No No Yes Young Yes Yes Monosymptom-
better atic better
Mortality, Yes Yes c! Worse Yes Young Yes Yes Progr. bouts
incapacity better unfavorable
Disability, work- No ? Yes Old Yes Yes Progr. from onset
ing capacity better unfavorable
Our. of dis. No ? Yes Old Yes Yes According to clin.
better symptomatol.
Working cap. No ? No Yes ?

Our. of dis. No Yes Cjl Worse Yes Old Yes Yes Chron. progr. +
incap. better acute forms unfav.
Our. of dis., No ? Yes Yes Yes Oligosymptom-
disability atic better
Incap. (ability to No ? ? ? Yes As long as ambu-
walk or to work) latory fav.
Our. of dis., Yes No No Yes Yes Yes Chron. progr.
disability unfav.
Our. of dis., No ? ? ? Yes Yes Oligosympt. bet-
work. ability ter, cere bell. worse
Neurologic No No No ? Yes Progr. worse
deficit score
Our. of dis., No Yes c! Worse No ? ? Yes ?
mortality
Our. of dis., Yes Yes c! Worse Yes Yg.bet. ? ? ?
work. ability for Cjl
Working No ? ? Yes Remitting
ability better
Disability No No Yes Young ? ?
better
Disability Yes Yes Cjl Worse Yes Young Yes No Yes Progr. worse
better
Dur. of dis. No No No Yes ? Yes Progr. from onset
unfavorable
Our. of dis., No ? No Yes Yes Yes ?
disability
Our. of dis., Yes Yes c! Worse Yes Yes Yes Yes Depending on
disability numb. of bouts
Neurologic No ? Yes Yes Yes Yes Depending on
deficit score progr.
Our. of dis., No ? Yes Young Yes Yes Chronic progr.
abil. to walk better worse
Disability Yes No No Yes Yes ?

Mortality Yes Yes ~ Worse ? ?

Frequency No ? No Yes Depending on

of bouts no. of bouts
Ability to work Yes No No ? ? Yes Progressive
and to walk worse
58

suggested that age at onset clearly determines the prognosis and influences
the disease course.
An analysis of the results given in Leibowitz' book on Table 3.16, page 38,
shows that there is no statistically significant deviation in the age at onset
in the group of severely handicapped patients (p > 0.05). However, a dif-
ference was found in the course of the disease in this group (p < 0.05).
Leibowitz grouped the patients according to "degree of malignancy" and
found only then that the age at onset was the most relevant factor for
prognosis. The results of Leibowitz et at. could be biased by selection. All
his patients were immigrants to Israel and there is no way to find out if the
severity of the disease influenced their decisions to emigrate. Dean et al.
(1976) also encountered the problem of biased population. It is possible
that young patients with an unfavorable course were underrepresented in
the sample. After a mean disease duration of 11.5 years, 63% of Leibowitz'
patients had a remitting course without progression, possibly another indi-
cation of a sample with a particularly high number of benign cases. Our
corresponding figures are: a remitting course in 42% of the patients in our
main pool sample with mean disease duration of 8.7 years, and a remitting
course in 43% of patients in the epidemiologic sample with a mean disease
duration of 13.0 years.
R. Muller (1949) made a great effort to get a representative sample. He
gathered information from 810 patients registered in different institutions
around Stockholm during the previous 25 years and reexamined 582 of
them. Results were obtained from the whole group of 582 patients as well
as from three subgroups individually. These subgroups were defined accord-
ing to the place of registration (outpatient departments, private practice,
and internal neurology departments of several hospitals). There were no im-
portant differences in results from the various subgroups and also none be-
tween the subgroups and the whole sample; the latter was thus regarded as
representative. As regards prognosis, the sample was divided into patients
with remittent and with progressive bouts. R. Muller gave neither the num-
ber of patients without progression, nor the number of those with primary
progression at the time of examination. This makes a comparison of his
results with ours difficult.
The frequency of clinical signs and symptoms are similar to those in
other studies (see Table 3), whereas the duration of the disease was longer
(15 years), and the age at onset lower (26 years; taken from Fig. 1 on p. 63
of his book). More than half of his patients (411 out of 810) were regis-
tered as ill before the age of 24, the corresponding figure in our material
being 218 out of 812 (27%). These differences suggest that perhaps his
method of registration (examination of survivors) resulted in overrepresen-
tation of patients with low age at onset having a benign course. Young
patients with an unfavorable course could have died of MS in the mean-
time.
 59

The mean age at onset of 31 years in our study is similar to that found
recently by Leibowitz et aI. (1973) and Gudmundsson et aI. (1974). Older
statistics often give a lower age at onset. Gudmundsson et aI. (1974) pointed
out a significant rise of the mean age at onset during the last decades (from
26.5 to 31.6 years). A similar trend was mentioned by Broman et aI. (1972).
The mean age at onset recorded in a prevalence study of patients in and
around Goteborg in 1960 was 29 years; it was 32 years in the same area in
1972 (incidence material). If this rise in the mean age at onset can be con-
firmed by long-term prospective studies, it would be of great interest to
test for correlations with other factors (antibody titers, age during measles
infection, etc.). It might be possible to find clues about pathogenesis from
such a study. A difference in age at onset between males and females has
been reported by some authors (survey: see McAlpine et aI., 1972; Firn-
haber, 1973), but could not be confirmed by others (Panelius, 1969;
Tavolato, 1974; present study). Again, prospective studies might explain
these discrepancies.

4.1.1.2 Disease Course and Prognosis

Significant differences were found in the degree of disability among patients
with different disease courses. These differences were similar for the pool
sample and for the epidemiologic group. Comparable degrees of disability
were recorded in patients of different ages at onset, but with the same dis-
ease course. That is, our results seem to indicate that loss of performance
depends on the disease course rather than on age at onset. However, the
chronic-progressive form is seen more often in older patients; therefore, old
age at onset seems to bear an unfavorable prognosis. Bouts and remissions
do occur in older patients, but in these cases the prognosis is as good as for
younger patients.
In common with the findings of R. Millier (1949), McAlpine (1961), and
Bauer et al. (1965), our results suggest that a progressive course from dis-
ease onset or transition into a chronic-progressive course after initial bouts
and remissions indicate a poor prognosis. Poeck et al. (1964) arrived at the
same conclusion in a different way. They showed that the mean life expec-
tancy was greater than 20 additional years for patients with a remittent
course and of different age at onset. Patients with a progressive course from
the beginning had only 15 more years to live on the average (again, regard-
less of age at onset).
McAlpine (1961) distinguished three types of disease course. The first
type, the "remittent" course, is characterized by full remissions between
bouts. In the second type, "remittent and progressive", a remittent phase
is followed by a chronic progression. A chronic progression is present from
the beginning in the third type, "progressive from onset". In the literature
60

the differences in the type of onset and the development of the disease have
usually been regarded as variations of the same basic process. Different man-
ifestations have been assumed to reflect a different immunologic status of
patients. There is a malignant form with rapid progression and possible
death within a few months (Brain 1936; McIntyre et aI. 1943), and a benign
course with little disability over many years or decades (McAlpine, 1961;
Mackay et aI., 1967; Lehoczy et aI., 1963; Bonduelle, 1969), and a variety
of forms in between. Some authors stress the peculiarities of the primary
progression (Friedman et aI., 1945; Leibowitz et aI., 1967) and separate it
from other forms of the disease (Glatzel et aI., 1968).
Fog et aI. (1970) divided the course of MS into three phases: a hypothet-
ical incubation period (phase I), a prephase (phase II) characterized by an
intermittent course, and a progressive phase (phase III). They suggested
that all patients go through these three phases, although MS is not diag-
nosed in some patients until they are in the progressive phase. This model
reflects the apparent predilection of the progressive course for older ages.
Its relevance, however, must be confirmed by large prospective studies.

4.1.1.3 Duration of the Disease and Prognosis

There is general agreement in the literature that in most patients the degree
of disability increases with time, i.e., with duration of the disease. However,
the speed of this deterioration varies widely in the different studies. The
results of major papers are given in Table 16. The proportion of patients
with little or no disability after 8-15 years is shown to facilitate compari-
son.
Some of the discrepancies can be explained by different selection of the
patients; for example, MacLean et aI. (1951), who recorded remarkably good
performances, studied only ambulatory patients with a remittent course.

Table 16. Influence of duration of MS on the performance of patients; survey of the

literature

Author Year After n years Percentage Criterion applied

MacLean et a1. 1951 >10 42% Ability to walk and to

work preserved
McAlpine 1961 10-14 42% No disability
Abb et a1. 1956 >10 41% Ability to work
preserved
R. MUller 1949 15 34% No invalidity
Bauer et a1. 1963 15 32% } Ability to work
H. R. MUller 1966 11-15 27% fully or partly
Thygesen 1949 8-15 25% preserved
Kolb 1950 15 Ability to work
preserved
 61

Percy et ai. (1971) confinned this favorable prognosis; two-thirds of the

patients from the Mayo Clinic were still able to walk after 25 years of ill-
ness.
The criteria applied for prognosis may have an influence on the results.
For instance, the ability to work is not only dependent on physical or on
mental findings, but also on social factors (see Sect. 3.6.3). On the other
hand, the ability to walk, which is taken as a parameter for "disability"
(McAlpine) or "invalidity" (R. MUller), does not completely detennine per-
fonnance. For instance, an incapacitating tremor of the anns can be found
in connection with a preserved ability to walk.
In our study, prognosis is considered in terms of both the ability to work
and the ability to walk. After 15 years of illness, 30% of our patients
showed little or no disturbance in their ability to work; the corresponding
figure for the ability to walk was 39%.
This is in general agreement with other studies (see table 16).

4.1.1.4 Sex and Prognosis

Male patients with MS often appear to have a less favorable prognosis than
females CR. MUller, 1949; H. R. MUller, 1966; Panelius, 1969). However,
according to Henner et ai. (1939), Lazarte (1950), Leibowitz et ai. (1973),
and Dassel (1973), males have a better prognosis. Dassel based his results on
mortality data, which are probably of limited value for statements on prog-
nosis (Stazio et aI., 1964). A statistical analysis was not made by Henner et
ai. or by Lazarte. There was no significance in the data of Leibowitz et aI.
In several other studies, including ours, no difference in prognosis between
males and females could be found (McAlpine et aI., 1952; Alexander et aI.,
1958;Poecketal., 1964; Gudmundsson, 1971).

4.1.1.5 Symptomatology and Prognosis

The symptoms of MS have often been related to prognosis. Classifying pa-
tients according to symptomatology (Oppenheim, 1911; Carter et al., 1950;
Kurtzke et aI., 1968) can reveal different prognosis for the different groups.
However, the pattern of symptoms can vary widely during the course, which
means that a penn anent reassessment of the classification is needed.
We were unable to include systematic follow-up studies in the present
investigation and were therefore unable to correlate symptomatology to
the course and prognosis of disease.
62

4.1.2 The Problem of Diagnosis

Computer-assisted diagnosis has attracted the interest of numerous investi-

gators (survey: see Pirtkien, 1971; Jacques, 1972). In other fields it has
already proved to be a valuable aid to the clinician (Horrocks et aI., 1972;
Hirschfeld et aI., 1974; Levi et aI., 1976).
It would be tempting to develop a similar tool for the diagnosis of MS. In
the Scandinavian countries preliminary work in this direction is now in pro-
gress (Bergmann et aI., 1965; Broman et aI., 1969). Markov et ai. (1969)
reported on the successful use of a computer for differential diagnosis, i. e.,
in differentiating between MS and acute allergic encephalomyelitis.
The reliability of clinical diagnosis was defined in our study as: definite,
probable, or possible. In the beginning it was not necessary to set down
rigid criteria in order to decide among these categories. The study of C. M.
Poser (1965) showed that the age, experience, and nationality of a neurol-
ogist have little influence on his ability to make a correct diagnostic classi-
fication of MS. However, it is necessary to have standardized criteria for the
development of a computer-assisted study. These criteria were given on the
new set of data sheets (see Fig. 5; Bauer, 1972). The symptomatology of
patients with different certainty of diagnosis of MS and those with other
similar diseases should now be recorded in a standardized manner. Hope-
fully, analysis of such data will allow computer-assisted diagnosis in the
future, in spite of the warning of J. K. Kurtzke (1967): "caveat comput-
ator".
Several authors had tried to construct a diagnostic classification system
independently (Allison et aI., 1954; Gilland, 1965; Schumacher et aI., 1965),
but up to now no general agreement has been reached. This still makes a
comparison of prevalence and incidence data in epidemiologic studies very
difficult. Even if similar diagnostic criteria are applied, there is the problem
of deciding whether or not possible cases should be included. The same
is true for statistics on symptomatology. For instance, Leibowitz et ai.
(1973) included possible cases and suggested that bias of selection would
increase if they were excluded. Patients with a progressive course from dis-
ease onset and spinal cases would be lost, because they do not fulfill the
classic criteria (Leibowitz et aI., 1973). Kurtzke et ai. (1969) and Panelius
(1969), on the other hand, did not include the possible cases. As long as dif-
ferent diagnostic criteria are applied and the selection of patients varies
widely, a comparison of data from different studies is difficult. A first step
has been made in this direction by the construction of a standardized multi-
center recording system.
 63

4.1.3 Statistics on Signs and Symptoms

For the reasons mentioned above (see Sect. 1.3) it did not seem worthwhile
comparing the frequencies of single signs and symptoms with those in the
literature, particularly with data gained in retrospect from traditional medi-
cal records (Sallstrom, 1942; Abb et aI., 1956 ;Kurtzke, 1970; Morsier,
1971). Even for samples recorded in a similar semi-prospective way, com-
parison is difficult. The signs and symptoms registered by R. Muller (1949)
are listed in Table 3. Only data concerning general disturbances of function-
al systems were recorded in the study of Kurtzke (1961). These were not
mentioned by Muller, who preferred to record more detailed findings. This
made comparison difficult; but where a comparison was possible, no obvi-
ous deviations were noticed, except for cerebral (= mental) symptoms. Ex-
act registration of mental status during a neurologic examination is almost
impossible. Knowledge of the patient's personality before the onset of the
disease and psychological tests would be desirable, but are rarely available.
Consistency in the frequency of other signs and symptoms in Table 3 does
not necessarily mean that these statistics are representative for MS. Results
from large, strictly prospective studies, where data are always recorded
from the very beginning of the disease, are not yet available. The data col-
lection in the present investigation is an attempt to solve this problem, but
success depends on the early registration of all cases, as well as on long-term
follow-up examinations.

4.1.4 Follow-Up Examinations

A total of 178 follow-up examinations were recorded on the original sheet.

It was found that the symptomatology could not be registered in sufficient
detail. This disadvantage does not apply to the new documentation system.
A detailed clinical status can be recorded on GD II (see Fig. 6), including
small changes seen during the course of the disease. Follow-up studies in the
literature were mostly based on "disability" or on other rating scales. Unfor-
tunately, the original findings were not presented. Records of original find-
ings, such as neurologic symptomatology, always contain more information
and are more easily reproducible than a summary or a general grading sys-
tem (Hall et aI., 1976).

4.2 Critical Comments on the Method

It is doubtful whether the documentation method developed here can be

applied to all the special projects, as originally planned. Although the need
64

for more detailed information was felt by all members of the study, active
participation decreased, and the error rate increased after introduction of
the new documentation system. It is hoped that familiarity with the sheets
will reduce these difficulties. However, good motivation is necessary for
successful cooperation, particularly when busy physicians are involved.
One improvement in this direction has been the development of a printed
record, which is sent back to the physician (see Fig. 28: program written
by Mr. Kerscher, EDP-Department, Gottingen University). The time usually
needed for dictating and writing a medical record can then be used for the
documentation process. Another way of maintaining the clinician's interest
in the program is to give him access to the data store. This idea is now being
developed, and every effort is being made to facilitate the handling of data.
Even physicians with no computer experience should be able to address
their questions directly to the EDP department and obtain answers in an
appropiately designed print-out. A good design was developed by Wingert
(1972) and has already been applied to the correlation of EEG findings to
cerebral tumors by Patzold et al. (1973) and Haller et al. (1973).
The optical mark reader sheet was found to have an added advantage; be-
cause it could be read without computer equipment, this project was not
interrupted at times when the EDP department was too busy to work for
us. Analysis of findings concerning the 226 patients from the epidemiolo-
gic area was only possible by a manual process. In the daily routine of pa-
tient care, the copy sheets are useful, too; it was some time before the
printed text was returned.
Regardless of the quality of computer facilities in the future, there will
always be a personnel problem. The computer staff have many other duties
and differing appreciation of medical problems, while the physicians have
limited time and differing attitudes toward the use of computers in medi-
cine. In our program the physicians were interested in problems ofMS and
participated voluntarily. Some of the above difficulties were encountered
when all members of the regular staff had to participate in the testing of
the documentation program; a particularly high error rate in form-filling
resulted; also, some patients were not recorded at all. Baird et al. (1965),
Ehlers (1970), and Penin et al. (1972) had similar experiences with optical
mark reader systems. When planning medical computing systems, these
problems must be kept in mind. Although optical mark reader sheets seem
to be of limited value in everyday clinical documentation, they are certainly
a valuable tool for multicenter studies, when computer analysis is required.
 65

ANAI1NESTIC DATA AND CLINICAL FINDINGS IN DISSEMINATED ENCEPHALOMYELITIS COFG FOCAL POINT PROGRA/III, FORM 1

PATIENT NO : 2222221 DATE OF EXlMINATIOhf : 09/19174

COURSE OF DISEASE EPISOOIC I (HROIIIIC PROGRESSIVE

CERTAINTY OF THE CLINICAL DIAGNOSIS DEFINYTe

FIRST APPEARANCE 1963

INITIAL SIGNS AND SYMPTOMS PARESIS, SENSITIVITY OISTURBANCE-S

NUMBER OF EPISODES 1~ THE FIRST YEAR

NUMBER OF EPIsoneS IN THE FURTHER COURSe

DISORDERS IIIHIeH APPEARED IN THE COURSE SPASTICITY/BAFHNSKI, PARESIS, SENSITIVITY, OPTIC,

TRIGEMINAL/FACIAL, velieTAT!VF

DEFECT SINCE {MORE THAN) 4 YEARS

PROGRESSIVE SINCE (MORE THAN) 2 YFAR 5

OJ SOROER5 AS PRESEfoiT DEFECT SPASTICITY/BABINSKI. PARESIS, OPTlC, VEGETATIVE

III FINDINGS IN THE PRESENT EXA~INATION III

EP ISOOE NO

WASHING, DRESSING, EATING SERVERELY OISTURBED

ABILITY TO wALK SERVERElY DISTURBEO, WHEHOtAIP, ~EDRIDOEN

ABLE TO PRACTISE PROFESSION NO

ABLE TO WORK NO

RETIRED YES

DISA8ILITY (KURTZKE SCALE)

COMPLICATIONS !\lONE

PAIN NONE

CSF CTAKEN EARUER, YES CELL NO UNKNOwN "IA.STIX CURVE :UNKNOWN IM~UNf)Gln13UlIN IJNI<Nr'lWN

CSF (TAKEN AT EXAMINATION' NO

OTHER DI SEASES UROGENITAL, SKIN/ALLERGy ,ENDOCRINOLOGICAL, LnrOMOTI')R APPhRATUS,

SEQUelAE QF INJURIES, NEUROlor;ICAl. PSVC~IATPtC

ANA'-'NEST[C DATA AND CLINICAL FINI'lIf<.lGS IN DISSEMINttTEtJ ENC:~P~"'U1MY'EL[TlS (I)FG FO(flL POINT PROGRAM) FOR'" I

..... * /11 IF FORM 2 IS AVAILA3lE FOR THIS FXAMINATP1N, TIIEN PASS OVER TH[ FOLLOWING nPREssrON 1/1

1/1 PRFSFNT CI)'jDlTION III

SPAS TIC I TY IBAH INSK I qTGHT ~RM. Q.IGHT lfG, LFFT l~r.

PARESIS R Ir.HT . . R.M. Q. IGHT IF';, LETT L-=r;

SENSllIVITY OJ STUR8ANC!: ~IG'-1T TRUNKIlEG

VISUAL DISTURBANCE iIT~OPHY RIGHT, ATQ.nPHY LEFT

DlS'1PDEP OF OC.UlAQ MOTILITY

TR IGEMINAl-FA.C I Al 111 SQROf:R

DISORDER OF BRAfNST!:"1/CEREBELlUM

Fig. 28. Print-out of data recorded on the documentation sheet

66

4.3 The Contribution of the New Documentation System to MS Research

The success of any documentation system depends on careful planning of

criteria and definitions to be applied. It was sometimes difficult to come to
a general agreement, and extra definitions had to be included in the new
documentation system for the most controversial items. The work involved
in building up this mutually acceptable system has now been rewarded. Pa-
tients from a variety of institutions in different parts of the country (see
Fig. 27) can be included; a data pool can be established on a large scale and
used for many purposes.
The sample was large enough to give clear results when analyzed statisti-
cally. Questions previously open to discussion in the literature could be
answered (see, for example, Sect. 3.6.4). All members of the study have
permanent access to the data pool. Selection and analysis of certain cases
or of a group can be made in a few days. Statistics on signs and symptoms
will be of value in any future computerized diagnostic system. An attempt
to correlate laboratory results with clinical findings is now being made
(Hauptvogel et aI., 1974). On the whole, the new documentation system
has lived up to our expectations, and although revisions were made as vari-
ous weaknesses came to light, there is still room for improvement.
5. Outlook
68

Projects affiliated with this program that are now taking advantage of the
new documentation system are summarized in the following sections.

5.1 Neuropathology

Characteristic morphologic features of MS have long been recognized.

Attempts to correlate pathologic findings with clinical symptomatology
were made as early as 1868 (Charcot). These efforts have been continued
up to the present time (Fog, 1965b; H. Strotker, 1968; S. Strotker, 1969;
Lumsden, 1970). Morphologic changes can be analyzed in great detail. For
instance, Fog (1965b) applied a technique of serial sections and called the
specific localization of typical plaques around small vessels "periphlebitis
cerebrospinalis et retinalis." Lumsden (1970) confirmed the findings of
Fog and observed clear-cut, reproducible changes in the tissue, although
the intensity, extent, and speed of this process vary.
In contrast to the large number of sophisticated methods and results avail-
able in pathology, clinical findings were usually not sufficiently detailed.
Thus, correlations could only be made for small samples (H. Strotker, 1968;
S. Strotker, 1969). A continous follow-up of the clinical course is now
needed for future correlation of morphologic findings with symptomatol-
ogy; this could reveal new information about pathogenesis (Lumsden, 1970).
Recent clinical findings concerning a particularly interesting patient (re-
cord No. 957/72) were recorded on the documentation sheets, which also
included information on the dynamics of the final process. Subsequent elec-
tron microscopic studies revealed two types of virus particles; nucleocapsid-
like structures and particles similar to the papovavirus (Bauer et aI., 1975).
Similar structures have been seen by other authors (Narang et aI., 1973;
Barbosa et aI., 1973; Prine as, 1972; Raine et al., 1974). Whether they are
relevant to the etiology or pathogenesis of MS remains to be seen.

5.2 Virology

Ter Meulen et aI. (1972) were able to isolate a virus from MS brain tissue.
This was exciting news, but the significance of this so-called 6/94 virus is
still unclear. Further cultures and analysis of results gained by other meth-
ods are still necessary (Iwasaki et aI., 1973). The early sterile autopsy,
which is considered the most practical way of obtaining tissue for cultures
and ultrastructure studies (Bauer et aI., 1975), present problems. Good
communication between clinicians and research groups of the DFG-pro-
 69

gram facilitates the inclusion of cases and data that would otherwise be lost
because of organizational problems.
The determination of antibody titers against the isolated virus might
also give information about the virus and its relevance. Two groups of pa-
tients seemed particularly interesting in this context: first, patients who
exhibited CSF activity during the preceding year (their selection has been
mentioned above; see Sect. 3.8.1); and secondly, patients from the epidemi-
ologic area. Blood was taken from 226 patients, and a clinical examination
was made at the same time. Data on previous childhood infections, on vac-
cinations, and on infectious diseases later in life are known for all the pa-
tients as well as for the following control groups (Poser et aI., 1976b) :
1. Relatives or friends who had lived with or close to them during childhood
and who were born within 3 years of the patient.
2. Psychiatric patients aged 30-60 years.
3. Patients with disc lesions aged 30-60 years.
Antibody titers of measles virus were also determined in all these persons.
The role of measles virus in MS is still unclear. Elevated antibody titers
were found by most authors in serum and/or CSF specimens of MS pa-
tients (for a survey of the literature until 1972, see McAlpine et aI., 1972;
Anonymous, 1974; for recent papers see Panelius et at., 1973; Salmi, 1973;
Salmi et aI., 1973; Salmi et aI., 1974; Cendrowski et aI., 1974; Nemo et aI.,
1974; Norrby et aI., 1974a, b; Woyciechowska et aI., 1974; Vandvik et aI.,
1975). The decreased serum/CSF antibody ratios support the hypothesis
that local production of measles antibodies takes place in the central ner-
vous system of some MS patients, in certain patients with optic neuritis
(Link et aI., 1973; Nikoskelainen et aI., 1975a, b), as well as in a particular
group of patients with chronic myelopathy (Link et aI., 1976). Haire et ai.
(1973, 1974) were able to demonstrate high titers of specific anti-measles
IgG and IgM antibodies in the serum of MS patients and of IgG (but not
of IgM) in the CSF. These observations are suggestive of continuing active
systemic infection by the measles virus (Anonymous, 1974), but they are by
no means conclusive (Anonymous, 1976). The older interpretation of eleva-
ted measles antibodies as an anamnestic or nonspecific response (Brody et
aI., 1971; Daniel, 1972) was based on the finding ofraised serum an tibod-
ies against several other viruses, most of which could not be confirmed by
more specific methods.
There are several discrepancies in the results of published antibody
studies, probably for methodologic reasons. The tests applied vary consid-
erably (e.g., hemagglutination inhibition and hemolyzing inhibition of
nucleocapsid complement-fixing antibodies differ in their specifities; see
Salmi et aI., 1973). There is also the usual problem of selecting the right per-
sons as controls. The observation that in cases of acute neurosyphilis, spe-
70

cific measles antibodies can be detected in the CSF could support the hy-
pothesis that measles virus is ubiquitous and can be reactivated by any kind
of immunologic process (ter Meulen, 1976).
Investigation of a cell-mediated immunologic mechanism in MS showed an
anergy toward measles in the study of Utermohlen et aI., 1973. However,
Cunningham-Run dies et al. (1975) and Bartfeld et al. (1976) could not con-
firm this fmding. The observation that MS patients acquire measles later in
life than controls (Alter, 1976) was based on the retrospective data of 30
MS patients (Alter et aI., 1976).
In future studies it will be necessary to correlate the nature and titer of
serum and of CSF antibodies and of cell-mediated mechanisms with clini-
cal findings, including the history of previous infections. The standardized
documentation system is an invaluable tool in this context.

S.3 Immunology

Further immunologic studies are planned with patients from the pool and
from the epidemiologic area. The genetically determined histocompatibil-
ity (HL-A) antigens show different patterns in MS patients and in controls
(Bertrams et aI., 1972; Jersild et aI., 1972; 1973a, b; Naito et aI., 1972). It
is important to know whether or not the HL-A antigens have an influence on
the course of the disease. A correlation between the HL-A pattern and clin-
ical findings was observed by Jersild et al. (1973b) and by Bertrams et al.
(1974a). In the Danish study (Jersild et aI., 1973b) detailed data concern-
ing the course and symptomatology were given, but the same sample was
small (28 patients). Bertrams et aI. (1974a) reported on a larger group, but
they did not give detailed information about clinical findings.
These results should now be confirmed and specified by making HL-A
typings on a large number of patients whose clinical data are recorded in
sufficient detail. The pool material here should be useful in this context,
too.
It is still debatable whether there is a correlation of HL-A antigens and
antibody titers to measles virus in MS patients. Jersild et al. (1973c) found
high-titer antibodies to measles in 13 out of 57 MS patients carrying the
HL-A antigens known to be increased in MS, but in only 2 out of 45 MS
patients lacking these particular antigens. These findings were confirmed by
Cazzullo et al. (1974), but not by Bertrams et al. (1973).
Antibody titer to measles virus and detailed clinical information are al-
ready available from patients from the epidemiologic area. An analysis of
the HL-A antigens in these patients and in their relatives is planned. The
HL-A pattern of the relatives should be interesting for two reasons: firstly,
 71

to obtain more knowledge of HL-A pecularities of MS patients themselves

(Bertrams et al., 1974b); and secondly, to elucidate the frequent occurrence
of familial cases (Zander et al., 1976).
Lymphocyte-defmed determinants have shown an even higher correlation
to MS than the serologically determined HL-A antigens (see Jersild et al.,
1975; Bertrams, 1976).
A 100% association of MS with alloafltigens, which are exclusively located
on B-lymphocytes (so called Ag 7a), has recently been reported (Winchester
et al., 1975).
Immunological phenomena associated with experimental allergic enceph-
alomyelitis, an animal model for MS, have been investigated in MS patients
(Bornstein, 1972; survey: see Nilsson, 1972). The role of serum induced
demyelination (Raine et al., 1973) is still unclear. Follow-up studies of in-
dividual patients and close correlation with the clinical course promise an
insight into the pathogenetic mechanisms involved. Our documentation
system provides clinical data in a practical way and will be used by others
(Bornstein, 1976) in this context.

5.4 Relevance of CSF Findings

An increase of the 'Y-globulin fraction (mainly IgG) has proved to be the

only result of diagnostic value so far obtained from analysis of the CSF of
MS patients (Bauer et al., 1969; Olsson et al., 1973). It is still debatable
whether or not this increase is correlated with the existence of auto-aggres-
sive or protective antibodies or even whether or not it is related to patho-
genesis. The determination of 'Y-globulin fractions presents no problems;
special methods are already available (Bauer et al., 1969; Olsson et al., 1973;
Iwashita et al., 1974).
However, the diagnosis of MS cannot be made from CSF findings alone
without knowledge of the clinical picture. The combination of a non-com-
puter-compatible form with an optical mark reader sheet makes a comput-
erized correlation of CSF with clinical findings possible (Hauptvogel et al.,
1974).
Follow-up studies ofMS patients should give useful information on the
dynamics of the clinical course and corresponding CSF changes.

5.5 Epidemiology

Information on environmental and social factors concerning MS patients

were gained together with clinical and serologic findings. Analysis and
72

correlation of these data by a computer program (written by Mr. Brauns,

EDP Department, G6ttingen University) is now in progress. A preliminary
survey confIrms the fmdings of Firnhaber (1969); it was not possible to
find any association between environmental factors and the frequency of
occurrence of MS. We were mainly interested in the social factors. It soon
became evident that, although medical care seems to be sufficient, the social
needs of MS patients are met very poorly.
The close contact between physicians and patients in the epidemiologic
area should be valuable in future prevalence and incidence studies. In our
investigation the prevalence rate in the epidemiologic area increased as the
methods of finding and documenting patients improved. This observation
had already been made by Broman (1976).
There is no evidence at the moment that MS is really becoming more fre-
quent, except in some special areas (Bird et aI., 1975).
Cooperation with a Japanese research group should reveal new epidemi-
ologic findings. Reported differences between MS patients in Western coun-
tries and in Japan in the context of clinical symptomatology (Kuroiwa et
aI., 1973) will be reassessed after recording the data on our documentation
sheets in both countries.

5.6 The Standardized Medical Record

The printed version of the data which originally appeared on the documen-
tation sheet has two advantages: First, it saves time, because the traditional
method of writing or dictating the medical record can be replaced; secondly,
it can be requested by any member of the program who wants full informa-
tion on individual patients and their follow-up examinations. Numerous
other applications of the documentation system are possible and have al-
ready been discussed. Only a few of them will be realized immediately, but
others should gather momentum as new data accumulate.
Summary

A variety of new findings in multiple sclerosis research has yielded clues to

its etiology and pathogenesis. One reason why some of the results remain
inconclusive or even contradictory, and why the final solution of the prob-
lem is still pending, is the lack of communication among the different
branches of research, as well as their isolation from the patient and his clin-
ical symptomatology. The DFG (Deutsche Forschungsgemeinschaft)pro-
gram "Atiologie and Pathogenese der Multiplen Sklerose und verwandter
Erkrankungen" was started in 1970 with a view to creating better exchange
of information among immunologic, virologic, neuropathologic, biochem-
ical, and epidemiologic investigators. Clinical findings were also regarded as
an essential part of all research activities.
Because data recorded in traditional medical records are often found to
be incomplete and disorganized, a standardized documentation method has
been developed. The optical mark reader system was adapted to the prob-
lem and proved to be particularly appropiate for this multicenter program,
in which 17 hospitals and 8 research institutions participated. The data of
947 MS patients were recorded on optical mark reader sheets and fed into a
Siemens 4004/35 computer for analysis from January 1972 to August 1973.
Incompletely or incorrectly marked data sheets were refused with the help
of a plausibility control program, which also produced a protocol of the
errors made. The initial error rate of 20%-30% was reduced to 10%-15%.
Different features of MS, as well as statistical information on signs and
symptoms, were gained by correlation and selection of data from the 812
first examinations.
The results can be summarized as follows:
The mean age at disease onset was 31.1 years, the mean duration of the
disease 8.7 years, and the sex ratio 64% females to 36% males. Differences
between the sexes were found in single signs and symptoms (pareses, ataxia,
sensory and sexual disturbances), but not in general performance or in the
ability to walk and to work, and also not in the age at disease onset. With
very few exceptions (e.g., mental disturbances), the frequency of signs and
symptoms was found to be in good agreement with that in the literature.
74

The ability to walk and to work, used as a parameter for prognosis, was
compared in different groups of patients. Both the duration and course of
MS had a significant influence on the disability, but the age at onset in
itself was found to be less important.
The correlation of clinical parameters with the duration of the disease
provided information about the dynamics of certain signs and symptoms
and about the ability to walk and to work over the years. A detailed anal-
ysis of certain signs and symptoms was performed, keeping any future com-
puter program for diagnostic help in view. Certain groups of patients were
selected for special therapeutic (e.g., stereotactic surgery) and research pro-
cedures (e.g., antibody determinations). In an attempt to test for possible
bias in the selection of our patients, the data of a group of 226 patients
from an epidemiologic area were compared with our results and found to be
very similar in respect of the above statements.
The experience gathered with the aid of the first documentation sheet
was helpful in the development of two new sheets that allow for the regis-
tration of more details. With increasing amount of data, there is inevitably
an increase in common interests and goals and improvement in communica-
tion among the fields of biochemistry, virology, immunology, epidemiology,
and neuropathology. Clinicians should profit from the computerized medi-
cal record developed from the new documentation sheets. The optical mark
reader documentation method has limitations, but it is suitable for multi-
center research studies.

Acknowledgments. This study was supported by the Deutsche Forschungsgemeinschaft

in the frame of the Schwerpunktprogramm: )ftiologie und Pathogenese der Multiplen
Sklerose und verwandter Erkrankungen. I would like to thank Professor Bauer, who
initiated the program, and all members who participated in the data collection.
Miss Jane Houchin was most helpful in the revision of the English text, Mrs. Ingrid
Karstens in typing parts of the manuscript.
Participating hospitals:
I Neurologische Universitatsklinik, Gottingen
2 Taunusklinik, Falkenstein
3 KamiIlusklinik, Asbach
4 Neurologische Klinik der Med. Akademie, LUbeck
5 Neurologische Klinik der Med. Hochschule, Hannover
6 Neurologische Universitatsklinik, Wiirzburg
7 Centrum voor Multiple Sclerose, Melsbroek
8 Kommunehospitalet, Kopenhagen
9 Karl-Bonhoeffer-Nervenklinik, Berlin
10 Nervenklinik der Universitat, Miinchen
II Allgemeines Krankenhaus St. Georg, Hamburg
12 Neurologische Universitatsklinik, Hamburg
13 Neurologische Klinik der Hochschule, Essen
14 SchloJ:.parkklinik, Berlin
IS Neurologische Universitatsklinik, Berlin-Steglitz
16 Rudolf-Virchow-Krankenhaus, Berlin
17 Neurologische Klinik der Stadtischen Krankenanstalten, Darmstadt
 75

References

Abb, L., Schaltenbrand, G.: Statistische Untersuchungen zum Problem der Multiplen
Sklerose.lI. Mitteilung. Dtsch. Z. Nervenheilkd. 174, 199-218 (1956)
Albert, H. H. von: Personal communication (1973)
Alexander, L.: New concept of critical steps in course of chronic debilitating neurolog-
ic disease in evaluation of therapeutic response. Arch. Neurol. Psychiatry (Chic.)
66,253-271 (1951)
Alexander, L., Berkeley, A. W., Alexander, A. M.: Prognosis and treatment of multiple
sclerosis - quantitative nosometric study. J. Am. Med. Assoc. 166, 1943-1949
(1958)
Allison, R. S.: Survival in disseminated sclerosis: a clinical study of a series of cases first
seen twenty years ago. Brain 73, 103-120 (1950)
Allison, R. S., Millar, J. H. D.: Prevalence of disseminated sclerosis in Northern Ireland.
Ulster Med. J. 23 (Suppl. 2), 5-27 (1954)
Alter, M.: Is multiple sclerosis an age-dependent host response to measles? Lancet
1976/1,456-457
Alter, M., Cendrowski, W.: Multiple sclerosis and childhood infections. Neurology 26,
201-204 (1976)
Angst, J., Battegay, R., Bente, D., Berner, P., Broeren, W., Cornu, F., Dick, P., Engel-
meier, M. P., Heimann, H., Heinrich, K., Helmchen, H., Hippius, H., P61dinger, W.,
Schmidlin, P., Schmitt, W., Weis, P.: Das Dokumentationssystem der Arbeitsge-
meinschaft fUr Methodik und Dokumentation in der Psychiatrie (AMP). Arzneim.
Forsch. 19,399-405 (1969)
Angst, J., Jaenicke, U., Peter, J., P6ldinger, W.: Vergleichende Studie mit den tricycli-
schen Antidepressiva Noxiptilin und Dibenzepin. Arzneim. Forsch. 21, 635-638
(1971 )
Anonymous: Measles and multiple sclerosis. Lancet 1974/1,247-249
Anonymous: Multiple sclerosis. Lancet 1976/1, 129-131
Arkin, H., Sherman, I. c., Weinberg, S. L.: Tetraethylammonium chloride in the treat-
ment of multiple sclerosis. Arch. Neurol. Psychiatry (Chic.) 64, 536-545 (1950)
Bader, R., Rieder, H. P., Kaeser, H. E.: Die Bedeutung der diskontinuierlichen Zonie-
rung des Immunglobulinbereiches fUr die Diagnose neurologischer Erkrankun-
gen. J. Neurol. 206, 25-38 (1973)
Baird, H. W., Garfunkel, J. M.: Electronic data processing of medical records. N. Engl.
J. Med. 272,1211-1215 (1965)
Barbosa, L. H., Hamilton, R.: Virological studies with multiple sclerosis brain tissues.
Lancet 1973/1, 1415-1417
Bartfeld, H., Zaia, J. A., Donnenfeld, H.: Cellular immunity in multiple sclerosis. Lancet
1976/1,317.
Bauer, H. J.: Multiple Sklerose: Grundlagen und Hypothesen der modernen Ursachen-
forschung. J. Neurol. 198,5-32 (1970)
Bauer, H. J.: Communication to: judgement of the validity of a clinical MS-diagnosis.
Int. Symp. Multiple Sclerosis, G6teborg, 1972
76

Bauer, H. J.: Discussion report: studies in progress on the relevance of virus isolation to
the etiology of MS. 10. Int. Congr. of Neurol., Barcelona, 1973
Bauer, H., Firnhaber, W.: Zur Leistungsprognose Multiple-Sklerose-Kranker. Dtsch.
Med. Wochenschr. 88,1357-1364 (1963)
Bauer, H. J., Firnhaber, W., Rauschelbach, J.: Multiple Sklerose. In: Arbeit und Gesund-
heit. Stuttgart: Georg Thieme 1978 (to be published)
Bauer, H. J., Firnhaber, W., Winkler, W.: Prognostic criteria in multiple sclerosis. Ann.
N. Y. Acad. Sci. 122,542-551 (1965)
Bauer, H., Gottesleben, A.: Quantitative immunochemical studies of cerebrospinal fluid
proteins in relation to clinical activity of multiple sclerosis. In: Pathogenesis and
Etiology of Demyelinating Diseases. Burdzy, K., Kallos, P., (eds.), Basel-New York:
Karger 1969, pp. 643-648.
Bauer, H. J., Meulen, V. ter: Koprowski, H., Argyrakis, A., Orthner, H.: Early sterile
autopsy in etiological studies on multiple sclerosis. J. Neurol. 208 159-174
(1975)
Baust, W.: Basisdokumentation von neurologischen Krankenblattern. Nervenarzt 42,
547-549 (1971)
Baust, W.: Das Informationssystem der Neurologischen Universitatsklinik DUsseldorf.
Siemens Data Rep. 8,10-15 (1973)
Bente, D., Feder, J., Helmchen, H., Hippius, H., Mauruschat, W.: Multidimensionale
pharmakopsychiatrische Untersuchungen mit dem Neurolepticum Perazin. Phar-
makopsychiatr. Neuropsychopharmakol. 7, 8-17 (1974)
Berger, A.: Eine Statistik Uber 206 Falle von Multipler Sklerose. Jb. Psychiatr. Neurol.
25, 168-188 (1905)
Bergmann, L., Broman, T.: A point scale for the diagnostic probability of MS. Acta
Neurol. Scand. 41 (Suppl. 13),549-550 (1965)
Berner, P., Gulli, H., Hofmann, G., Kryspin-Exner, K., KUfferle, B.: Doppelblindprtifung
von Antidepressiva (Noxiptilin-Imipramin). Arneim. Forsch. 21, 638-640 (1971)
Bertrams, J.: HL-A Antigene und Krankheitsempfanglichkeit. Dtsch. Med. Wochenschr.
101,178-184(1976)
Bertrams, J., Fisenne, E. von, Hoher, P. G., Kuwert, E.: Lack of association between
HL-A antigens and measles antibody in multiple sclerosis. Lancet 1973/11, 441
Bertrams, J., Hoher, P. G., Kuwert, E.: HL-A antigens in multiple sclerosis. Lancet
1974 a/I, 1287.
Bertrams, J., Kuwert, E.: HL-A antigen segregation analysis in multiple sclerosis. Lancet
1974 b/ll, 43-44.
Bertrams, J., Kuwert, E., Liedtke, U.: HL-A antigens and multiple sclerosis. Tissue
Antigens 2, 405-408 (1972)
Bird, A. V., Satoyoshi, E.: Comparative epidemiological studies of multiple sclerosis in
South Africa and Japan. J. Neurol. Neurosurg. Psychiatry 38, 911-918 (1975)
Bleuler, E.: Das autistisch-undisziplinierte Denken in der Medizin und seine Dberwin-
dung. 5th ed. Berlin-Gottingen-Heidelberg: Springer-Verlag 1962
Bochnik, H. J., Mentzos, St.: DirektverschlUsselung von EEG-Befunden fUr maschinelle
Datenverarbeitung. Methods Inf. Med. 3,64-67 (1964)
Bohmig, W.: Statistische Bemerkungen zur Klinik der Multiplen Sklerose. Monatsschr.
Psychiatr. Neurol. 58,277-288 (1925)
Bonduelle, M.: Die benignen Formen der MuItiplen Sklerose. Wien. Z. Nervenheilkd.
Suppl. II, 177-188 (1969)
Bornstein, M. B.: Anti-glial and anti-neuronal factors in experimental allergic enceph-
alomyelitis and multiple sclerosis. In: Multiple Sclerosis. Wolfgram, F., Ellison,
G. W., Stevens, J. G., Andrews, J. M., (eds.). New York-London: Academic Press
1972, pp. 119-125
Bornstein, M. B.: Personal communication (1976)
Bradshaw, P.: The relation between clinical activity and the level of gamma globulin in
the cerebrospinal fluid in patients with multiple sclerosis. J. Neurol. Sci. 1,374-
379 (1964)
 77

Brain, W. R.: Prognosis of disseminated sclerosis. Lancet 1936/11, 866-867.

Bramwell, B.: The prognosis of disseminated sclerosis. Rev. Neurol. Psychiatry 3,161-
170 (1905)
Bramwell, B.: The prognosis in disseminated sclerosis. Edinb. Med. J. 18, 16-23 (1917)
Brody, J. A., Sever, J. L., Henson, Th. E.: Virus antibody titers in multiple sclerosis
patients, siblings and controls. J. Am. Med. Assoc. 216, 1441-1446 (1971)
Broman, T.: Personal communication (1976)
Broman, T., Bergmann, L., Andersen, 0.: Multiple sclerosis in G6teborg. Int. Syrup. on
Multiple Sclerosis, G6teborg, 1972
Broman, T., Bergmann, L., Fog, T., Gilland, 0., Hyllested, K., Lindberg-Broman, A. M.,
Pedersen, E., Presthus, J.: Aspects on classification methods in multiple sclerosis.
Acta Neurol. Scand. 41 (Suppl. 13),543-548 (1965)
Broman, T., Bergmann, L., Lindberg-Broman, A.: Principles for calculations of diagnostic
probability. Wien. Z. Nervenheilkd. Suppl. II, 150-151 (1969)
BUren, P. von, WUthrich, R.: Untersuchungen zur Frage der "benignen Form" der Mul-
tip len Sklerose. Acta Neurol. Belg. 72, 291-303 (1972)
Canter, G. J., Torre, R. de la, Mier, M.: A method for evaluating disability in patients
with Parkinson's disease. J. Nerv. Ment. Dis. 133, 143-147 (1961)
Carter, S., Sciarra, D., Merritt, H. H.: The course of multiple sclerosis as determined by
autopsy proven cases. Assoc. Res. Nerv. Dis. Proc. 28,471-511 (1950)
Caselmann, G.: Eine jahreszeitliche Studie Uber Erstsymptome bzw. KrankheitsschUbe
bei der multiplen Sklerose. Thesis, Univ. of G6ttingen, 1968
Castaigne, P., Lhermitte, F., Schuller, E., Loridan, M.: Etude electrophoretique des
proteines du liquide cephalorachidien au cours de la sclerose en plaques. Rev.
Eur. Etud. Clin. BioI. 16,610-615 (1971)
Cazzullo, C. L., Smeraldi, E.: Multiple sclerosis immunogenetics: a) Associations be-
tween HL-A antigens and high measles antibody levels. b) Existence of common
MLR/immune response determinants in MS patients. Boll. 1st. Sieroter. Milan. 53,
615-624 (1974)
Cendrowski, W.: Numerical rating as a measure for assessment of the neurological status
in patients with disseminated sclerosis. Neurol. Neurochir. Pol. 5, 843-848
(1971)
Cendrowski, W., Niedzielska, K.: Multiple sclerosis: etiologic and diagnostic significance
of measles virus antibodies in the cerebrospinal fluid and serum. Schweiz. Arch.
Neurol. Neurochir. Psychiatr. 114,215-228 (1974)
Charcot, M.: Le<;:ons sur les maladies chroniques du systeme nerveux. Gaz. Hop. (Paris)
102,405-406 (1868); 103, 409 (1868)
Claussen, C. F.: tiber eine Computerdatei mit 3500 Patientendatensatzen als Entschei-
dungshilfe bei der Bewertung neurootologischer Anamnesen und Funktionsprii-
fungen (NODEC I). Arch. Klin. Exp. Ohr.-, Nas.-, u. Kehlk.-Heilkd. 205,376-380
(1973)
Cunningham-Rundles, S., Dupont, B., Posner, J. B., Hansen, J. A., Good, R. A.: Lym-
phocyte transformation in vitro to paramyxovirus antigens in multiple sclerosis.
Lancet 1975/11, 1204
Daniel, P.: Profil virologique de la sclerose en plaques. Nouv. Presse MM. 1, 1939·,·1942
(1972)
Dassel, H.: The mortality from multiple sclerosis in the Netherlands. Acta Neurol.
Scand.49,659-674(1973)
Dean, G., McLoughlin, H., Brady, R., Adelstein, A. M., Tallett-Williams, J.: Multiple
sclerosis among immigrants in Greater London. Br. Med. J. 1,861-864 (1976)
Documenta Geigy: Wissenschaftliche Tabellen, 6th ed. Basle: Geigy 1960
Dold, U.: Der Stand der FrUhdiagnostik beim Bronchialkarzinom. Dtsch. Med. Wo-
chenschr. 95, 53-59 (1970)
Doll, R.: Hospital records in the computer age. Proc. R. Soc. Med. 61, 709-715 (1968)
Doose, H., Scheffner, D.: Maschinelle Dokumentation von klinischen und EEG-Verlaufs-
beobachtungen in einer Anfallsambulanz. Methods Inf. Med. 1,62-64 (1962)
78

Eckmann, F., Helmchen, H., Schulte, P. W., Seelheim, H., Zander, H.: Die psychiatri-
sche Ba.sisdokumentation. Nervenarzt 44, 561-568 (1973)
Ehlers, C. Th.: Direkte maschinelle Erfassung von Krankenblattdaten. Methods Inf.
Med. 6,108-115 (1967a)
Ehlers, C. Th.: Moglichkeiten der modernen Datenverarbeitung bei der Erfassung und
Beurteilung medizinischer Sachverhalte. Thesis for the habilitation, Univ. of
TUbingen, 1967b
Ehlers, C. Th.: Einsatz elektronischer Datenverarbeitungsanlagen bei der Erfassung und
Bearbeitung von Krankenblattdaten. Hippokrates 41,109-121 (1970)
Ehlers, C. Th., Matis, P., Morl, F. K.: Datenerfassung mit dem Markierungsleser im Rah-
men eines klinischen Gro~versuchs. In: Automatisierung des klinischen Laborato-
riums. Griesser, G., Wagner, G., (eds.). Stuttgart-New York: Schattauer, 1968,
pp.22l-229
Ehlers, C. Th., Poser, S.: Dokumentation klinischer Befunde. In: Handbuch der medizi-
nischen Dokumentation und Datenverarbeitung. Koller, S., Wagner, G. (eds.).
Stuttgart-New York: Schattauer, 1975, pp. 407 -430
Fairman, D., Schwab, R. S.: A graphic method for evaluation of Parkinsonian patients
under treatment. J. Am. Geriat. Soc. 4, 1240-1245 (1956)
Feinstein, A. R.: Quality of data in the medical record. Comput. Biomed. Res. 3,426-
435 (1970)
Firnhaber, W.: Vorkommen der Multiplen Sklerose und epidemiologische Aspekte in
einem umschriebenen Gebiet SUdniedersachsens. Thesis for the habilitation, Univ.
of Gottingen, 1969
Firnhaber, W.: Klinische und sozialmedizinische Aspekte bei der Multiplen Sklerose.
Nervenarzt 44,117-127 (1973)
Fletcher, C. M.: The problem of observer variation in medical diagnosis with special
reference to chest diseases. Methods Inf. Med. 3,98-105 (1963)
Fog, T.: A scoring system for neurological impairment in multiple sclerosis. Acta Neurol.
Scand. 41 (Suppl. 13),551-555 (1965 a)
Fog, T.: The topography of plaques in multiple sclerosis. Acta Neurol. Scand. 41
(Suppl. 15), 1-161 (1965 b)
Fog, T., Linnemann, F.: The course of multiple sclerosis. Acta Neurol. Scand. 46
(Suppl. 47), 1-175 (1970)
Fog, T., Raun, N. E.: Computerized forms in multiple sclerosis for medical history and
full neurology examination. Copenhagen 1976
Frick, E., Angstwurm, H., Spath, G.: Immunosuppressive Therapie der Multiplen Skle-
rose. MUnch. Med. Wochenschr. 113,221-231 (1971)
Frick, E., Stickl, H., Zinn, K.-H.: Lymphocytentransformation bei Multipler Sklerose.
Klin. Wochenschr. 52,238-245 (1974)
Friedman, A. P., Davison, Ch.: Multiple sclerosis with late onset of symptoms. Arch.
Neurol. Psychiatry (Chic.) 54, 348-360 (1945)
Galicich, J. H., Williams, J. B.: A computerized echoencephalograph. J. Neurosurg. 35,
453-460 (1971)
Giere, W., Kanzler, G., Schropl, Fr.: Health testing at the Deutsche Klinik fUr Diagnostik
(German Diagnostic Clinic). Med. Prog. Technol. 1,35-44 (1972)
Gill, P. W., Leaper, D. J., Guillou, P. J., Staniland, J. R., Horrocks, J. C., Dombal, F. T.
de: Observer variation in clinical diagnosis. Methods Inf. Med. 12, 108-113
(1973)
Gilland, 0.: Multiple sclerosis classification scheme integrating clinical and CSF findings.
Acta Neurol. Scand. 41 (Suppl. 13),563-575 (1965)
Glatzel, J., Lungershausen, E.: Klinisch-statistische Verlaufsuntersuchungen bei der En-
cephalomyelitis disseminata. Arch. Psychiatr. Nervenkr. 211, 109-117 (1968)
Gordon, B. L.: Terminology and content of the medical record. Comput. Biomed.
Res. 3,436-444 (1970)
Griesser, G.: Symptomenstatistik. Methods Inf. Med. 4,79-82 (1965)
 79

GrUninger, W., Mertens, H. G.: tiber die immunsuppressive Langzeitbehandlung der

Multiplen Sklerose mit Azathioprin. Excerpta Med. (Arnst.), Int. Congr. Ser. 296,
148 (1973)
Grund-Krehl, K.: Untersuchungen zur Systematisierung der Anamnese - dargestellt am
Beispiel einer Chirurgischen Klinik. Thesis, Univ. of Tiibingen, 1973
Gudmundsson, K. R.: Clinical studies of multiple sclerosis in Iceland. Acta Neurol.
Scand. 47, (Suppl. 48),1-78 (1971)
Gudmundsson, K. R., Bergmann, S., Bjornsson, O. J., Ellertsson, A. B.: Further studies
on multiple sclerosis in Iceland. J. Neurol. Sci. 21,47-58 (1974)
Haire, M., Fraser, K.B., Millar, J. H. D.: Measles and other virus-specific immunoglobu-
lins in multiple sclerosis. Br. Med. J. 3,612-615 (1973)
Haire, M., Millar, J. H. D., Merrett, J. D.: Measles virus-specific IgG in cerebrospinal
fluid in multiple sclerosis Br. Med. J. 4, 192-193 (1974)
Hall, R., Horrocks, J. C., Clamp, S. E., Dombal, F. T. de: Observer variations in assess-
ment of results of surgery for peptic ulceration. Br. Med. J. 1, 814-->8 16 (1976)
Haller, P., Patzold, U.: Der diagnostische Wert epileptischer Anfiille fiir Topik und Mor-
phologie von Hirngeschwillsten. J. Neurol. 203,311-336 (1973)
Hauptvogel, H., Poser, S.: Erfassung von neurologisch relevanten Labordaten mit einem
kombinierten Klartext-Markierungsbeleg. J. Neurol. 206,243-252 (1974)
Heier, D.: Die Lebenssituation von Multiple Sklerose-Kranken. From the Inst. for Inde-
pendent Occupations, Nuremberg, 1973
Heiss, W. D., Herles, H. J., Prosenz, P.: Die Anwendung von Computern flir die Auswer-
tung von Gehirnszintigrammen und fiir die Berechnung der regionalen Hirndurch-
blutung. In: Computers in Radiology. De Haene, R., Wambersie, A., Basle-Munich-
Paris-New York: Karger 1970, pp. 578-584
Helmchen, H.: Diskussionsbemerkung zum Beitrag "Einfiihrung eines systematischen
Verzeichnisses neurologisch-neurochirurgischer Krankheiten" von D. Seitz. Ner-
venarzt 45,109 (1974)
Helmchen, H., Kiinkel, H., Oberhoffer, G., Penin, H.: EEG-Befund-Dokumentation mit
optischem Markierungsleser. Nervenarzt 39,408-413 (1968)
Henner, K., Pitha, V., Vinar, J.: Sclerose en plaques en Boheme et Moravie. Cas. Lek.
Cesk. 78, 940-943 (1939)
Hirschfeld, R., Spitzer, R. L., Miller, R. G.: Computer diagnosis in psychiatry: a Bayes
approach. J. Nerv. Ment. Dis. 158,399-407 (1974)
Hopf, H. C., Stamatovic, A. M., Wahren, W.: Die cerebral en Anfiille bei der Multiplen
Sklerose. J. Neurol. 198,256-279 (1970)
Horrocks, J. C., McCann, A. P., Staniland, J. R., Leaper, D. J., Dombal, F. T. de: Com-
puter-aided diagnosis: description of an adaptable system, and operational experi-
ence with 2034 cases. Br. Med. J. 2, 5-9 (1972)
Hosemann, H.: tiber die Dauer der Geburt. Dtsch. Med. Wochenschr. 71, 181-184
(1946)
Hyllested, K.: Disseminated sclerosis in Denmark. Copenhagen: Jorgensen, 1956
Hyllested, K.: Lethality, duration and mortality of disseminated sclerosis in Denmark.
Acta Psychiatr. Scand. 36, 553-564 (1961)
IBM-DP-Anwendungen: Datenerfassung mit Markierungsbelegen im Krankenhaus.
IBM Form 80728-0,1-20 (1968)
Immich, H.: Fehler bei der Erhebung und Dokumentation klinischer Befunde. Methods
Inf. Med. 3,95-98 (1964)
Iwasaki, Y., Koprowski, H., Milller, D., Meulen, V. ter, Kackell, Y. M.: Morphogenesis
and structure of a virus in cells cultured from brain tissue from two cases of mul-
tiple sclerosis. Lab. Invest. 28,494-500 (1973)
Iwashita, H., Grunwald, F., Bauer, H.: Double ring formation in single radial immunodif-
fusion for kappa chains in multiple sclerosis cerebrospinal fluid. J. Neurol. 207,
45-52 (1974)
Jacques, J. A. (ed.): Computer Diagnosis and Diagnostic Methods. Springfield: Ch. C.
Thomas, 1972
80

Jenkins, D. R.: Problems of computer applications in medical research. Trans. N. Y.

Acad. Sci. 28,439-447 (1966)
Jersild, C., Svejgaard, A., Fog, T.: HL-A antigens and multiple sclerosis. Lancet 1972/1,
1240-1241
Jersild, C., Svejgaard, A., Fog, T., Ammitzboll, T.: HL-A antigens and diseases. I. Mul-
tiple sclerosis. Tissue Antigens 3, 243-250 (1973a)
Jersild, C., Fog, T., Hansen, G. S., Thomsen, M., Svejgaard, A., Dupont, B.: Histocom-
patibility determinants in multiple sclerosis with special reference to clinical
course. Lancet 1973 b/ll, 1221-1225
Jersild, C., Ammitzboll, T., Clausen, J., Fog, T.: Association between HL-A antigens and
measles antibody in multiple sclerosis. Lancet 1973c/l, 151-152
Jersild, C., Dupont, B., Fog, T., Platz, P. J., Svejgaard, A.: Histocompatibility determi-
nants in multiple sclerosis. Transplant. Rev. 22, 148-163 (1975)
Kiippeli, F., WUthrich, R.: Untersuchungen Uber den Erstschub bei Multipler Sklerose
und dessen Bedeutung fUr die Diagnosestellung. Praxis 61,1226-1231 (1972)
Kolb, L. C.: The social significance of multiple sclerosis. Assoc. Res. Nerv. Dis. Proc. 28,
28-44 (1950)
Korein, J., Goodgold, A., Randt, C. T.: Computer processing of narrative medical data.
Neurology 16, 848-857 (1966)
Korein, J., Kricheff, I. I., Chase, N. E., Randt, C. T.: Computer processing of neuroradi-
ological reports. Radiology 84, 197-203 (1965)
Kraepelin, E.: Die Erforschung psychischer Krankheitsformen. J. Neurol. 51,224-246
(I919)
Kricheff, I. I., Chase, N. E., Korein, J.: Computer processing of clinical medical data.
In: Computers in Radiology. De Haene, R., Wambersie, A. (eds.). Basle-Munich-
Paris-New York: Karger 1970, pp. 289-305
Kroner, B.: Elliot'sche Trepanation und Iridenkleisis in der Universitiits-Augenklinik
TUbingen. Doc. Ophthalmol. 27,90-95 (1969)
Kullback, S., Leibler, R. A.: On information and sufficiency. Ann. Math. Stat. 22,
79-86 (1951)
Kuroiwa, Y., Shibasaki, H.: Clinical studies of multiple sclerosis in Japan. Neurology 23,
609-617,618-622 (1973)
Kurtzke, J. F.: On the evaluation of disability in multiple sclerosis. Neurology 11,
686-694 (1961)
Kurtzke, J. F.: Further notes on disability evaluation in multiple sclerosis, with scale
modifications. Neurology 15,654-661 (1965)
Kurtzke, J. F.: Caveat computator. Methods Inf. Med. 6,127-130 (1967)
Kurtzke, J. F.: Clinical manifestations of multiple sclerosis. In: Handbook of Clinical
Neurology. Vinken, P. J., Bruyn, G. W. (eds.). New York: American Elsevier 1970,
Vol. IX, pp. 161-216
Kurtzke, J. F., Auth, Th. L., Beebe, G. W., Kurland, L. T., Nagler, B., Nefzger, M. D.:
Survival in multiple sclerosis. Trans. Am. Neurol. Assoc. 94,134-139 (1969)
Kurtzke, J. F., Beebe, G. W., Nagler, B., Auth, Th. L., Kurland, L. T., Nefzger, M. D.:
Studies on natural history of multiple sclerosis. Acta Neurol. Scand. 44, 467-494
(1968)
Kuzma, J. W., Tourtellotte, W. W., Remington, R. D.: Quantitative clinical neurological
testing. J. Chron. Dis. 18, 303-311 (1965)
Lange, H., Schudt, H.-P., Holweg, H., Geyer, H.: Erfassung von Leistungsdaten und
Befunden Uber Markierungsbelege mittels eines universellen Verarbeitungspro-
gramms. In: Krankenhaus-Informationssysteme. Fuchs, G., Wagner, G. (eds.).
Stuttgart-New York: Schattauer 1972, pp. 299-304
Lazarte, J. A.: Multiple sclerosis: prognosis for ambulatory and nonambulatory patients.
Assoc. Res. Nerv. Dis. Proc. 28, 512-523 (1950)
Lehoczky, T., Halasy-Lehoczky, M.: Forme "benigne" de la sclerose en plaques. Pre sse
Med. 71, 2294-2296 (1963)
 81

Leibowitz, U., Alter, M.: Clinical factors associated with increased disability in mul-
tiple sclerosis. Acta Neurol. Scand. 46, 53-70 (1970)
Leibowitz, U., Alter, M.: Multiple Sclerosis. Clues to its Cause. New York: American
Elsevier 1973
Leibowitz, U., Halpern, L., Alter, M.: Clinical studies of multiple sclerosis in Israel. I.
Arch. Neurol. 10, 502-512 (1964a)
Leibowitz, U., Alter, M., Halpern, L.: Clinical studies of multiple sclerosis in Israel. III.
Neurology 14,926-932 (1964b)
Leibowitz, U., Halpern, L., Alter, M.: Clinical studies of multiple sclerosis in Israel. V.
Neurology 17,988-992 (1967)
Levi, S., Grant, J. R., Westphal, M. C., Lurie, D.: Development of a decision guide-
Optimal discriminators for meningitis as determined by statistical analysis.
Methods Inf. Med. 15,87-90 (1976)
Lhermitte, F., Marteau, R., Gazengel, J., Dordain, G., Deloche, G.: The frequency of
relapse in multiple sclerosis. J. Neurol. 205,47-59 (1973)
Lienert, G. A.: Verteilungsfreie Methoden in der Biostatistik. Meisenheim: Hain, 1973,
Vol.I,p.582
Limburg, Ch. C.: The geographic distribution of multiple sclerosis and its estimated
prevalence in the United States. Assoc. Res. Nerv. Dis. Proc. 28,15-23 (1950)
Link, H., Norrby, E., Olsson, J.-E.: Immunoglobulins and measles antibodies in optic
neuritis. N. Engl. J. Med. 289,1103-1107 (1973)
Link, H., Norrby, E., Olsson, J.-E.: Immunoglobulin abnormalities and measles anti-
body response in chronic myelopathy. Arch. Neurol. 33, 26-32 (1976)
Lowitzsch, K.: Quantification of spasticity and assessment of drug action in multiple
sclerosis patients by a scoring system based on an optical mark reader documen-
tation system. Acta Neurol. Scand. 49, 613-625 (1973)
Lumsden, C. E.: The neuropathology of multiple sclerosis. In: Handbook of Clinical
Neurology. Vinken, P. J., Bruyn, G. W. (eds.). North Holland Publ. Co., Amster-
dam; New York: American Elsevier 1970, Vol. IX, pp. 217-309
Mackay, R. P., Hirano, A.: Forms of benign multiple sclerosis. Arch. Neurol. 17,588-
600 (1967)
MacLean, A. R., Berkson, J.: Mortality and disability in multiple sclerosis. J. Am. Med.
Assoc. 146, 1367-1369(1951)
Marburg, 0.: Zur Statistik der Multiplen Sklerose. Jb. Psychiatr. Neurol. 48, 303-316
(1932)
Markov, D. A., Blokh, A. Sh., Leonovich, A. L., Mirkin, G. I., Orlov, V. A.: The use of
computer machines for the diagnosis of disseminated sclerosis. Zh. Nevropatol.
Psikhiatr. 69, 1624-1628 (1969)
McAlpine, D.: The benign form of multiple sclerosis. Brain 84, 186-203 (1961)
McAlpine, D.: The benign form of multiple sclerosis: results of a long-term study.
Br. Med. J. 2, 1029-1032 (1964)
McAlpine, D., Compston, N.: Some aspects of the natural history of disseminated scle-
rosis. Quart. J. Med. 21,135-167 (1952)
McAlpine, D., Lumsden, Ch. E., Acheson, E. D.: Multiple Sclerosis. A Reappraisal.
2nd ed. Edinburgh-London: Churchill Livingstone 1972
McDermott, J. R., Field, E. J., Caspary, E. A.: Relation of measles virus to encephali-
togenic factor with reference to the aetiopathogenesis of multiple sclerosis.
J. Neurol. Neurosurg. Psychiatry 37,282-287 (1974)
Mcintyre, H. D., Mcintyre, A. P.: Prognosis of multiple sclerosis. Arch. Neurol. Psychi-
atry (Chic.) 50, 431-438 (1943)
Metcalf, D. R., Locketz, H. D., Turrell, E. S.: A flexible IBM system for collating EEG
and clinical data. Electroencephalogr. clin. Neurophysiol. 12, 202-208 (1960)
Meulen, V. ter: Personal communication (1976)
Meulen, V. ter, Koprowski, H., Iwasaki, Y, Kackell, Y. M., Milller, D.: Fusion of cul-
tured multiple sclerosis brain cells with indicator cells: presence of nucleocapsids
and virions and isolation of parainfluenza-type virus. Lancet 1972/11, 1-5
82

Micheloyannakis, J., Esser, K.-J.: Anwendung eines EMG Loch- und Markierungsbeleges
fUr den klinischen Routinebetrieb. Z. EEG-EMG 5, 59-62 (1974)
Millar, J. H. D.: Disseminated sclerosis. Lancet 1949/11,556-559
Moiseeva, N. I.: Systematization and classification of reflexes and pathological symp-
toms. J. Neurol. Sci. 5,377-387 (1967)
Morsier, G. de: Sur 1351 cas de nevraxite (sclerose en plaques). Rev. Neurol. 125, 103-
118 (1971)
MUller, E.: Die Multiple Sklerose des Gehirns und RUckenmarks. Jena: Gustav Fischer
1904
MUller, H. R.: Die Prognose der Multiplen Sklerose. Dtsch. Med. Wochenschr. 86, 1800-
1808 (1961)
Milller, H. R.: Zur Frage von Krankheitsdauer und Invaliditat bei der Multiplen Sklerose.
Dtsch. Med. Wochenschr. 91, 996-998. (1966)
MUller, R.: Studies on disseminated sclerosis. With special reference to symptomatology,
course and prognosis. Acta Med. Scand. [ Suppl. 222], 1-214 (1949)
MUller, R.: Course and prognosis of disseminated sclerosis in relation to age at onset.
Arch. Neurol. Psychiatry (Chic.) 66, 561-570 (1951)
Nacke, 0., Wagner, G.: Bibliographie zum Thema "Die Rolle des Fehlers in der Medizin;
Fehlerforschung als Aufgabe der medizinischen Dokumentation". Methods Inf.
Med.3,132-150(1964)
Naito, S., Namerow, N., Mickey, M. R., Terasaki, P. I.: Multiple sclerosis: association
with HL-A 3. Tissue Antigens 2,1-4 (1972)
Narang, H. K., Field, E. J.: An electron-microscopic study of multiple sclerosis biopsy
material: some unusual inclusions. J. Neurol. Sci. 18, 287 -300 (1973)
Nemo, G. J., Brody, J. A.: Serological responses of multiple-sclerosis patients and con-
trols to a virus isolated from a multiple-sclerosis case. Lancet 1974/11, 1044-1046
Nikoskelainen, E., Nikoskelainen, J., Salmi, A. A., Halonen, P. E.: Virus antibody levels
in serum specimens from patients with optic neuritis and from matched controls.
Acta Neurol. Scand. 51, 333-346 (1975 a)
Nikoskelainen, E., Nikoskelainen, J., Salmi, A. A., Halonen, P. E.: Virus antibody levels
in the cerebrospinal fluid from patients with optic neuritis. Acta Neurol. Scand.
51,347-364 (1975b)
Nilsson, 0.: Immunological aspects on demyelinating disease. Acta Neurol. Scand. 48
(Suppl. 51),321-336 (1972)
Norrby, E., Link, H., Olsson, J.-E.: Measles virus antibodies in multiple sclerosis. Arch.
Neurol. 30, 285-292 (1974 a)
Norrby, E., Link, H., Olsson, J.-E., Panelius, M., Salmi, A., Vandvik, B.: Comparison of
antibodies against different viruses in cerebrospinal fluid and serum samples from
patients with multiple sclerosis. Infect. Immun. 10,688-694 (1974b)
Oberhoffer, G.: Prinzipien und Methoden der klinischen Befunddokumentation unter
besonderer BerUcksichtigung des Markierungslese-Verfahrens. Elektromedizin 12,
165-170 (1967)
Obstander, E.: Klinisch-statistischer Beitrag zur Kenntnis der Multiplen Sklerose. Mo-
natsschr. Psychiatr. Neurol. 61, 350-364 (1926)
Offner, H., Ammitzboll, T., Clausen, J.: The occurrence of measles antigen precipitating
antibodies in sera from patients with multiple sclerosis and their relatives. Acta
Pathol. Microbiol. Scand. [B] 81,157--164 (1973)
Olsson, J. E., Link, H.: Immunoglobulin abnormalities in multiple sclerosis. Arch. Neurol.
28,392-399(1973)
Oppenheim, H.: Discussion on the different types of multiple sclerosis. Br. Med. J. 2,
729-733 (1911)
Panelius, M.: Studies on epidemiological, clinical and etiological aspects of multiple
sclerosis. Acta Neurol. Scand. 45 (Suppl. 39), 1-82 (1969)
Panelius, M., Salmi, A., Halonen, P. E., Kivalo, E., Rinne, U. K., Penttinen, K.: Virus
antibodies in serum specimens from patients with multiple sclerosis, from siblings
and matched controls. Acta Neurol. Scand. 49, 85-107 (1973)
 83

Papac, R.: Multiple sclerosis: a clinical review. Stanf. Med. Bull. 15,75-77 (1957)
Patzold, D., Haller, P.: Epileptische Anfiille bei Hirngeschwillsten. 1. Neurol. 205, 307-
322 (1973)
Patzold, D., Weinrich, W.: Vorschlag einer neurologischen Befunddokumentation mit-
tels Markierungsbeleg. Nervenarzt 46,550-556 (1975)
Payk, Th. R.: Psychopathologische Besonderheiten bei Kranken mit Encephalomyelitis
disseminata ("Multiple Sklerose"). Nervenarzt 44, 378-380 (1973)
Pedersen, E.: A rating system for neurological impairment in multiple sclerosis. Acta
Neurol. Scand. 41 (Suppl. 13),557-558 (1965)
Penin, H., Helmchen, H., Jacobitz, K., Kanowski, S., KUnkel, H., Zenker, K.: Anwen-
dung einer EEG-Befund-Dokumentation auf wissenschaftliche Fragestellungen.
Z. EEG-EMG 3, 6-15 (1972)
Percy, A. K., Nobrega, F. T., Okazaki, H., Glattre, E., Kurland, L. T.: Multiple sclerosis
in Rochester, Minn. Arch. Neurol. 25, 105-111 (1971)
Pfanzagl, J.: Allgemeine Methodenlehre der Statistik. I. Berlin: de Gruyter 1966, Vol.
CCCMIVL/CCCMIVL a, pp. 120-128
Pirtkien, R.: Moglichkeiten einer DnterstUtzung der Diagnostik durch Computer. Hippo-
krates 42,3-24 (1971)
Poeck, K.: Leserbrief zu der Arbeit "Psychopathologische Besonderheiten bei Kranken
mit Encephalomyelitis disseminata (,Multiple Sklerose')" von T. R. Payk. Nerven-
arzt 44, 656 (1973)
Poeck, K., Markus, P.: Gibt es eine gutartige Verlaufsform der Multiplen Sklerose?
MUnch. Med. Wochenschr. 106,2190-2197 (1964)
Poser, Ch. M.: Clinical diagnostic criteria in epidemiological studies of multiple scle-
rosis. Ann. N. Y. Acad. Sci. 122,506-519 (1965)
Poser, S.: Datenverarbeitung als Hilfsmittel zur Erforschung der Multiplen Sklerose.
Thesis for the habilitation, Dniv. of Gottingen, 1974
Poser, S., Bauer, H. J.: Bemerkung zum Leserbrief von K. Poeck Uber die Euphorie bei
Patienten mit Multipler Sklerose. Nervenarzt 45, 223 (l974a)
Poser, S., Brauns, K.-H.: Der Einsatz des Markierungsbelegverfahrens im Rahmen einer
multizentrischen Studie Uber die Multiple Sklerose. Methods Inf. Med. 13, 70-79
(1974b)
Poser, S., Hauptvogel, H.: Clinical data from 418 MS patients in relation to the diagnosis.
Acta Neurol. Scand. 49, 473-479 (1973a)
Poser, S., Hauptvogel, H., Bauer, H. J.: Methodik der maschinellen Erfassung von Daten
bei einer multizentrischen Studie Uber die Multiple Sklerose. J. Neurol. 204, 301-
308 (l973b)
Poser, S., Firnhaber, W., Hauptvogel, H.: Diskussionsbemerkung zur Arbeit von D. Pat-
zold, W. Weinrich: "Vorschlag einer neurologischen Befunddokumentation mittels
Markierungsbe1eg" und zum Diskussionsbeitrag von W. Baust. Nervenarzt 47, 276
(1976a)
Poser, S., Poser, W., Bauer, H. J., Meyer, D.: Immunological findings in multiple sclerosis.
Br. Med. J. 1,834 (1976 b)
Poskanzer, D. C., Schapira, K., Miller, H.: Multiple sclerosis and poliomyelitis. In: Stud-
ies in Multiple Sclerosis. Hyllested, K., Kurland, L. T., (eds.). Acta Neurol. Scand.
42 (Suppl. 19), 85-90 (1966)
Prineas, J.: Paramyxovirus-like particles associated with acute demyelination in chronic
relapsing multiple sclerosis. Science 178, 760-763 (1972)
Proppe, A.: Der Primat der Fragestellung fUr eine wissenschaftlich nutzbare Dokumenta-
tion. Med. Dokum. 4, 73-78 (1960)
Proppe, A., Wagner, G.: Die Alterdisposition beim Lupus vulgaris. Z. Hautkr. 14,376-
381 (1953)
Proppe, A., Wagner, G.: tiber die Zuverlassigkeit medizinischer Dokumente und Befunde.
Med. Sachverstand. 52, 121-127 (1956)
Raine, C. S., Hummelgard, A., Swanson, E., Bornstein, M. B.: Multiple sclerosis: serum
induced demyelination in vitro. J. Neurol. Sci. 20,127-148 (1973)
84

Raine, C. S., Powers, J. M., Suzuki, K.: Acute multiple sclerosis. Arch. Neurol. 30, 39-
46 (1974)
Reichertz, P. L.: Aufbau eines Informations- und Terminalsystems in einem Klinikum.
In: Computersysteme in der Medizin. Graul, E. H., Habermehl, A. (eds.). Kaln:
Dtsch. Arzte-Verl. 1973, pp. 93-116
Reissner, I.: Einfiihrung in die medizinische Dokumentation, Frankfurt/Main: Akademi-
sche VerI. Ges. 1967
Riechert, T.: Neuere Indikationen der stereotaktischen Operationen. Z. Allgemeinmed.
49,253-256 (1973)
Riser, M., Geraud, J., Rascol, A., Benazet, A.-M., Segria, M.-G.: L'evolution de 1a scle-
rose en plaques. Rev. Neurol. 124,479-485 (1971)
Ritter, G., Poser, S.: Epi1epsie und Multiple Sk1erose. MUnch. Med. Wochenschr. 116,
1984-1986 (1974)
Roser, W., Wunderlich, C. A.: tiber die Mangel der heutigen deutschen Medizin und Uber
die Nothwendigkeit einer entschieden wissenschaftlichen Richtung in derselben.
Stuttgart: Ebner und Seubert 1841
Rudin, H.-J.: Untersuchungen Uber die saisonale Inzidenz bei Multipler Sklerose. 3. Mit-
teilung. Schweiz. Arch. Neurol. Psychiatr. 102,133-143 (1968)
Sachs, L.: Statistische Auswertungsmethoden, Berlin-Heidelberg-New York: Springer-
Verlag (ed.) 1968
Sallstram, Th.: Das Vorkommen und die Verbreitung der Multiplen Sklerose in Schwe-
den. Acta Med. Scand. [Suppl. 137], 1-141 (1942)
Salmi, A. A.: Virus antibodies in patients with multiple sclerosis. Ann. Clin. Res. 5,
319-329 (1973)
Salmi, A., Gollmar, Y., Norrby, E., Panelius, M.: Antibodies against three different
structural components of measles virus in patients with multiple sclerosis, their
siblings and matched controls. Acta Pathol. Microbiol. Scand. [B] 81, 627-634
(1973)
Salmi, A., Panelius, M., Vainionpaa, R.: Antibodies against different viral antigens in
cerebrospinal fluid of patients with multiple sclerosis and other neurological
diseases. Acta Neurol. Scand. 50,183-193 (1974)
Schmitt, W.: tiber die Dokumentation klinischer Daten und Befunde. In: Psychiatrie
im tibergang. Kranz, H., Heinrich, K. (eds.). Stuttgart: G. Thieme 1969, pp. 132-
139
Schrader, A.: Die Behandlung Multiple-Sklerose-Kranker. Dtsch. Aerztebl. 71,2858-
2861 (1974)
Schuller, E., Delasnerie, N., Deloche, G., Loridan, M.: Multiple sclerosis: a two-phase
disease? Acta Neurol. Scand. 49,453-460 (1973)
Schumacher, G. A., Beebe, G., Kibler, R. F., Kurland, L. T., Kurtzke, J. F., McDowell, F.,
Nagler, B., Sibley, W. A., Tourtellotte, W. W., Willmon, T. L.: Problems of experi-
mental trials of therapy in multiple sclerosis: report by the panel on the evaluation
of experimental trials of therapy in multiple sclerosis. Ann. N. Y. Acad. Sci. 122,
552-568 (1965)
Schwartz, S., Rieder, H. P., WUthrich, R.: The protein fractions in cerebrospinal fluid in
the various states of multiple sclerosis. Eur. Neurol. 4, 267-282 (1970)
Seitz, D.: Einfiihrung eines systematischen Verzeichnisses neurologisch-neurochirurgi-
scher Krankheiten. Nervenarzt 44, 611 (1973)
Spitzer, R. L., Endicott, J.: An integrated group of forms for automated psychiatric
case records. Arch. Gen. Psychiatry 24, 540-547 (1971)
Statistisches Jahrbuch fUr die Bundesrepublik Deutschland 1973, Statist. Bundesamt
Wiesbaden (ed.). Stuttgart-Mainz: Kohlhammer 1973
Stazio, A., Kurland, L. T., Bell, L. G., Saunders, M. G., Rogot, Eu.: Multiple sclerosis
in Winnipeg, Manitoba: methodological considerations of epidemiologic survey.
J. Chron. Dis. 17,415-438 (1964)
 85

Stenuit, J.: Correlations entre la cytologie et Ie proteinogramme du liquide cephalo-

rachidien et certains parametres cliniques, dans la sclerose en plaques. Acta
Neurol. Belg. 72,265-278 (1972)
Strotker, H.: Quantitative morphologisch-klinische Studien an 25 Fiillen von chroni-
scher Multipler Sklerose. Thesis, Univ. of Gottingen, 1968
Strotker, S.: Quantitative morphologisch-klinische Studien an 15 Fiillen von akuter,
subakuter und subchronischer disseminierter Entmarkungsenzephalomyelitis.
Thesis, Univ. of Gottingen, 1969
Tavolato, B. F.: Multiple sclerosis in der Padova Province (Italy). Acta Neurol. Scand.
50,76-90 (1974)
Thygesen, P.: Prognosis in initial stage of disseminated primary demyelinating disease
of central nervous system. Arch. Neurol. Psychiatry 61, 339-351 (1949)
Thygesen, P.: The course of disseminated sclerosis. Copenhagen: Rosenkilde and
Bagger 1953
Tichy, J., Vymazal, J.: Changes of some serum fatty acids and lipids in relation to the
clinical course of multiple sclerosis. Acta Neurol. Scand. 49, 345-354 (1973)
Tourtellotte, W. W., Haerer, A. F., Simpson, J. F., Kuzma, J. W., Sikorski, J.: Quantita-
tive clinical neurological testing. I. Ann. N. Y. Acad. Sci. 122,480-505 (1965)
Utermohlen, V., Zabriskie, J. B.: A suppression of cellular immunity in patients with
multiple sclerosis. J. Exp. Med. 138, 1591-1596 (1973)
Vandvik, B., Degre, M.: Measles virus antibodies in serum and cerebrospinal fluid in
patients with multiple sclerosis and other neurological disorders, with special
reference to measles antibody synthesis within the central nervous system.
J. Neurol. Sci. 24, 201-219 (1975)
Vastola, E. F., Thomasino, J. Steger, L., Lindsay, W.: Evaluation of a computer pro-
gram for neurological screening. Biomed. Comput. 4, 117-129 (1973)
Vymazal, J., Polacek, L.: Gamma-Globulinwerte im Liquor und ihre Beziehung zum
klinischen Bild und Verlauf der Multiplen Sklerose. Psychiatr. Neurol. Med.
Psychol. (Leipz.) 18,136-141 (1966)
Wagner, G.: Versuchsplanung in der Fehlerforschung. Methods Inf. Med. 3, 117-127
(1964)
Wagner, G.: Die Bedeutung moderner Datenverarbeitungsmethoden fUr die Medizin
von heute und morgen. Doc. Ophthalmol. 27,1-11 (1969)
Webster, D. D.: Critical analysis of the disability in Parkinson's disease. Mod. Treatm. 5,
257-282 (1968)
Wersig, G., Fuchs, G.: Dokumentation medizinischer Daten. Med. Klin. 66, 767-771
(1971)
Winchester, R. J., Ebers, G., Fu, S. M., Espinosa, L., Zabriskie, J., Kunkel, H. G.: B-cell
alloantigen Ag 7 a in multiple sclerosis. Lancet 1975/11,814
Wingert, F.: Paula: Programm zur Auswertung logischer AusdrUcke. Methods Inf. Med.
11, 96-103 (1972)
Woyciechowska, J., Brzosko, W. J.: Multiple sclerosis and measles virus. N. Eng. J. Med.
290,1036 (1974)
WUthrich, R., Rieder, H. P.: Untersuchungen Uber die saisonale lnzidenz bei Multipler
Sklerose. I. Mitteilung. Schweiz. Arch. Neurol. Psychiatr. 101, 88-98 (1968)
Zander, H., Kuntz, B., Scholz, S., Albert, E. D.: Analysis for joint segregation of HL-A
and multiple sclerosis in families. Abstr. submitted to the 1. Int. Symp. on HL-A
and Disease. Paris, 1976
Subject Index

Numbers refer to pages. Page numbers followed by f indicate figure. Page numbers
followed by t indicate table

ability to walk 39 amaurosis 34 t

and age at onset 40, 41 t, 42 t analysis of bouts 46
and gait disturbance 40 t computerized 14
and course of MS 43 t, 45 t of data 14,64
and duration of MS 39,60 t, 61 of errors 11, 20
epidemiologic area 49,50 t of all examinations 25, 26 t
females 30 t of first examinations 26, 27 f, 28 f,
males 30 t 29 f, 30 t, 31 t, 33 tH, 34 t+f, 35 f
ability to work 14,39 of signs and symptoms 32
and age at onset 40, 41 t, 42 f, of variance 17
42 t ambulatory disturbance 39, 40 t
and course of MS 43 t, 45 t, 46, see also ability to walk
47 f ankle-jerk 35 f
and duration of MS 39 f, 60 t, antibody titers, measles virus 69
61 aphasia 34 t
females 30 t ataxia 30 t
males 30 t and age at onset 42 t
access to data 12, 14, 64, 66 cerebellar 40 t
affective disorder 34 f, 35 and course of disease 43 t
see also mental changes and duration of disease 37
aftercare facilities 52 females 30 t
age at onset 27, 29 f, 41 t, 59 gait 30 t, 40 t, 43 t
and ability to walk + work 40, 41 t, limbs 27,30 t, 32 t, 35 f, 43 t
45 t males 30 t
and course 41 t, 43 t and mental disturbances 36 t
and diagnostic classification 41 t and performance 40 t
and duration of disease 41 t spinal 40 t
epidemiologic group 49, 50 t atrophy of muscles 32 t, 35 f
females 27, 29 f, 30 t optic disc 34 t
grouping according to 14,40,41 t, automat isms, see involuntary spasms
42 f
males 27, 29 f, 30 t Babinski-sign 35 f
mean 27,42 t, 59 balance disturbance 30 t
and mental disturbances 36 t see also ataxia
and performance 40 basic documentation I 2, 16, fig. 5
and prognosis 40,50,55,56 t, 59 (inside back cover)
sex 27, 41 t basic documentation 112,16, fig. 6
and signs and symptoms 40,41 t, 42 t (inside back cover)
88

bias in selection 26, 47, 50, 54, 55, 58 course of disease 30 t, 43, 50, 55
biochemistry 3 and ability to walk and work
bladder, dysfunction of 30 t 43 t, 44 f, 45 t, 46, 47 f
infection of 28,30 t, 37, 38 f and age at onset 41 t, 43 t, 56 t
see also micturition benign 40, 49, 55, 58, 60
bout, analysis of 46 chronic-progressive 30 t, 43,
definition of, back of fig. 5 56 t, 59
(inside back cover) and CSF findings 48
first bout and month 27 f and diagnostic classification
and remission see course, remitting 43 t
bowel dysfunction 21, 30 t and disability 50, 56 t
brainstem symptoms 25,26 t, 31 t, 33 f documentation of 25,55
34t,41t and duration of disease 43 t
and age at onset 41 t epidemiologic study 49, 50 t,
and course of disease 43 t 55
females 30 t grouping according to 14,44 f
males 30 t and histocompatibility antigens
bulbar palsy 26 t, 34 t 70
see also brainstem symptoms malignant 40, 58,60
and mental disturbances 36 t
cell count, see CSF and performance 43 t, 44 f,
cell mediated immune mechanism 70 56 t
cerebellar ataxia, see ataxia primary progressive 30 t, 43,
form of MS and euphoria 37 59,60
cerebral signs, symptoms, see mental and prognosis 46, 56 t, 59
changes progressive 30 t, 43, 58, 59
childhood infections 69 remitting 43, 58, 59
chronic myelopathy, measles antibodies remitting and progressive 30 t,
69 43,58,59
circulatory regulations 21 sex 30 t, 43 t
classification, diagnostic, see diagnosis and signs and symptoms 43 t
of reflexes 4 cranial nerve disturbances 25,26 t, 31 t,
coefficient of constriction 16 34 t, 35 f
correlation 16 and age at onset 41 t
colloidal curve, see CSF and course of disease 43 t
computer diagnosis 4,32,62,66 criterion for diagnosis 55, back of fig. 5
facilities 64 (inside back cover)
print-out 14, 15, 16,64,65 f, 72 prognosis 55, 56 t, 60 t, 61
program 12, 14 CSF (cerebrospinal fluid) 2, 10, 11,48
questionnaire 9 correlation with clinical findings 66,
coordination disturbance 30 t 71
and age at onset 41 t and course 48 f, 69
see also ataxia, brainstem symptoms findings of 48, 69, 71
correlations 3, 35 lumbar puncture 48
antibody titers 70 optical mark reader sheet 66
CSF 48, 66, 71
clinical data 3,4,9, 14 data, file of 14, 20
EEG findings 4, 64 pool 11,63,66
histocompatibility antigens 70 DE (disseminated sclerosis)
immunological phenomena 71 compare MS (multiple sclerosis)
laboratory findings 3, 9, 14, 71 defecation, see bowel
mental changes 35, 36 t definitions 16, back of figs. 5+6
pathological findings 68 (inside back cover)
research findings 3 of criteria 24, 66
 89

dementia 29, 31 t, 34 f, 36 t cranial nerves, see cranial nerves

demyelination 71 facial sensation, see trigeminal
depression 34 f, 36 t functional systems 29, 30 t, 31 t,
and age at onset 41 t fig. 5 (inside back cover)
with apathy 34 f gait, see gait
with dementia 34 f motor performance, see paresis,
and duration of disease 37,38 f performance
females 30 t pupillary reactions 34 t
with labile affect 34 f reflexes 32 t, 35 f
with loss of interest 34 f respiration 34 t
males 30 t sensory functions, see sensory
DFG (Deutsche Forschungsgemein- disturbances
schaft) 2, 3, 5, 68, 73 speech 34 t
Schwerpunktprogramm (Priority vision, see visual disturbances
program) 3, 5,11 drug treatment, early 54
diagnosis documentation 3, 8
and age at onset 41 t of case histories 3
classification of 47, 62 of clinical findings 3, 4, 8, 10
computerized 4, 62 of course of disease 25
and course of disease 43 t of diagnoses 8
and CSF-findings 71 difficulties of 20, 21, 64
definite 26. 47 of disability 4
definition of back of fig. 5 (inside in the field of brain scan 4
back cover) field of echoencephalography 4
documentation of 8 field of electroencephalog-
epidemiologic area 49,50 t raphy 4
possible 26, 47, 49, 50 t field of electromyography 4
probability of 14 field of general neurology 4
probable 26, 47 in tl field of multiple sclerosis 4, 9, 26
problem of 2,47,54,62 field of neurootology 4
differential diagnosis 62 field of neuroradiology 4
diplopia 26 t, 34 t, 35 f field of parkinsonism 4
and age at onset 41 t, 42 t field of psychiatry 8
females 30 t of follow-up examinations 25
males 30 t method 20,63
disability 5, 39, 61 procedure 11
and age at onset 41 t sheet 10, 12, 16, figs. 1, 5,6
and course of disease 50 (inside back cover)
definition of 61, back of fig. 5 of signs and symptoms 5
(inside back cover) system, standardized 2,4,5,9,66
epidemiologic study 49, 50 t of therapy 4
and duration of disease 60 t duration of MS 27, 50 t
recording of 9, 63 and ability to walk 39, 60 t
scale 49, fig. 5 (inside back cover) and ability to work 39 f, 60 t
disorder, see disturbance and age at onset 41 t
distribution of data 12, 14, 64, 66 and bladder infection 38 f
hospitals participating 5 1 f and bladder dysfunction 38 f
signs and symptoms 35 f and course of disease 43 t, 50
disturbance of balance, see ataxia and depression 38 f
brainstem functions, see brain- and disability 39, 60 t
stem symptoms epidemologic study 49, 50 t
cerebral functions, see mental and euphoria 37,38 f
changes females 27, 30 t
consciousness 36 t, 37 grouping according to 14
coordination, see ataxia males 27, 30 t
90

duration of MS free text 9, 11, 21

and mental disturbances 36 t frequency of, see the particular item
and micturition 37, 38 f f. ex. ataxia
and paresis 37 f distribution 16
and performance 39, 60 t functional systems, see disturbance of
and prognosis 60 t
and sensory disturbances 37 f gait disturbance 30 t, 40 t
and signs, symptoms 37 and ability to work 40 t
and spasticity 37 f and mental disturbances 36 t
dysaithria 26 t gamma-globulin fraction 71
dysdiadochokinesis 35 f see also CSF
dysphagia 26 t, 34 t genetic factors 32
dysphoric, see depression and mental see also histocompatibility antigens
changes glossary 11, 24, back of figs. 5, 6
(inside back cover)
EAE 71
graphic presentation 17
early stages of MS 54
sterile autopsy 68 "Grunddokumentationsbogen" I, II 2,
electronic data processing 3, 4 16,63, figs. 5 + 6 (inside back cover)
environmental factors 72
epidemiologic area 26, 51 f,55 hearing loss 34 t
study 2, 26, 49,50 t, 55, 58, 62,64, heredity 31 , 32
69, 70, 72 histocompatibility antigens 3, 32, 70,
epidemiology 3, 71, 72 71
epileptic seizures and MS 31 and antibody titers 70
error, analysis of 11, 20 H-test of Kruskal and Wallis 17,41 t
correction of 14 hyperreflexia 21,32 t, 35 f
frequency of 20, 64 females 30 t
pattern of 21 males 30 t
protocol of 14
source of 20, 64 I-test 16,41 t
euphoria 31 t, 34 f, 36 t, 38 f IgG, IgM 69, 71
and age at onset 41 t see also CSF
with apathy 34 f immunology 3, 70, 71
and cerebellar ataxia 37 immunosuppressive therapy 54
with dementia 34 f incubation period 60
and duration of disease 38 f incidence, familial 31
females 30 t study 59,62,72
with labile affect 34 f infection of urinary tract
with loss of interest 34 f females 28, 30 t
males 30 t males 28, 30 t
infectious agent in MS, see virus
extensor plantar response,
see Babinski-sign disease and MS 49, 69, 70
intellectual deterioration, see mental
facial palsy 34 t, 35 f changes
central 34 t invalidity 60 t, 61
peripheral 34 t see also ability to walk + work
sensation, see trigeminal see also disability
weakness 26 t, 34 t see also performance
familial cases 31, 70 involuntary spasms 32 t, 35 f
females, see sex differences
figure-writing, disturbance of 30 t jaw weakness 26 t, 34 t, 35 f
see also sensory disturbances
file, see data file knee-jerk 35 f
follow-up examination 25, 55,63,68
study 71,72 laboratory findings 48, 68-71
 91

labile affect 36 t documentation system, fields

with depression 34 f of medicine 4, 9
euphoria 34 f documentation system,
see also mental changes multicenter use 9
life expectancy 59 documentation system,
limb, ataxia of 27, 30 t, 32 t, 35 f multiple sclerosis 9
motor involvement 33 t, 35 f documentation system, neu-
literature survey 56 t, 60 t rology 4, 64
location of pareses 33 t, 35 f documentation system, psy-
lumbar puncture, see CSF chiatry 9
males, see sex differences documentation system, spas-
mastication, see jaw weakness ticity 31
measles virus antibody titers 69 documentation system,
medical recording, see recording therapeutic trials 9
mental changes 29, 31 t, 32, 34 f, 35, documentation system, clinical
36 t, 38 f, 63 findings 9
and age at onset 41 t sheet 11, 64, figs. I, 5, 6
and course of disease 43 t (inside back cover)
and duration of disease 38 f outpatient departments 26,55
method, see documentation
of investigation 56 t pain
micturition 21, 30 t trigeminal 34 t
see also bladder sensation of, see sensory disturbances
and age at onset 41 t, 42 t papillitis 34 t
and course of disease 43 t paresis,
and duration of disease 38 f and age at onset 41 t, 42 t
and mental disturbances 36 t and ability to work 40 t
month of onset, 14,27 f and course of disease 43 t
morphology 3, 68 definition of, fig 6 (inside back cover)
mortality data 56 t, 61 and duration of disease 37 f
motivation 26, 64 females 27, 30 t
motor performance 32, 33 t, 35 f frequency of 30 t, 32 t
and spasticity 3 I and gait 40 t
multicenter study 5, 8, 9, 62, 64 limbs 35 f
multiple examinations II and mental disturbances 36 t
MS (multiple sclerosis) 2, 5 location 32, 33 t, 35 f
research 66 males 27, 30 t
syndrome 2 pattern of errors 21
signs and symptoms, see the performance 32, 33 t, 35, 61
particular sign and age at onset 40, 42 f
and course 43, 44 f
neurological departments 26,50,51 f, 74
and duration of disease 39, 60 t, 61
neuropathology, see morphology
disturbance of, see disability
nystagmus 33 f
epidemiologic study 50 t
optic disc 34 t and gait 40 t
neuritis 34 t, 69 and mental disturbances 36 t
optical mark reader 8, 12 and spasticity 31
documentation system 4, 8, periphlebitis 34 t, 68
63,64 personal data 8
documentation system, case sheet 16, fig. 7 (inside back
histories 9 cover)
documentation system, CSF- personnel problem 64
findings 48, 71 phases of MS 60
92

plausibility control 8, 16,20 representative sample, see selection of

program II, 12 patients
pleocytosis, see CSF respiration, disorder of 34 t
possible, see diagnosis retrospective analysis 5, 55, 63
precision of recording 21, 22 f, 23 f
present age 27 scoring system 49, 55, fig. 5 (inside back
females 27, 28 f cover)
males 27,28 f scotoma 34 t
prevalence 2, 31 semiprospective study 54, 63
study 59, 62, 72 sensory disturbances 30 t, 32 t, 33 f
print out, see computer print-out and age at onset 41 t, 42 t
printed record, see computer print-out and course of disease 43 t
probability of diagnosis, see diagnosis different qualities 33 f
prognosis 5, 54, 56 t and duration of disease 37 f
and age at onset 55, 56 t females 28, 30 t
and course 46, 56 t, 58, 59 frequency of 32, 33 f
criteria of 60, 61 males 28, 30 t
and duration of disease 60 t selection of patients 14,26,31,49,56 t
epidemiologic study 49, 50 t 58,60,66
literature survey 56 t bias in 26,50,55,58,60
and location of patients 51 t literature survey 56 t, 60
and sex 56 t, 61 for special investigation 14,31,49,
and symptomatology 56 t, 61 69
prospective studies 54, 59, 63 for therapeutic procedures 14, 31
protein, see CSF serological studies 49
psychopathological phenomena, see titers 69
mental changes sex
punched card 4, 5, 8, 9,12,13 f, 14 and age at onset 41 t, 59
punching document 4, 5, 8, 9,12,13 f, and course of disease 43 t
14 differences 27,28, 30 t
pupillary reactions 34 t grouping according to 14
pyramidal tract dysfunction 30 t and prognosis 56 t, 61
ratio 28, 29, 30 t, 50 t, 56 t
quality control II sexual disturbance, females 21 , 28, 30 t
of recording 20, 21, 22 f, 23 f males 21, 28, 30t
significance tests 16, 17
rating scales 55, 56 t, 63 signs, symptoms
record, medical 3, 5, 65 f, 72 comparison of 30 t, 63
standardized 5, 62, 72 and course of disease 43 t
traditional 3, 5, 63, 72 and duration of disease 37
recording, see also documentation frequency of 30 t, 32
of difficulties 21 pattern of 32
on line 4 and prognosis 56 t, 61
precision of 21 statistics on 32, 58, 63
quality of, see quality size of study 20
system 62 social factors 2, 39,49,72
technique 3 spasticity 31
refusal of sheets 11,20,64 and ability to work 40 t _
reflex, abnormalities, see hyperreflexia and age at onset 41 t, 42 t
definitions, back of fig. 6 (inside and course of disease 43 t
back cover) definition of, back of fig. 6 (inside
registration, see also documentation back cover)
of personal data 16, fig. 7 (inside and duration of disease 37 f
back cover) females 30 t
reliability of data II frequency of 32 t, 35 f
of diagnosis 62 and gait 40 t
 93

males 30 t neuralgia 34 t
optical mark reader sheet 31 pain 34 t
therapeutic study 31 trophic regulations 21
special hospitals for MS 26, 50, 51 f, 52,
74 university hospitals 26, 50, 51 f, 74
speech disorder 34 t urinary dysfunction 30 t
spinal ataxia, see ataxia see also micturition
fluid, see CSF females 30 t
form.of MS 62 males 30 t
symptomatology, see signs infection, see bladder
and histocompatibility pattern 70
and prognosis 56 t, 61 vaccination 69
symptoms, see signs validity of data 11, 21, 24 f, 25 f
syntropism of MS and epilepsy 3 1 vegetative disturbances 21
"Stammdatenbogen" 16, fig. 7 (inside see also bladder, bowel, micturition
back cover) vertigo 26 t, 34 t
standardized virology 3, 68
criteria 62 virus, antibody titers 49, 69, 70
documentation 8 brain tissue 68
ofMS 9 parainfluenza- 49, 68
statistical analysis 32, 55, 56 t particles 68
data 32, 63 slow 2
methods 14, 16 vision, see visual disturbance
on signs and symptoms 32, 63, 66 visual disturbance 30 t, 34 t
stereotactic operation, selection for 31 and age at onset 41 t, 42 t
and course of disease 43 t
therapy 2, 4, 54 females 30 t
selection for 14, 31 males 30 t
titer, see virus
tremor 31, 32 t walking ability, see ability to walk,
stereotactic operation of 31 performance
triad of Charcot 34 t Wilcoxon's rank test 17
trigeminal nerve 34 t weighted mean 17
disturbance of corneal reflex 34 t working ability, see ability to work
hypaesthesia 26 t, 34 t
motor disturbance 34 t "Zahlkarte" 3, 8
Schriftenreihe Band 6: J. Ulrich: Die cerebralen
Entmarkungskrankheiten im
Band 14: E. Sluga: Polyneuro-
pathien. Typen und Differenzierung
Neurologie Kindesalter. Diffuse Himsklerosen.
Mit einem Geleitwort von F. Luthy
Ergebnisse bioptischer Unter-
suchungen.
1971. 35 Abbildungen, 1 Farbtafe!' 1974.20 Abbildungen, 5 Schemata.
Neurology XV, 202 Seiten
ISBN 3-540-05244-5
X. 155 Seiten
ISBN 3-540-06945-3
Series Band 7: K.H. Puff: Die klinische
Band 15: H.F.Herrschaft: Die
regionale Gehimdurchblutung.
Elekromyographie in der Differen- Mef3methoden. Regulation, Ver-
Herausgeber: tialdiagnose von Neuro- und Myo- iinderung bei den cerebralen Durch-
H. J. Bauer, H. Ganshirt, P. Vogel pathien. Eine Bilanz. blutungsst6rungen und pharmako-
1971. 12 Abbildungen. logische Beeinfluf3barkeit.
Die Bezieherdes Archiv fUr Psychia- VIII, 84 Seiten 1975.25 Abbildungen, 34 Tabellen.
trie und Nervenkrankheiten, der ISBN 3-540-05527-4 X. 239 Seiten
Zeitschrift fUr Neurologie/ Journal ISBN 3-540-07363-9
of Neurology und des Zentralblatt
fUr die gesamte Neurologie und Band 8: K. Piscol: Die Blutver-
sorgung des Ruckenmarkes und Band 16: R.Heene: Experimental
Psychiatrie erhalten die Schriften- Myopathies and Muscular Dystro-
ihre klinische Relevanz.
reihe zu einem um 10 Prozent er- 1972.37 Abbildungen, 3 Tabellen. phy. Studies in the Formal Patho-
maf3igten Vorzugspreis VI, 91 Seiten genesis of the Myopathy of2,
ISBN 3-540-05740-4 4-Dichlorophenoxyacetate.
1975. 17 figures. VI, 97 pages
ISBN 3-540-07376-0
Band 1: W. Kahle:Die Entwicklung Band 9: M. Wiesendanger: Patho-
der menschlichen Grof3himhemis- physiology of Muscle Tone. Band 17: T.Tsuboi, W.Christian:
phare 1972.4 figures. VI, 46 pages Epilepsy. A Clinical, Electroen-
1969.55 Abbildungen. ISBN 3-540-05761-7 cephalographic and Statistical Study
VII, 116 Seiten of 466 Patients.
ISBN 3-540-04703-4 1976. 11 figures, 45 tables.
Band 10: H.Spiess: Schiidigungen VII, 171 pages
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Symptomatologie der akuten und ionisierende Strahl en. Mit ausfUhr-
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Befunde zur pathogene tisch en fassung. Facial Palsies. Investigations on the
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trolyt- und Wasserhaushaltsst6run- VIII, 71 Seiten Meato-Labyrinthine Facial Palsies.
gen sowie zur Pathologie der Blut/ ISBN 3-540-05763-3 With a foreword by U. Fisch
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1969.49 Abbildungen.
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Karl R. Popper
Penn, Great Britain

John C. Eccles
The Self
Contra, Switzerland
and Its Brain
1977. 66 figures. XVI, 597 pages.
ISBN 3-540-08307-3

Contents:
Materialism Transcends Itself. The Worlds 1,2 and 3. Materialism
Criticized. Some Remarks on the Self. Historical Comments on
the Mind-Body Problem. Summary. - The Cerebral Cortex. Cons-
coius Perception. Voluntary Movement. The Language Centres of
the Human Brain. Global Lesions of the Human Cerebrum. Cir-
cumscribed Cerebral Lesions. - The Self-Conscoius Mind and the
Brain. Conscious Memory: The Cerebral Processes Concerned
in Storage and Retrieval. - Dialogues between the two authors.

This book iss timely, as it appears at a point of impasse between

philosophy and science. It creates the first link between the philo-
sophy of the selfand neurobiology. In dealing with the self, philo-
sophers have so far taken little account of scientific knowledge of
the brain; scientists, fortheirpart, have traditionally avoided philo-
sophy in favour of purely material evidence.

Eccles (a neurobiologist) and Popper (a philosopher), both belie-

vers in dualism and interactionism, consider the existence ofcons-
ciousness one ofthe greatest riddles of cosmology.

Part I, Popper discusses the philosophical issue between dualist

or even pluralist interactionism on the one side, and materialism
and parallelism on the other. There is also a historical review of
these issues.

In Part II, Eccles examines the mind from the neurological stand-
point: the structure ofthe brain and its functional performance
under normal as well as abnormal circumstances, for example
when lesions (especially those surgically induced) are present. The
result is a radical and intriguing hypothesis on the interaction bet-
ween mental events and detailed neurological occurrences in the
cerebral cortex.

Part III, based on twelve recorded conversations, reflects the exci-

ting exchange between the authors as they attempt to come to
terms with their conflicting opinions. This part preserves the inti-
Springer mate quality of these dialogues, ans shows how some ofthe
authors' viewpoints changed in the course of these daily dis-
International cussions.