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VIEWS: 8 PAGES: 5

									                                                       SPECIAL ARTICLE



                    New Diagnostic Criteria
                     for Multiple Sclerosis:
                Guidelines for Research Protocols
       Charles M. Poser, MD,l Donald W. Paty, MD,’ Labe Scheinberg, MD,3 W. Ian McDonald, FRCP,4
       Floyd A. Davis, MD,’ George C. Ebers, MD,‘ Kenneth P. Johnson, MD,’ William A. Sibley, MD,8
                        Donald H. Silberberg, MD,9 and Wallace W. Tourtellotte, MD”




Several schemes for the diagnosis and clinical clas-                 Method and Procedure
sification of multiple sclerosis (MS) have been ad-
                                                                     O n April 26 and 27, 1982, the following persons participated
vanced [l}. The best known is that published by                      in a Workshop on the Diagnosis of Multiple Sclerosis, held in
Schumacher et alC31. The criteria for this scheme were               Washington, DC, for the purpose of establishing new diag-
established in order to select patients for participation            nostic criteria for MS: Bruce Becker (National Naval Medical
in therapeutic trials, and pertain only to what might be             Center),Jerry Blaivas (Columbia), Keith Chiappa (Harvard),
called definite MS. No provision was made for incor-                 Floyd Davis (Rush), Burton Drayer (Duke), George Ebers
porating supportive laboratory data into the diagnostic              (Western Ontario), Andrew Eism (British Columbia),
criteria.                                                            Robert Herndon (Rochester, NY), Kenneth Johnson (Mary-
   As no reliable specific laboratory test for the diag-             land), Ian McDonald (National Hospital, London), Dale
nosis of MS has been discovered, the diagnosis remains               McFarlin (NINCDS), Donald Paty, Co-chairman (British
a clinical one, and there is still a need for clinical diag-         Columbia),Janis Peyser (Vermont), Charles Poser, Chairman
                                                                     (Boston), David Regan (Dalhousie), Daniel Sax (Boston),
nostic criteria. However, several laboratory and clinical
                                                                     Labe Scheinberg, Co-chairman (Albert Einstein), Simon
procedures have been developed within the last decade
                                                                     Sears (Texas-Houston), William Sibley (Arizona), Donald
which aid greatly in demonstrating neurological dys-                 Silberberg (Pennsylvania), Robert Slater (National MS Soci-
function attributable to lesions, and even the lesions               ety), Emanuel Stadlan (NINCDS), Wallace Tourtellotte
themselves.                                                          (Wadsworth VAIUCLA), and Byron Waksman (National MS
   One problem with the various published diagnostic                 Society). D r Robert Daroff (Case-Western Reserve) made
classifications is their discrepant terminology: what is             many useful suggestions. The disciplines represented in-
considered “probable” in one is called “definite” in                 cluded neurology, neuropsychology, urology, immunology,
another. Another problem is that all the proposed                    neuroradiology, neuroophthalmology, clinical neurophysiol-
schemes require much subjective judgment, a difficulty               ogy, and neuropathology.
which cannot be completely overcome but can be di-                      The participants reviewed in detail historical and clinical
                                                                     symptomatology in MS; immunological observations; cere-
minished by adding to the clinical evaluation the results
                                                                     brospinal fluid (CSF) tests; neurophysiological procedures in-
of laboratory, neuroimaging, neuropsychological, and                 cluding visual, brainstern auditory, trigeminal, and somato-
neurophysiological procedures. Today there is a need                 sensory evoked potential measurements; the evoked blink
for more exact criteria than existed earlier in order to             reflex; a variety of physiological and psychophysiological
conduct therapeutic trials in multicenter programs, to               procedures; neuropsychological assessment; tissue imaging
compare epidemiological surveys, to evaluate new                     procedures such as computer assisted tomography (CT scan-
diagnostic procedures, and to estimate the activity of               ning) and nuclear magnetic resonance (NMR); and urological
the disease process in MS.                                           studies of bladder, bowel, and sexual dysfunction. This re-




                                                                                                                                  ~




‘Department of Neurology, Boston University School of Medicine,      sity of Maryland School of Medicine, Baltimore, MD, ’Department
Boston, MA, ’Division of Neurology, Vancouver General Hospital,      of Neurology, university of Arizona School of Medicine, Tucson,
University of British Columbia, Vancouver BC, Canada, ’Multiple      AZ, 9Department of Neurology, University of Pennsylvania School
Sclerosis Center, Albert Einstein College of Medicine, Bronx, NY,    of Medicine, Philadelphia, PA “’Wadsworth VA Medical Center,
*National Hospital, Queen Square, London, England, 5Departrnent      University of California School of Medicine, Los Angeles, CA.
of Neurological Sciences, Rush-Presbyterian-St. Luke’s Medical       Address reprint requests to D~ poser, D~~~~~~~~ ~
                                                                                                                     of            ~   ~
Center, Chicago, IL, ‘Division of Neurology, University of Western   Boston University Medical Center, 80 E Concord St, Boston, MA
Ontario, London, Ont, Canada, ’Department of Neurology, IJniver-     02 18,



                                                                                                                                227
view resulted in formulation of guidelines for the perfor-                    5 . Typical of MS: MS is known to involve certain
mance of these procedures and for evaluation of the results                parts of the CNS much more frequently than others,
that will be published with recommendations regarding their                and thus certain signs and symptoms are more fre-
usefulness in the diagnosis of MS 12). The diagnostic criteria             quently noted. Gray matter lesions occur rarely enough
presented here represent the views of the majority of the                  in MS that they should not be considered in establish-
workshop participants.                                                     ing the diagnosis. Lesions of the peripheral nervous
                                                                           system, except when accounted for by their in-
Definitions                                                                tramedullary course (e.g., oculomotor, trigeminal, or
1. Attack (bout, episode, exacerbation): The occurrence of                 facial nerves), may not be counted. Complaints such as
a symptom or symptoms of neurological dysfunction,                         headaches, convulsive seizures, depression, or alter-
with or without abjective confirmation, lasting more                       ations of the state of consciousness are too nonspecific
than 24 hours constitutes an attack. This may be com-                      to be considered in the diagnostic construct.
pletely subjective and anamnestic, eg., the patient re-                       6. Remission: A definite improvement of signs, symp-
ports having had double vision for three days but did                      toms, or both that has been present for at least 24
not consult a physician; or numbness and tingling of a                     hours is called a remission for the purpose of these
leg caused a visit to a physician who was unable to                        guidelines. A remission must last at least one month to
demonstrate objective changes; or the patient was hos-                     be considered significant.
pitalized because of severe ataxia and was found to                           7. Separate lesions: Separate signs or symptoms cannot
have signs of cerebellar dysfunction, bilateral Babinski                   be explainable on the basis of a single lesion; simulta-
signs, and left facial weakness. Individual symptoms,                      neously occurring internuclear ophthalmoplegia, facial
however, may last for considerably less time than that:                    weakness, and signs of involvement of the corticospinal
e.g., a Lhermitte sign (which is really a symptom) or                      tracts could have been caused by a single lesion (e.g.,
vertigo may last for only seconds; these manifestations                    brainstem infarction) and thus would not be acceptable.
cannot be considered attacks in this context.                              Optic neuritis involving both eyes occurring simulta-
    2. Historical infomtion: The description of symp-                      neously, or the second eye becoming involved within
toms by the patient. The example just cited (under the                      15 days of the first (provided that compression of the
definition of attack) of the episode of diplopia would be                  chiasm by tumor or aneurysm has been ruled out), is
historical, and so would the leg numbness, although                        considered to represent a single lesion. Only lesions
medical corroboration would strengthen the latter. Ide-                    that involve distinctly different parts of the CNS are
ally, medical records which confirm anamnestic infor-                      called separate lesions.
mation should be obtained.                                                    8. Laboratoy support: The term is applied here only
    3. Clinical evidence o f a lesion: Signs of neurological               to the examination of CSF for oligoclonal bands and
dysfunction demonstrable by neurological examina-                           increased production of immunoglobulin G (1gG). All
tion. Such neurological signs are acceptable even if no                     other laboratory procedures, such as evoked responses
longer present, provided that they were elicited and                       or tissue imaging techniques, are considered to be ex-
recorded in the past by a competent examiner.                               tensions of the clinical examination.
    4. PararlinicaP evidnce of a lesion: The demonstration
 by means of various tests and procedures of the exis-                     General Considerations
 tence of a lesion of the central nervous system (CNS)                     The acceptable age of onset for research purposes is
which has not produced signs of neurological dysfunc-                      between 10 and 59 years inclusive. The manifestations
 tion but which may or may not have caused symptoms in                     of the disease offered in evidence must be shown to be
the past. Such tests and procedures include the hot                        characteristic of MS and not attributable to another
 bath test, evoked response studies, tissue imaging pro-                   condition. Such a decision must be made by a physician
cedures, and reliable, expert urological assessment,                       who is experienced in clinical neurology. It is strongly
provided that these tests and procedures follow the                        recommended that the diagnosis of MS be established
guidelines and are interpreted according to the newly                      only by a competent neurologist. Although extended
                                             Z.
established criteria to be published [ } These diag-                       and expensive investigations are not encouraged, other
 nostic procedures represent various options, all of                       illnesses capable of producing signs and symptoms of
which may not be available and some of which may not                       multiple lesions of the CNS must be considered. More
 be deemed suitable or reliable enough by individual                       important, clinical observation over several weeks or
 neurologists.                                                             months may obviate the need for much laboratory in-
                                                                           vestigation. A steadily progressive disease from onset,
                                                                           without reliable evidence of exacerbations or remis-
"Webster's Third New International Dictionuty, unabridged, 1971,           sions, with manifestations reflecting a single lesion, and
gives the following definitions for para-: la. beside, alongside of; Id.
associated in a subsidiary or accessory capacity. Paraclinical would       without paraclinical evidence of a lesion elsewhere in
appear more suitable than subclinical.                                     the CNS is not to be classified as MS for research


228     Annals of Neurology Vol 13 N o 3                    March 1983
Nrw Diagnostic Criteria for Mtiltiple Sclerosis
                                                                        Clinical              Paraclinical           CSF
Category                                             Attacks            Evidence              Evidence               OBiIgG
A. Clinically definite
   CDMS A1                                           2                  2
   CDMS A2                                           2                  1          and         1
B. Laboratory-supported
     definite
   LSDMS B1                                                             1          or          1                     +
   LSDMS B2                                                             2                                            +
   LSDMS B3                                                             1          and         1                     +
C. Clinically probable
   CPMS C1                                           2                  1
   CPMS C2                                           1                  2
   CPMS C3                                           1                  1          and         1
D. Laboratory-supported
     probable
   LSPMS D1                                          2                                                               +
OBiIgG   =   oligoclonal bands or increased IgG



purposes, even in the presence of oligoclonal bands or            fore the age of 50 with loss of vision and with pain on
increased IgG production in the CSF. Most neurolog-               motion of the eye or, if no substantial loss of vision has
ical clinicians will regard such patients as probable cases       occurred, with description of visual field defect or alter-
of MS; nevertheless, they should not be enrolled in               ation of color vision; transient paraparesis with pares-
research protocols.                                               thesias; oscillopsia; typical diplopia (in the absence of
                                                                  thyroid disease or a prior history of orbital trauma) that
Classification of Multiple Sclerosis                              is abolished by closing either eye; and trigeminal
The proposed classification of MS for use in research             neuralgia with onset before the age of 40. Extreme
protocols consists of two major groups, definite and              caution must be exercised in making such a substitu-
probable, each with two subgroups, clinical and labora-           tion. If possible, confirmation by a relative or friend
tory supported (Table). The traditional possible MS               should be obtained if the attack was not observed and
group is not included because patients so labeled would           recorded by a physician.
not be acceptable for research studies.                              Many individuals have become quite familiar with
                                                                  the symptoms of MS from articles published in lay
A. Clinically definite MS (CDMS)                                  magazines and other easily available sources of infor-
   1. Two attacks and clinical evidence of two sepa-              mation. MS Munchausens are known to exist, and es-
      rate lesions                                                tablishment of the diagnosis of MS may be of advan-
   2. Two attacks; clinical evidence of one lesion and            tage to some individuals in some circumstances.
      paraclinical evidence of another, separate lesion              Paraclinical evidence of CNS lesions may be elicited
                                                                  by a variety of means, including induced hyperthermia,
COMMENT. The two attacks must involve different                   evoked potential studies, CT and NMR scans, or spe-
parts of the CNS, must be separated by a period of at             cial urological studies. Neuropsychological evaluation
least one month, and must each last a minimum of 24               by an expert examiner that indicates definite cognitive
hours.                                                            impairment in a patient under the age of 50 may be
   Certain historical information may be substituted for          suggestive and helpful but not yet specific enough to be
clinical evidence of one of the two lesions (in category          fully diagnostic. N o other explanation for these lesions
A l ) if it fulfills the following conditions: the informa-       must be evident. Use of the procedures and evaluation
tion is reliable, is adequate to localize a lesion typical of     of results must follow the guidelines, which will be
MS, and has no other explanation. Examples include a              published shortly {2].
Lhermitte sign in any person under the age of 50 years
who does not have radiologically demonstrable evi-                B. Lubwatoq-supported definite MS ILSDMS)
dence of cervical spine disease; a useless hand due to               The laboratory support consists of demonstration in
severe impairment of position sense causing severe                   CSF of IgG oligoclonal bands (OB) or of increased
stereoanesthesia; a typical optic neuritis occurring be-             CNS synthesis of IgG. Oligoclonal bands must not


                                                          Special Article: Poser et al: Diagnosis of Multiple Sclerosis   229
   be present in the patient’s serum, and the serum        COMMENT. The two attacks must involve different
   IgG level must be normal. This assumes that other       parts of the CNS, must be separated by a minimum of
   conditions causing CSF changes, such as syphilis,       one month, and must each have lasted at least 24 hours.
   subacute sclerosing panencephalitis, sarcoidosis,
   collagen vascular disease, and similar disorders,       Discussion
   have been ruled out.                                    The main reason for establishing these criteria is to
                                                           restrict therapeutic trials and other research protocols
   1. Two attacks; either clinical or paraclinical evi-    to patients with definite MS; the category of probable is
      dence of one lesion; and CSF OBiIgG                  designed for the purpose of prospectively evaluating
                                                           new diagnostic methods. The introduction of the cate-
COMMENT.    The two attacks must involve different         gories of laboratory-supported definite and probable
parts of the CNS and be separated by a minimum of          MS extends the limits of the diagnostic criteria, thus
one month, each having lasted at least 24 hours. One of    making available a larger reservoir of patients for inves-
the episodes must involve a part of the CNS distinct       tigative purposes. Naturally, investigators retain the
from that demonstrated by the clinical or paraclinical     prerogative of availing themselves of this additional
evidence.                                                  group of patients or restricting their choice on the basis
                                                           of the classic clinical criteria.
   2. One attack; clinical evidence of two separate le-       The guidelines may appear unduly complicated to
      sions; and CSF OB/IgG                                the neurological practitioner. They are not meant to
   3. One attack; clinical evidence of one lesion and      deter the clinician in the effort to establish a diagnosis
      paraclinical evidence of another, separate lesion;   of MS. They will not replace the intuitive feelings de-
      and CSF OBlIgG                                       rived from subtle indices that so often lead an experi-
                                                           enced physician to the solution of the problem; rather,
COMMENT.      Historical information cannot be sub-        they should help guide the diagnostic investigation in
stituted for the clinical evidence. Whether the evidence   the right direction. To a physician, the distinction be-
is clinical or paraclinical, both lesions must not have    tween definite and probable MS may matter very little.
been present at the time of the first examination and      T o a patient, the end of uncertainty is important. If the
must be separated by at least one month. This separa-      guidelines result in diminution of the patient’s (and the
tion in time is designed to reduce the possibility of      family’s) search for alternative or confirmatory opin-
including a case of acute disseminated encephalomyeli-     ions, they will be worthwhile.
tis. In a patient with the so-called progressive form of      A major concern in establishing diagnostic criteria
MS, i.e., without remissions and exacerbations, evi-       for MS is differentiation of the disease from acute dis-
dence of clinical or paraclinical optic nerve involve-     seminated encephalomyelitis (ADEM) with its multiple
ment, for example, should not have been present at the     separate lesions. With rare exceptions, ADEM is a
time the paraparesis first appeared. Under those cir-      monophasic illness, all its lesions occurring within a
cumstances, and only if steady progression has taken       couple of weeks in most instances. Patients with
place for at least six months, may such a case be ac-      ADEM may also have CSF oligoclonal bands or in-
cepted as MS.                                              creased CNS production of IgG. The problem of
                                                           steadily progressive myelopathy is equally difficult to
C. Clinically probable MS (CPMS)                           resolve, and a prolonged period of observation may be
   1. Two attacks and clinical evidence of one lesion      necessary. The need to make the diagnostic criteria
                                                           fairly rigid for the intended purposes means that some
COMMENT. The two attacks must involve separate             types of patients will not fit any of the proposed catego-
parts of the CNS. Historical information cannot be         ries despite the fact that many neurologists would con-
considered as a substitute for the clinical evidence.      sider them to have definite MS; for example, a young
                                                           woman who during the course of an employment phys-
   2. One attack and clinical evidence of two separate     ical examination is found ro have monocular optic at-
      lesions                                              rophy, sustained nystagmus on left lateral gaze, and a
   3. One attack; clinical evidence of one lesion and      right Babinski sign but who denies ever having had
      paraclinical evidence of another, separate lesion     symptoms referable to the CNS will almost certainly
                                                           be so diagnosed, as will a young man who, following an
COMMENT.    See under B3.                                  automobile accident, is found to have several separate,
                                                           contrast-enhancing periventricular lesions on CT scan.
D. Laboratory-supported probable MS (LSPMS)                The former patient in fact may well have had a single
   1. Two attacks and CSF OB/IgG                            episode of ADEM that manifested itself only as a cou-



230 Annals of Neurology      Vol 13 No 3      March 1983
ple of days of headache, malaise, and slight nausea, a                tiple Sclerosis Society and by the Kroc Foundarion, for which grati-
constellation of symptoms hardly suggestive of MS. It                 tude is also expressed.
can be argued that such asymptomatic patients should                 The financial support provided by these organizations neither
not be included as subjects for therapeutic trials.                  signifies nor implies endorsement of these diagnostic criteria.
  The Schumacher criteria have served us well, but                   The organizational skills of Suzanne Morin contributed to the success
                                                                     of the deliberations which led to this report.
presently available reliable and productive ancillary
procedures must be incorporated into more up-to-date
guidelines. These diagnostic criteria were developed to               References
                                                                         Brown JR, Beebe GW, Kurtzke JF, Loewenson RB, Silberberg
delineate groups of patients whose diagnosis will be                     DH, Tourtellotte WW: The design of clinical studies to assess
accepted by a wide range of investigators worldwide for                  therapeutic efficacy in multiple sclerosis. Neurology (NY)
inclusion in various studies and protocols.                              29(2):3-23, 1979
                                                                         Poser CM, Paty DW, Scheinberg L, McDonald WI, Ebers GC
                                                                         (eds): The Diagnosis of Multiple Sclerosis. New York, Thieme-
The Workshop on the Diagnosis of Multiple Sclerosis was sponsored        Stratton (in press)
by the Department of Neurology of Boston University School of            Schumacher GA, Beebe GW, Kibler RF, Kurland LT, Kurtzke
Medicine. The generous support of the Technology and Research            JF, McDowell F, Nagler B, Sibley WA, Tourtellotte WW, Will-
Foundation of the Paralyzed Veterans of America is gratefully ac-        mon TL: Problems of experimental trials of therapy in multiple
knowledged. Additional support was provided by the National Mul-         sclerosis. Ann N Y Acad Sci 122:552-568, 1965




                                                              Special Article: Poser et al: Diagnosis of Multiple Sclerosis          231

								
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