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Application of the poser criteria in primary progressive multiple sclerosis.

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Ibuprofen Does Not Suppress Active Multiple
Sclerosis Lesions on Gadolinium-Enhanced MR
Frederik Barkhof, MD,
Jan-Hein T. M. van Waesberghe, MD,
Bernard M. J. Uitdehaag, MD,
and Chris H . Polman, M D
M R Centre f i r MS Research, Department of Diagnostic
Radiology and Neurology, Academic Hospital of the Wrije
Universiteit, Amsterdam, The Netherlands
Several immunomodulatory drugs have been approved for
the treatment of patients with multiple sclerosis (MS), including interferon P (IFNP). Both IFNP-la and IFNP-lb
show a beneficial effect on clinical and magnetic resonance
(MR) imaging measures of disease activity [ l , 21. In the
study with IFNP-la as reported by ’Jacobs and colleagues [ l ] ,
the side effects of treatment with IFNP, were treated with
acetaminophen, whereas in the final s h # y report with
IFNP-lb [2], it was stated that “systemic flulike symptoms
can be substantially, and in some cases comdletely, suppressed in the initial weeks of IFNP use by concod$tant use
of non-steroidal anti-inflammatory drug (NSAID), fuch as
ibuprofen.” Although Jacobs and associates [ 11 discuss that
the results of the trial are probably not influenced by-concomitant corticosteroid treatment, the use of acetaminopken
and NSAIDs in general has not been considered as a possible
confounder. In this pilot study, we investigated the possible
effect of a commonly used NSAID, ibuprofen, on disease
activity as measured by MR.
Eight patients with active disease were studied before and
after treatment with ibuprofen (1,600 mg/day) for 7 days.
Contiguous 3-mm gadolinium-enhanced (0.3 mmol/kg) M R
images were obtained immediately before and after treatment
at 1.5 tesla (TR 645/TE 15/2 excitations). The M R images
were evaluated by a radiologist blinded ro the order of scanning. The study was approved by the institutional review
board, and all patients gave informed consent after the nature of the procedures had been fully explained.
The imaging results are summarized in the Table. N o statistically significant difference was found for the number of
enhancing lesions (2= -0.94, p = 0.3452). The lesion
load after ibuprofen therapy was marginally lower (3%) than
lesion load before ibuprofen ( Z = - 1.96, p = 0.049).
The minimal effect of ibuprofen on enhancing lesions in
vivo is in keeping with an in vitro study showing that macrophages of MS patients are not very sensitive to NSAID
treatment even though they produce elevated levels of prostaglandin E [3]. We conclude that ibuprofen does not influ-
Tab1e. M R Imaging Findings Before and .43er I Week
Treatment with Ibuprofen
Number of
L.esion Load (cm3)
ence the number or volume of active lesions on M R imaging
in MS. It is therefore unlikely that the use of NSAID confounded the pronounced effect of IFNP on gadoliniumenhancing M R lesions in recent clinical trials [ l , 21.
1. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-la for disease progression in relapsing multiple
sclerosis: the Multiple Sclerosis Collaborative Research Group
(MSCRG). Ann Neurol 1996;39:285-294
2. Interferon beta-lb in the treatment of multiple sclerosis: final
outcome of the randomized controlled trial. The IFNB Multiple
Sclerosis Study Group and the University of British Columbia
MS/MRI Analysis Group. Neurology 1995;45:1277-1 285
3. Merrill JE, Strom SR, Ellison GW, Myers LW. In vitro study of
mediators of inflammation in multiple sclerosis. J Clin Immunol
Application of the Poser Criteria in Primary
Progressive Multiple Sclerosis
G. V. McDonnell, MRCP,* and S. A. Hawkins, FRCPt
The Poser criteria [I] are widely accepted and applied for the
diagnosis of multiple scberosis (MS). The diagnosis of clinically definite MS (CDMS) by these criteria requires the occurrence of at least two attacks. Patients with primary progressive disease (PPMS), representing around 10% of all
cases, have by definition a progressive course from bnset
without relapse or remission. Designation of such patients as
having CDMS therefore appears incongruous. This difficulty
with the diagnostic criteria in PPMS has recently been discussed [2]. Given the mounting evidence for significant heterogeneity in MS [3, 41 and the advent of treatment trials in
PPMS, appropriate ascertainment and classification of patients are increasingly important. W e have therefore sought
to assess the relevance of the Poser criteria in PPMS by applying them to a significant population of such patients.
In Northern Ireland, 11 1 patients were identified as having PPMS after investigation and interview and examination
by two neurologists. Only those with a progressive course
from onset without relapses were so categorized, although
periods of apparent stability where no progression occurred
were also allowed.
Where possible, each patient was assigned to one of the
Poser categories, namely, CDMS, laboratory-supported definite MS (LSDMS), clinically probable MS (CPMS), or
laboratory-supported probable MS (LSPMS). Those patients
not satisfying the criteria for any category were designated as
having “suspected MS.” Disease onset was defined as the first
and only “attack.” For comparative purposes, a similar exercise was carried out in a recent prevalence study of MS in
Northern Ireland that used the Poser criteria in patient classification [5].
982 Copyright 0 1997 by the American Neurological Association
There were 63 females and 48 males (ratio 1.3:1), with a
mean age of 53.5 years and mean age o f onset of 39.9 years.
Because of the lack of relapses and therefore the absence of a
second genuine attack, no patients could be classified as having either CDMS or LSPMS. Forty-one patients (36.9%)
were designated as having LSDMS, and 51 were considered
to have CPMS (45.9%). Nineteen patients (17.1%) did not
satisfy the criteria for any of the Poser groups and were
therefore designated as suspected cases, 3 patients being excluded from the classification because of onset of symptoms
after the age of 59 years.
By comparison with these data, the recent Northern Ireland epidemiological study (12.5% of patients had PPMS)
provided the following proportions in the Poser groups [5]:
CDMS (64%), CPMS (15%), LSDMS (8%), LSPMS (1%).
Suspected cases represented 12% o f these cases.
The Poser criteria provide an excellent and widely accepted standard in MS diagnosis. However, the definition of
"attacks" and the absence of these in the clinical course of
patients with PPMS strictly limits the diagnostic categories
available for classification of such patients, a significant proportion not satisfying any of the Poser categories. The age
limits in the Poser criteria increase the potential for exclusion
of PPMS patients who tend to have a significantly later age
of onset than those with relapsing-remitting or secondary
progressive disease. Overall, these results indicate a need for
re-evaluation of the diagnostic criteria with regard to PPMS
to allow the valid assessment and comparison of epidemiological and scientific data and to permit appropriate, inclusive recruitment of patients for therapeutic trials.
*Northern IreLand Neurology Service, Royal Victoria Hospital,
Be&; And fDepartment o f Medicine, The Queen >
University of Belfast, Be& Northern Ireland
1. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann
Neurol 1983;13:227-231
2. Thompson AJ, Polrnan CH, Miller DH, et al. Primary progressive multiple sclerosis. Brain 1997;120:1085-1096
3. Hillert J, Gronning M, Nyland H, et al. An irnmunogenetic heterogeneity in multiple sclerosis. J Neurol Neurosurg Psychiatry
4. Revesz T, Kidd D, Thompson AJ, et al. A comparison of the
pathology o f primary and secondary progressive multiple sclerosis. Brain 1994;117:759-765
5. Hawkins SA, McDonnell GV. Changing epidemiology o f multiple sclerosis (MS) in Northern Ireland (NI). Neurology 1997;
48:A429 (Abstract)
Cortical Matching of Visual and Vestibular 3D
Coordinate Maps
Thomas Brandt, M D
Tilts of subjective visual vertical (SVV) [I] and room tilt
illusions [2, 31 (transient 180" upside-down vision or apparent 90" tilts of the visual scene) are vestibuIar signs that in-
dicate spatial disorientation. Are both phenomena the same,
their net tilt angles differing only in size? There is evidence
that they are different and that room tilt illusions may be the
perceptual result of a transient erroneous cortical mismatch
o f the visual and vestibular coordinate maps.
Spatial orientation is based on visual-vestibular interaction
[4,51. Both senses provide us with visual cues about vertical
orientation in a three-dimensional (3D) coordinate system.
These are the three major planes of action of the vestibular
system: the frontal roll plane, the sagittal pitch plane, and
the horizontal yaw plane. Because two different verticalsvisual and vestibular-cannot be perceived at the same time,
there must be a cortical mechanism that integrates visualvestibular input (by aligning the pair of axes) to determine
the current percept of a unique verticality.
Both SW tilts and room tilt illusions involve "graviceptive" pathways that extend from the otoliths and the vertical
semicircular canals through the vestibular nuclei and the
thalamus to the parietoinsular vestibular cortex. Directionspecific S W tilts are the most sensitive sign of an acute unilateral brainstem lesion; they have been reported in lesions of
all these structures [I]. Room tilt illusions have also been
reported to occur with brainstem lesions as a manifestation
of a dynamic mismatch between inappropriate otolithic input and correct visual input [3]. Why are S W tilt and room
tilt illusions different phenomena?
S W tilts are usually stable signs and recovery occurs
gradually, within days to weeks; room tilt illusions are
paroxysmal or transient phenomena.
S W tilts manifest as a continuum of angle of tilt up to
about 30" as a maximum; room tilt illusions occur in 90"
steps as a lateral tilt or as 180" tilt with upside-down vision.
S W tiIts are not usually associated with the perception of
room tilt.
S W tilt is a sensitive measure (in degrees) of a graviceptive vestibular tone imbalance when determined without additional visual cues of orientation [ 11. Because patients with
significant tilts of the S W do not usually complain spontaneously about an apparent tilt of the visual scene (room tilt),
this deviation must be largely compensated for by the cortical match o f visual-vestibular coordinates. This matching of
separate sensory 3D coordinate maps is a continuous and
robust process that must tolerate slight incongruencies between expected and actually received sensory inputs. Furthermore, it must be plastic to compensate for an acquired vestibular tone imbalance (eg, unilateral labyrinthine loss) or to
adapt to unusual environments (microgravity).
In brief, room tilt illusions are transient mismatches of the
cortical visual and vestibular 3D coordinate maps that consequently occur in 90" or 180" steps as the erroneous result
of the attempt to match the pair of axes in acute vestibular
tone imbalances. Perceived tilt in one plane causes the afflicted person to attribute upright to horizontal or even
down. The visual scene, however, which itself contains empirical spatial cues for upright, will then in turn "dominate
Annals of Neurolow
Vol 42
No 6
December 1997 983
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progressive, application, posev, primary, criterias, sclerosis, multiple
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