Transcript THE RADIOLOGICALLY ISOLATED SYNDROME OF …

THE RADIOLOGICALLY ISOLATED
SYNDROME OF DEMYELINATION
Is it Early Multiple Sclerosis (MS)? What to do
When Confronted by a Patient with
Radiologically Isolated Syndrome (RIS)? To
Treat and/or to Wait?
Bartko D.1 2 5 , Rohalova J.2 5, Fabcin J.3 5, Kubovicova K.2 5, Ščerbíkova
M.4 5, Bielikova E.4 5, Latta V.6
Institute of Medical Sciences, Neurosciences and Military Health1,
Dept. of Neurology2, MRI Center3, Dept. of Ophtalmology4, Central
Military University Hosptital5, Ružomberok, Dept. of MRI6, Presov,
Slovak Republic
Suported by EU/gov. grants ITMS2202200099,ITMS 2202200153,
INTERREG IIIA 14140200032, APVV0586-06
Introduction Definition
Radiologically isolated syndrome of
demyelination (RIS Ocuda et al. 2009, they
introduced the term)
has been defined as the unanticipated
• MRI findings of white matter (WM) lesions
suggestive of demyelinating disease
• in subjects with a normal neurologic findings
and
• no medical history consistent with multiple
sclerosis (MS).
Although WM lesions may be detected in
asymptomatic subjects (De Stefano et al. 2011),
it is still unclear
whether RIS should be considered
a) a subclinical MS or
b) an independent entity or
c) it is MRI finding without any
association with MS
There are only few studies,
demonstrating the occurrence of a clinical
deterioration
in subjects with RIS correlated
to the presence of inflammatory markers
(Comi 2009, Trojano et al 2009, Lebrun et al. 2008)
They found approximately one-third of
subjects
with RIS associated later with
a clinically isolated syndrome (CIS)
particularly
those with asymptomatic cervical spinal
lesions (Okuda et al. 2011)
Aim
1. to present a case report and to discuss
questions:
2. is the RIS realy MS presenting with RIS?
and/or
3. it is not MS,it is ONLY RIS of demyelination?
4. If it is RIS, should we treat the patient
according to MS guide-line despite no
clinical neurologic symptoms exist? or
5. Should we wait?
6. What shoud we tell the patient?
Case Report History
In 2003
18 yrs old girl, uncertain, very mild
sighting problems, occasionally.
Ophtalmologist´s (University Professor)
diagnosis:
• uveitis
• Neurologic examination normal
* Brain MRI T1weighted, T2 weighted, Flair,
performed at local Faculty Hospital showed
5 small white matter abnormalities in
supraventricular and periventricular region
interpreted by radiologist (after Gd)
as demyelinating MS.
Spinal cord MRI not performed.
CONCLUSION : MRI brain lasions are typical
for MS
Patient was unsatisfied with this
conclusion
In 2003
she was admitted to another Univesity Dept. of
Neurology.
Neurological findings:
• normal, CSF, no oligoclonal bounds.
• VEPs, SEPs, ABEPs normal findings,
• Boreliosis in CSF negat.
• MRI (from 2003): interpreted as no typical
for MS
Diagnosis: Neurasthenia, MS not confirmed.
In 2011
During period of 8 yrs patient
• without clinical symtoms,
• no relapses,
• no remissions,
• no treated.
• Neurological status normal,
• CSF: oligoclonal bounds:
positive.
• VEPs, SEPs, ABEPs normal
findings,
• Boreliosis in CSF negat.
• inflammation markers: norm
new MRI:
16
brain lesions interpreted again as
demyelinating.
Patient is unsatisfied again,
a little anxious
(of course, with such unclear diagnosis).
She was admitted at Central Military University
Hospital
Brain MRI
Brain MRI T2 weigted and Flair.
16 brain MRI lesions interpreted as
demyelinating. After Gd no symptoms of
inflammation
MRI of Cervical
Spinal Cord
MRI: one lesion (hyperintensity
signal) in C2/C3 of spinal cord,23×5
mm, without expansion,without
perifocal edem,without activity
after Gd. It was interpreted as
demyelinating lesion
Final Diagnosis
in Central Military University Hospital:
Multiple Sclerosis
with recommendation of DMT therapy
despite
the patient showed
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no clinical symtoms of MS,
no relapses,
no remissions,
no oligoclonal bands
• normal VEPs,SEPs,ABEPs
DMT therapy was not realized
March 2012
Patient want to be again examined by
neurologist
THEREFORE
readmission of patient to hospital (RK)
1. Neurological findings:
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9 years no pathological neurologic findings,
no history of attacks,
no history of remissions,
mild problem with visus
no oligoclonal bands in CSF
normal VEPs, SEPs, ABEPs
subjectivelly she is filling healthy
she is working for full day-time
At present: normal neurological status
2. Diagnostic programme
a) New Brain MRI and new cervical
spinal cord MRI
b) Optical Coherence Tomography (OCT)
c) Neurpsychological Assessment and
d) ADL and QoL Scales
Some studies confirmed that
a) evaluation of changes in morphology and
function of optical nerve by mean of highly
sophisticated methods ( RNFLT, OCT and others)
over time
was likely one of the best approach
to monitor early disease onset and progression
in MS
2. New Brain MRI ( March 26. 2012)
FLAIR tra Rbk
FLAIR Rbk
Brain MRI T2 weigted and Flair.
16 brain MRI lesions interpreted as demyelinating. After Gd no symptoms of
activity, no expansion, no perifocal edema.
Conclusions, the same findings comparing to MRI( 2011),
After Gd: no symptoms of infammation, no cortical atrophy
3. New Cervical Spinal Cord MRI
MRI of Cervical part of spinal cord.
MRI :one lesion (hyperintense signal) in
C2/C3, 23 × 5 mm, without expansion,
without perifocal edema and without
activity after Gd
Conclusions:
the same
findings
comparing to 2011
Do we know
Diagnostic Criteria for RIS ?
Comparison
of these Criteria
with the results
of our patient
Diagnostic criteria for the RIS
A. MRI criteria:
1. Ovoid, well-circumscribed. and
homogeneous foci with or without
involvement of the corpus callosum
2. T2 hyperintensities measuring >3 mm and
fulfilling Barkhoft criteria (at least 3 out of
4) for dissemination in space and time
3.CNS white matter anomalies not
consistent with a vascular pattern
B. No history of remitting clinical
symptoms consistent with
neurologic dysfunction
C. The MRI anomalies do not
correlate
1. with impairments in social,
2. in occupational, or
3. generalized areas of functioning
D. The MRI anomalies are not due to
1. the direct physiologic effects of substances
(recreational drug abuse, toxic exposure)
2. or a medical conditions
E. Exclusion of individuals
1. with MRI phenotypes suggestive of
leukoaraiosis
2. or extensive white matter pathology lacking
involvement of the corpus callosum
Our patient fulfils all these criteria
BUT
BUT
There exist another possibility for explaining
our main question:
1. Optical Coherence Tomography
2. Neurpsychological Assessment and
3. ADL and QoL Scales
4. Optical Coherence
Tomography
OCT (healthy subject
OCT MS patient
5. Neuropsychological
Assessment
1. London Handicap Scale: 6 points MS has no
infuence on social life of patient
2. Fatigue Severity Scale 28/63 points (mild
signs of fatigue)
3. Montreal Cognitive Assesment (MCCA) 28/30
points (normal findings, without cognitive
impairment)
4. Intrelect Potential Test (IPT) 20/29 points
(normal findings, time perception takes as
a stress)
5. Wechsler Memory Scale MQ=101, mild deficit
in logical memory
6. Rey Complex Figure
7. Disjunctive Reaction Time (DRT)
56/60 pointsperfect working tempo
8. Hospital Anxiety and Depression Scale
Anxiety Scale ´10 points,
Depression Scale = 2 points
9. Beck Depression Inventory 5/63
points, normal
10. Eisenck Personality Inventory
Extravesion Scale=10/24,
Neurotiscism Scale =19/24,
11. Sensefulness Life Scale
76/90 point
12. MSQOL-54 Škala kvality života
79/100
13. Physical Health Composit Score 82
14. Mental health Composite Score 76
15. ADL for MS 6 points (independant during
activity of daily living
Summarising:
all neuropsychological parameters
showed normal findings
COMMENT- DISCUSSION
In 2009, Okuda and colleagues" introduced
the term
“radiologically isolated syndrome” (RIS)
to describe patients who have
a) brain MRI abnormalities
b) suggestive of MS
but
c) who have no signs or symptoms of the disease.
d) without clinical evidence of MS
that ful- filled at least 3 of 4 Barkhof criteria.
Table. 1. Barkhof–Tintore
criteria
for anatomic dissemination by brain
MRI (greatest accuracy in predicting clinically
definite MS achieved with ≥3positive parameters)
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1.
At least one or more Gd enhancing lesions
or nine T2 hyperintense lesions if there is
no Gd enhancing lesion
2.
At least three or more periventricular lesions
3.
At least one or more infratentorial lesions
4.
At least one or more juxtacortical lesions
5. one or more spinal cord lesions (revisited
July 2011)
Two years later (2011) the same
authors described a retrospective study
of 71 subjects with RIS
who had cervical MRI scans performed.
•
35 % of the subjects with RIS had T2
hyperintensities in the cervical cord, and
•
84 % of these subsequently developed a CIS.
This study suggests that
1. pts who have RIS and
2. spinal cord T2 hyperintensities
3. may be at high risk of developing MS
while
4. those without spinal cord abnormalities
may have a very low risk.
5. This is an important re-definition of the
concept of RIS as a risk factor for developing
MS and may prove to be important for decision
for an early treatment of MS (Tinton 2006)
However,
a large prospective study is needed to delineate
accurately the natural history of RIS
This contribution
revisited
“the term RIS”
BUT despite of this,
the decision is not easy.
How are the possibilities
for right decision?
There are some
key points
1. to find new parameters which can
contribute to decision
new clinical or
radiological findings which can
2. to find
bring new dimension for more precise
diagnosis of MS
3. to find new approach which can
increase the accuracy of MS diagnosis
The first key point.
It is well known that
the basic characteristic of all diagnostic
criteria for MS
require
the demonstration of disease
dissemination
in space and time.
i.e. the confirmation
of two or more clinical attacks,
separated in time,
which involve
at least two separated areas
of the CNS (space).
Moreover,
CNS is not only brain but also
spinal cord
Therefore we have performed
MRI of the cervical spinal cord
and we have confirmed hyperintensities
in cervical spinal cord. This means
a) this parameter can contribute to the
decision
BUT
a) it doesn´t mean that it has to
confirmed the possibility of
subsequent MS.
b) This is very important to know
Why would spinal cord lesions
in RIS
have such a strong influence
on the risk of developing
symptomatic demyelinating
disease?
Because
demyelinating brain lesion can occur in
a variety of conditions
•
migraine,
•
age related changes,
•
asymptomatic cerebrovascular disease,
•
boreliosis,
•
others (not associated with age),
THEREFORE
an assumption that the brain abnormalities in RIS
represent areas
of demyelination associated with MS
is not warranted.
WHY?
The Barckroft criteria were developed as
a means of predicting
which patients with a first clinical
demyelinating event
were
at high risk of developing MS
and not to differentiate
MS from other causes
of white matter abnormalities.
OUR OPINION
RIS is heterogenic syndrome
(not simply presymptomatic MS)
consisting of pts
1. with MRI demyelinatig BRAIN lesions
!!!
a) without clinical neurologic correlation
b) without significant influence
c) on functional health of subject
AND/OR
2. with MRI demyelinatig BRAIN and
also SPINAL CORD lesions!!!
a) and therefore with possibility to
development of typical MRI
symptoms of MS
BUT
b) without clinical neurologic
correlation
therefore,
in this group of pts it not possible
to use Barkroft criteria
c) All diagnostic criteria for MS,
including the most recent
McDonald criteria,
require at least
one or two clinical events
consistent with MS, i.e,
disseminated in TIME
and SPACE
The second key point
is the time
of the starting inflammation or
demyelinating processes.
We should find
the marker or clinical sign of the
early
stage of the disease.
There are two possibilities
a) assessment of neuropsychological profil of
pts wit suspected MS.
Cognitive impairment could be the first
symptoms of the pathological changes in
the brain associated with MS
b) assessment of Optical Coherence
Tomography (OCT). Some studies have
employed OCT to evaluate changes in optic
nerv associated with multiple sclerosis
(MS)
c) we have used both these possibilities.
Why?
Approximately 50 % of patients with MS
have
disease-related cognitive deficits.
These deficits significantly interfere
with everyday life activities at home and
at work
and erode quality of life (QoL)
Amato et al (2012) in very well designed
publication reported cognitive impairment of
the same profile as that of RRMS in 27.6
subjects with RIS.
% of
On quantitative
MRI they found
comparable
levels of lesion loads and brain atrophy
a) in subjects with RIS and
b) well-established RRMS.
c) in subjects with RIS, high T1 lesion volume
(σ = 0.526,
p = 0.025)
and low cortical volume (σ = -0.481, p =
0.043)
They were associated with
worse cognitive performance
Figure. MRI data expressed in cm3 in RIS, RRMS, and healthy controls (HCs)
NBV = normalized brain volume; NCV = normalized cortical volume;
T1/LV = T1 lesion volume; T2/LV = T2 lesion volume (Amato et al. 2012)
We have performed in our patient
the comprehensive
assessment of
• psychological profil,
• ADL and
• QoL in our patient.
• This consists of 15 scales.
No significant changes in all
followed parameters were found.
It is well known that
MS can result in a variety of
ophthalmic
disorders, including optic neuritis (ON).
MRI is not sufficient modality for the
detection of
a)
b)
c)
d)
active inflammation,
chronic post-attack neuro-degeneration and
the number and volume of clinically silent lesions,
the correlation between lesion quantification
by conventional MRI and morphological and
functional disabilities of optic nerve is relatively
poor.
There exist several
new, highly
sophisticated
techniques (n = 5) for quantitative evaluation of
optic nerve:
a) peri-papillary retinal nerve fibre layer
thickness (RNFLT),
b) macular volume changes with a variety of
techniques,
such as red-free fundus photography,
c) scanning laser polarimetry,
d) Heidelberg retinal tomography or
e) optical coherence tomography
(OCT, Sic et al. 2010)
From this point of view, it seems to be
very useful
to include one of above mentioned
technique in the algorhythm of
diagnostic decision of RIS ,
We have used OTC.
The results clearly demonstrated the pathological
changes on OTC comparing to controls (see figure)
BUT
the results are limited by another
disease
of the patient “Dysplasia of optic
nerve”.
Therfore
it is very difficult to take this
parameter
as contributing factor for MS
1st QUESTION
Should we treat
pts with RIS (with only MRI brain
lesions) according to MS
guidelines?
ANSWER
1. we should not treat pts with RIS
without MRI spinal cord lesions
WHY?
a) The pts without spinal cord lesions
appear
to have a low risk of
developing MS
b) They are more likely to have another
explanation for their brain MRI
abnormalities
2nd QUESTION regarding therapy
What about the pts with RIS and
a)
b)
c)
d)
e)
MRI brain and spinal cord lesions
Gd enhancement,
brain atrophy,
T1 hypo intensities,
new lesions that might be suggestive
of presymptomatic MS?
Should we treat such pts?
ANSWER
1. Not to treat such patients,
WHY?
because
a) all these findings are laboratory
findings
b) there are no neurological symptoms
Moreover
c) there exist some other markers, they can
contribute to decision
Optical Coherence Tomography or
other parameters of morphology and function of
optic nerve (they can show eary changes of optical
nerve)
3rd QUESTION
1. Should we wait?
BUT
waiting can be associated
with the delay of therapy
Treating asymptomatic pts
based on
MRI
"suggestive of MS"
without prospective natural history
data
is no clever decision.
We treat the patient,
not the MRI scan !!!!
FINAL QUESTION
1. What to do with someone in whom
a) there were identified pathologies that are
very suspicious for MS
b) in whom MRI scan progresses over time?
ANSWER
We have no rights that anything what
we do,
is right decision
Moreover,
„we have not the right to say an individual
with RIS who has collected more MRI lesions
that he/she has MS"
And also,
we cannot advocate and recommend
DMT therapies,
because
we don't know to what extent this
diagnosis and this therapy will influence the
disease and, above all, the expectations of
future life of patient.
Conclusions
1. The concept of RIS is an exciting
concept for neurologists, showing
patients with evidence of MRI lesions, their
dissemination in time and space without
clinical correlations,
2. Discussion and decision,
a) if it is early sign of MS and , therefore to treat it
or
b) if it is not early sign of MS and therefore not to
treat it,
is not easy.
3. MRI of spinal cord can help and should be
performed not only in every subject with
suspected MS but also in every „patient“
with RIS (brain MRI) without clinical
correlation
4. The best solution, to perform
a) quantatative evaluation of brain volume and
cortical volume
b) to performe very precise and complex
evaluation of neuropsychological profil
of pts incl. QoL and ADL
c) and all possible inflammatory markers
5. In our opinion, pts showing only time
and space dissemination on MRI
without clinical symptoms and
cognitive impairemnt would
not be considered to have MS
and
therefore not to be treated
We treat the patient,
not the MRl scan!!!
Thank you
very much
for
your attention
LIFE is great
miracle,
because it is nonrepetitive