Download The cognitive-motor interference

Donne e Sclerosi Multipla
Problemi cognitivi e sclerosi multipla
Francesco Patti
Jean-Martin Charcot
Second Lecture on Multiple Sclerosis, 1868
There is marked enfeeblement of the memory;
conceptions are formed slowly; the intellectual
and emotional faculties are blunted in their
totality. The dominant feeling in the patients
appears to be a sort of almost stupid indifference
in reference to all things. It is not rare to see
them give way to foolish laughter for no cause,
and sometimes, on the contrary, to melt into tears
for no reason. Nor is it rare, amid this state of
mental depression, to find psychic disorders arise
which assume one or other of the classic forms of
mental alienation.
Long-Standing Misconceptions about Cognition in MS
 Cognitive impairment (CI) is rare in MS.
 CI only occurs in late stage MS or severe MS.
 MS is a white-matter disease and does not affect: 1) brain
volume, 2) gray matter, 3) the cerebral cortex.
 The mental status exam is enough to screening patients for
CI.
 Memory problems reported by MS patients are caused by
stress, anxiety, and/or depression.
 Discussing CI will upset MS patients/families and ruin the
“image” of MS.
Clinical Case
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Rey Test immediate recall 12.5 (nv >28.5)
Rey Test delayed recall 3.6 (nv >4.7)
Rey Test lerning curve 3-4-5-4-4 (nv 4-6-8-9-10)
Rey Test recency effect 57% (nv >19% <61%)
Rey Test recognition 15 correct – 12 false (nv ≥11 correct ≤2 false)
Digit span 4/2 (nv ≥5 /≤3)
Double barrage 6/13 correct 0/67 false (nv 12/13 correct, 0/67 false)
Double time barrage 180 sec.
Verbal fluency 12.1 (nv ≥17.35)
Stroop test T: 85.3 sec (nv ≤36.92)
Stroop test E: 5.2 (nv ≤4.24)
Clinical Case
Multiple sclerosis and cognition - basic facts
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20-70% of all MS patients suffer from cognitive impairment
(Bobholz et al. 2003; Patti 2009)
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Remarkable impact on social and occupational functioning and
QoL
(Rao et al.1991, Amato et al. 1995, Langdon et al. 1999, Hakim et al. 2000, Patti et al. 2011; Patti et al. 2012)
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Modest correlation with T2 burden, MT ratio and atrophy
(Rao et al. 1989, Huber et al. 1992, Rovaris et al. 1998, van Buchem et al. 1998, Filippi et al. 2000, Zivadinov et al. 2001;
Amato et al. 2004, 2007, Patti et al. 2009, Bastianello et al. 2011; Benedict et al. 2011, Filippi et al., 2013)
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Significant correlation with MRI cortical pathology
(Calabrese et al. 2007, 2009; Gallo et al. 2010)
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DMDs are effective in reducing cognitive impairment
(Fisher et al. 2000; Kappos et al. 2007, Patti et al. 2009, 2010, 2013)
Prevalence of cognitive impairment in MS
Rao et al., 1991
Patti et al, submitted
Peyser et al., 1986
Bertrando et al., 1983
Minden et al., 2006
Heaton et al., 1985
43%
44%
54%
55%
56%
56%
Parsons et al., 1957
60%
60%
64%
65%
De Smedt et al., 1984
65%
Lyon-Caen et al., 1986
Staples & Lincoln, 1979
Rao et al., 1984
Neuropsychological profile
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Frequency of impairment in 291 patients with MS by
cognitive domain
60
% of patients impaired
50
40
30
20
10
0
Fluency
VisuoImmediate Delayed
spatial
Verbal memory
perception
Benedict RHB et al. J Int Neuropsychol Soc. 2006;12:549-558.
Immediate Delayed
Visual memory
Working
memory/
speed
Processing Concept
speed
formation
Clinical correlates of cognitive impairment
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Disease duration and EDSS
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Mild to moderate correlations. Cognitive deficits also found
in
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Disease subtype
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early RRMS
probable MS
CIS
CIS < RR < SP > PP
“Benign MS”
Frequently associated with
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fatigue
depression
Patti F, Mult Scler 2009
Cognitive Impairment follow-up study
The percentage of people without
cognitive impairment gradually
decreases over a ten year period.
Impaired at Baseline:
• 26%
Impaired after 10 Years:
• 56%
Predictors of CI after 10 years:
• Higher EDSS
• Progressive course
• Older age
Adapted from Amato, MP et al, Archives of Neurology
2001;58:1602-1606.
Preclinical
CIS
RRMS
SPMS
?
Clinical
threshold
Atrophy and
axonal
degeneration
Cognitive deficits
Number of lesions
MRI lesion activity
?
Total lesion load
(T2 lesion volume)
Adapted from Trapp BD, et al. The Neuroscientist. 1999;5:48-57.
Simon JH Mult Scler 2006
Many factors can affect cognitive
functioning
Fatigue
Tiredness
Emotional
changes
Medications
Relapses
Permanent
Brain Lesions
Physical
Restrictions
Image retrieved by MS in Focus Cognition in MS, July 2013
Lifestyle
Changes etc.
Cognitive reserve and cortical atrophy
in multiple sclerosis
Brain atrophy
CRI
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Education
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Premorbid leisures activities
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IQ
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Normalized total brain
volume
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Normalized cortical volume
Progressing cortical atrophy and older age were the
only predictors
of deteriorating cognitive performance
An interaction between CRI and normalized cortical
volume predicted better cognitive performance
Amato et al. Neurology 2013
The Psychosocial Impact of Cognitive Changes
The ability to think, remember, and reason is central to a person’s identity.
Changes in cognitive abilities:
•Threaten the sense of self
•Damage self-esteem and self-confidence
Cognitive abilities form the basis of our interactions with others.
Cognitive impairments:
•Alter communication patterns
•Impact other people’s perceptions
•Interfere with role performance
•Affect the balance in a partnership
LaRocca & Kalb, 2006
The Impact of Cognitive Dysfunction in Daily Functioning
Patients with CI had significantly worsen scores at:
• Work status
• Social activity
• Personal assistance
45
40
% Employed
35
30
25
20
15
10
5
0
Rao et al. Neurology. 1991;41:692; Patti et al., Q Life Res 2012
Impaired
Not Impaired
The three tests as recommended by
BICAMS
SDMT
CVLT-II
BVMT-R
Investigations with DMDs to date*
Compound
Study
N
Cognitive tests
Publication
Interferon beta 1b
Subgroup of IFNB-1b pivotal trial, single
center, RRMS
30/372
Battery
Pliskin et al, Neurology, 1996
Interferon beta 1b
BENEFIT follow-up, CIS
358/468
PASAT as part of
MSFC
Kappos et al, Lancet Neurol 2009
Im interferon beta
1a
Subgroup of Avonex pivotal trial, RRMS
166/276
Battery
Fischer et al, Ann Neurol 2000
Interferon beta 1a
Impact study (Avonex 60 mcg in SPMS)
436
PASAT as part of
MSFC
Cohen et al, Neurology 2002
Sc interferon beta
1a
RRMS Cohort
550
331
BRB-N
Patti et al, Mult Scler, 2010, Plos One
2013
Glatiramer acetate
GA pivotal trial, RRMS
10-Years Follow-up
251
BRB-N
Weinstein et al, Arch Neurol, 1999
Schwid et al., J Neurol Sci 2007
Glatiramer acetate
vs INF
3-Year Follow-up
823
BRB-N
Falautano et al., ECTRIMS 2009
Interferon beta 1b
Subgroup of EU-SPMS study
196/718
BRB-N
Unpublished, abstract by Langdon et
al., ECTRIMS 2002
Natalizumab
AFFIRM, RRMS
627
Observational study
100
PASAT as part of
MSFC
CII
Unpublished, abstract by Galetta et al.
WCN 2005
Iaffaldano et al., Plos One 2013
Natalizumab
Observational study RRMS
660
SDMT & MSNQ
Morrow et al., Mult Scler 2012
Fingolimod
TRANSFORMS, RRMS
1292
PASAT as part of
MSFC
Unpublished, data available from FDA
background package 2010
Laquinimod
Allegro, RRMS
1106
MSFC
Comi et al., NEJM 2012
*only studies including more than 100 patients listed. Not all studies reported results favoring treatment
23
IFN β-1a (sc)
22 μg or 44 μg
tiw [76]
RRMS
(n= 459)
Prospective,
observational
cohort trial
(COGIMUS)
3 years
5 years
Proportion of
patient with
cognitive
imparment after 3
years, using Rao’s
BRB and Stroop
Color/word Task
Cognitive benefits of
sc IFN β-1a, which
may be dose
dependent
No placebo
control group,
treatment
groups were
randomized
Cognitive Rehab - Definition
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Cognitive Rehab is a systematically applied set of
therapeutic services designed to improve cognitive
functioning and participation in activities that may be
affected by difficulties in one or more cognitive domains
It is often part of a multidisciplinary comprehensive
program
It is based on scientific theoretical constructs
Computerized and behavioural interventions
Strategic approaches
Cognitive Rehab. – Why?
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Neuroplasticity: it refers to changes in neural pathways and
synapses which are due to changes in behavior, environment and
neural processes, as well as changes resulting from bodily injury
It is an umbrella term that encompasses both synaptic plasticity
and non-synaptic plasticity
Neuroplasticity challenges the idea that brain functions are fixed
in certain locations
Filippi et al, 2007
Cognitive Rehab. – Why?
Treatment of Cognitive Dysfunction
Symptomatic Cognitive rehabilitation: Disease modifying
treatments Computerized interventions
agents
or
Behavioural Interventions
Take home messages
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Cognitive impairment is frequent and can drive
therapeutic choice
It depends on brain lesions and brain atrophy
Therapy enhancers do not improve cognitive
performances
Etiologic therapies may soften cognitive decline
Cognitive reserve may increase the effects of etiologic
therapies
Combination therapies: etiologic, cognitive rehabilitation
and gamification could enhance cognitive functioning
Women are more protected than men in the
development of cognitive impairment