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Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis
NEUROL-881; No. of Pages 10 revue neurologique xxx (2012) xxx–xxx
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Recommendations
Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis Recommandations pour la de´tection et la prise en charge the´rapeutique des troubles cognitifs dans la scle´rose en plaques C. Bensa a,*, E. Bodiguel b,c, D. Brassat d, D. Laplaud e,f, L. Magy g, J.-C. Ouallet h, H. Zephir i, J. De Seze j,k, F. Blanc l,m a
Fondation Rothschild, service de neurologie, 25-29, rue Manin, 75019 Paris, France Poˆle urgences–re´seaux, hoˆpital europe´en Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France c Service de neurologie, centre hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France d Poˆle des neurosciences, Inserm U1043, universite´ Toulouse III, hoˆpital Purpan, place du Docteur-Baylac, BP 3028, 31024 Toulouse cedex 3, France e Service de neurologie, CHU de Nantes, 85, rue Saint-Jacques, 44093 Nantes cedex 1, France f Inserm UMR643, faculte´ de me´decine de Nantes, 30, boulevard Jean-Monnet, 44093 Nantes cedex 1, France g Service de neurologie, CHU de Limoges, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France h Poˆle des neurosciences cliniques, universite´ de Bordeaux-Segalen, CHU de Bordeaux Pellegrin-Tripode, place Emilie-Raba-Le´on, 33076 Bordeaux cedex, France i Poˆle de neurologie, universite´ Lille Nord-de-France, hoˆpital Roger-Salengro, CHRU de Lille, rue E´mile-Laine 59037 Lille, France j Service de neurologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), CHU de Strasbourg, faculte´ de psychologie, 12, rue Goethe, 67000 Strasbourg, France k CNRS, centre d’investigation clinique (CIC) de Strasbourg, universite´ de Strasbourg, 1, place de l’Hoˆpital, 67091 Strasbourg cedex, France l Service de neuropsychologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), de´partement de neurologie, CHU de Strasbourg, faculte´ de psychologie, 12, rue Goethe, 67000 Strasbourg, France m Service de neurologie, CNRS, centre me´moire de ressources et de recherche (CMRR), hoˆpital de Hautepierre, universite´ de Strasbourg, avenue Molie`re, BP 49, 67098 Strasbourg cedex, France b
info article
abstract
Article history:
The aim of the Multiple Sclerosis Think Tank (Groupe de re´flexion sur la scle´rose en plaques
Received 11 October 2011
[GRESEP]) is to prescribe recommendations following a systematic literature search and
Received in revised form
using a Rand Corporation and California University (RAND/UCLA) appropriateness derived
7 February 2012
method, in response to practical questions that are raised in the management of patients
Accepted 13 February 2012
with multiple sclerosis (MS). The topics of this working program were chosen because they were not addressed in the French recommendations and because of the few data in the literature that enabled practices to be based on validated data. Following the theme on useful serum testing with suspected multiple sclerosis, the subjects of the present work
Keywords :
concern the detection and management of cognitive impairment in the beginning stages of
Multiple sclerosis
the disease course. Two clinical questions were asked: which complementary exams
Cognitive disorders
(besides physical examination and neuropsychological tests) would help in the screening
Practice guideline
of cognitive impairment at the beginning of the disease? What care management should the
* Corresponding author. E-mail address : [email protected] (C. Bensa). 0035-3787/$ – see front matter # 2012 Publie´ par Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2012.02.009 Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
NEUROL-881; No. of Pages 10
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revue neurologique xxx (2012) xxx–xxx
RAND/UCLA appropriateness
person with MS and cognitive impairment be offered (treatments and neurocognitive
method
rehabilitation)? The recommendations are the result of a consensus amongst a working
Review
group, a rating group and a reading group comprised of hospital neurologists involved in the management of patients with multiple sclerosis. Each recommendation is presented with
Mots cle´s :
the degree of consensus that it was accorded. # 2012 Published by Elsevier Masson SAS.
Scle´rose en plaques Troubles cognitifs Recommandations de pratique clinique Consensus formalise´ d’experts Revue
r e´ s u m e´ L’objectif du Groupe de re´flexion sur la scle´rose en plaques (GRESEP) est de formuler des recommandations, apre`s une analyse syste´matique de la litte´rature et en utilisant la me´thode du consensus formalise´ d’experts, en re´ponse a` des questions pratiques qui se posent dans la prise en charge des patients atteints de scle´rose en plaques. Les the`mes de ce programme de travail ont e´te´ choisis parce qu’ils n’e´taient pas traite´s dans les recommandations francophones. Le pre´sent article porte sur la de´tection et de la prise en charge des troubles cognitifs au de´but de l’e´volution de la maladie. Les recommandations re´pondent a` deux questions cliniques : quels examens comple´mentaires permettent d’aider au de´pistage des troubles cognitifs au de´but de la maladie (hors examen clinique et tests neuropsychologiques) ? Quelle prise en charge proposer au patient SEP atteint de troubles cognitifs (traitements et neuro-reme´diation cognitive) ? Les recommandations sont le fruit d’un consensus au sein d’un groupe de travail, d’un groupe de cotation et d’un groupe de lecture forme´s de neurologues hospitaliers implique´s dans la prise en charge de patients atteints de scle´rose en plaques. Chaque recommandation est expose´e avec le degre´ de consensus dont elle a fait l’objet. # 2012 Publie´ par Elsevier Masson SAS.
1.
Objectives
The Multiple Sclerosis Think Tank (Groupe de re´flexion sur la scle´rose en plaques [GRESEP]) is a working group made up of hospital neurologists that are involved in multiple sclerosis (MS). Its members were chosen by Jerome de Se`ze, on the criterion of expertise in managing this pathology. The general objective of GRESEP is to guide deliberation on questions raised in practice with regard to MS, some of which were slightly developed during the 2001 Consensus Conference (Fe´de´ration franc¸aise de neurologie, 2001) or which had conceptually evolved since this date. Following the theme of useful serumtestingwith suspected MS (Ouallet et al., in press), we present recommendations aiming to help in the detection and hospital management of cognitive impairment in the early course of MS in adult patients.
2.
Methods
The methodology used was that of the adaptation of recommendations (Haute Autorite´ de sante´, 2007), then a Rand Corporation and California University (RAND/UCLA) appropriateness derived method (Haute Autorite´ de sante´, 2006) (Table 1). It was explained in detail in our previous work on the theme of serum exams (Ouallet et al., in press). The aim of the recommendations is to respond to the following two clinical questions: which complementary exams (besides physical examination and neuropsychological tests) would help in the screening of cognitive impairment at the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)?
The documentary research strategy is outlined in Fig. 1. A systematic analysis of the literature was done in January 2010 and concerned referenced publications between 1st January 2005 and 31st December 2010. Collaborators in charge of the cognition theme (C. Bensa and F. Blanc) then drafted the recommendation proposals and arguments. The working document was subjected to three cycles of writing – rating – revision. The results of the last rating are summarised in Table 2. One discordant vote could be discarded from the analysis of this last rating. The opinions of the reading group are summarised in Table 3. The steering committee validated the final document that was submitted for publication. Each recommendation is followed by its argument and the degree of consensus amongst the rating and reading groups (Table 4). The French version of the recommendations appears in Table 5. The sponsor attended the working sessions but without possibility of intervention, and participated neither in the choice of the topics, nor in the bibliography selection process, nor in the consensus debates, nor in the rating sessions, nor in writing of the manuscript.
3.
Recommendations
The recommendations aim to respond to two clinical questions: Which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment at the beginning of the disease?
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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Table 1 – Methodology of development of the recommendations. Me´thodologie de de´veloppement des recommandations. Participant
Action
Steering committee
Definition of the clinical questions Which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment in the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? Monitoring of the project with assistance from the methodology group
Working group Cognition subgroup
Analysis of the literature provided by the methodology group Writing the recommendation proposals and arguments Consideration of the opinions of the rating and reading groups
Rating group
Critical reading of the recommendations and the arguments Rating the degree of agreement with the form and the content of each recommendation
Reading group
Critical reading of the recommendations and the arguments Vote (agreement, indecision or disagreement) on each consensual recommendation between the working and rating groups
Steering group: J. De Seze (Strasbourg, President), C. Bensa (Paris), F. Blanc (Strasbourg), D. Brassat (Toulouse), D. Laplaud (Nantes), L. Magy (Limoges), J.-C. Ouallet (Bordeaux), H. Zephir (Lille). Cognition working subgroup: C. Bensa (Paris), F. Blanc (Strasbourg). Rating group: A. Alkhedr (Amiens), O. Anne (La Rochelle), E. Berger (Besanc¸on), O. Casez (Grenoble), I. Coman (Bobigny), M. Coustans (Quimper), N. Derache (Caen), A. Fromont (Dijon), A.M. Guennoc (Tours), P. Lozeron (Paris), S. Pittion (Nancy), F. Rouhart (Brest), E. Thouvenot (Montpellier), S. Wiertlewski (Nantes). Reading group: B. Barroso (Pau), J.-M. Boulesteix (Cahors), C. Clerc (Montbe´liard), R. Colamarino (Vichy), T. De Broucker (Saint-Denis), J.M. Faucheux (Agen), D. Ferriby (Tourcoing), C. Gaultier (Colmar), E. Godet (Metz-Thionville), J. Grimaud (Chartres), O. Heinzlef (Poissy), C. Henry (Saint-Denis), O. Ille (Mantes-la-Jolie), P. Lejeune (La Roche-sur-Yon), E. Manchon (Gonesse), M. Marcel (Lens), M. Merienne (Saint-Malo), L. Nahum-Moscovici (Aulnay-sous-Bois), C. Renglewicz (Colmar), A. Verier (Valenciennes), M. Wagner (Metz-Thionville). Methodology group: E. Bodiguel (Paris), N. Charbonnier (Paris), N. Freynet (Paris).
What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)?
4. Clinical question 1: which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment at the beginning of the disease? It’s necessary to follow three recommendations below: Recommendation 1.1. There is no complementary exam that replaces neuropsychological assessment for the screening of cognitive impairment (strong professional agreement); Recommendation 1.2. A significant lesion load on brain MRI must prompt the clinician to consider the existence of cognitive impairment in relapsing-remittent MS. Lesion load and cognitive impairment in an individual however are not necessarily related (strong professional agreement); Recommendation 1.3. The existence of cerebral atrophy, particularly enlargement of the third ventricle on brain MRI, must prompt the clinician to consider the existence of cognitive impairment in relapsing-remittent MS (relative professional agreement).
4.1.
Recommendation 1.1
On an individual level, there is no complementary exam that exhibits a sufficiently strong correlation with cognitive testing,
and there have been no studies specifically addressing this question. None of the following exams are sufficiently correlated to the results of neuropsychological testing to replace it: modification of focal or global cortical volume (Amato et al., 2007; Calabrese et al., 2009, 2010); modification of thalami volume (Houtchens et al., 2007); T1 hyposignal or T2 hypersignal lesion load; or focal or global cerebral volumetry (Benedict et al., 2004; Calabrese et al., 2009; Comi et al., 2000; Lazeron et al., 2005; Rao et al., 1989; Summers et al., 2008; Tiemann et al., 2009). Thus according to Lazeron et al. (2005), atrophy and lesion load only account for 10 to 25% of neuropsychological test variance. Several teams found significant relations between cortical lesion number and cognitive impairment (Nelson et al., 2011; Roosendaal et al., 2009). Other non-conventional MRI measures as magnetization transfer (MT) imaging may detect early tissue changes related to cognitive deficit (Deloire et al., 2011; Khalil et al., 2011). One objective of theses recommendations is their applicability in ordinary practice; so only routinely available MRI sequences (T1, T2, FLAIR–T2) have been retained for their writing.
4.2.
Recommendation 1.2
For this recommendation, lesion load does not require an automatic quantification but is led to the examinator’s appreciation. Several articles have found a correlation between lesion load on MRI and cognitive impairment. Rao et al. (1989) showed, in 53 patients with all types of MS, a link between total surface area of the lesions and memory, language, reasoning and visuo-spatial abilities. In 37 MS patients, Benedict et al. (2004) found a correlation between
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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BIBLIOGRAPHIC RESEARCH ON INTERNET
FRANCOPHONE AND ANGLOPHONE RECOMMENDATIONS
Internet sites of publication of recommendations and consensus: 152 references
Medline document database: 43 references
PUBLICATIONS WITH PEER-REVIEWING
Medline document database : 361 references
First selection on title and clinical topics addressed: 34 references
First selection on title and abstract: 85 references
Selection on quality criteria: 1 reference
Selection on reading grid: 41 references
atrophy of the thalami (Houtchens et al., 2007). Visual measurement of the third ventricle however is not very reliable. Decreased cerebral volume at 1 year of progression is correlated with the existence of cognitive impairment at 5 years (Summers et al., 2008). In addition, there is a distinct correlation between overall cortical thickness and cognitive impairment (Amato et al., 2007; Calabrese et al., 2010).
5. Clinical question 2: what care management should the person with multiple sclerosis (MS) and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? It’s necessary to follow three recommendations below:
Publications added by the experts: 24 references
Fig. 1 – Document selection strategy. 1: Keywords used: Clinical question 1: ‘‘Multiple Sclerosis’’ [Mesh] and ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ diagnosis’’ [Mesh] not ‘‘Psychological Tests’’ [Mesh]. Clinical question 2: ‘‘Multiple Sclerosis’’ [Mesh] and ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ drug therapy’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/prevention and control’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ rehabilitation’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/therapy’’ [Mesh] not ‘‘Terminal Care’’ [Mesh]. Strate´gie de se´lection documentaire. Date of Medline database search: 18th January 2010. Research of referenced publications between 1st January 2005 and 31st December 2010.
lesion load and the Symbol Digit Modalities Test ([SDMT] information processing speed). Other studies have had similar results, such as those of Arnett et al. (1994), Lazeron et al. (2005), Rovaris et al. (1998), and Swirsky-Sacchetti et al. (1992). In 56 patients in the early stage of the relapsing-remittent form, Deloire et al. (2005) showed that there was a correlation between lesion load, on the one hand, and SDMT and Paced Auditory Serial Addition Test ([PASAT] working memory, attention, processing speed) on the other, but not with memory tasks (Selective Reminding Test [SRT], 10/36) or tasks exploring inhibition abilities (Go-no-Go and Stroop). This correlation was not found by all the teams however, particularly in 92 patients with a clinically isolated syndrome (Glanz et al., 2007). Cognitive impairment is possible with a low lesion load, and such cases were found in most of the previously cited studies.
4.3.
Recommendation 2.1. There is no symptomatic drug treatment to date that has proven to be effective on cognitive impairment. Consequently, the prescription of symptomatic treatment is not recommended when cognitive impairment is diagnosed in patients with MS (strong professional agreement); Recommendation 2.2. On an individual basis, cognitive rehabilitation techniques may be beneficial (relative professional agreement); Recommendation 2.3. The existence of cognitive impairment is an additional argument for the establishment of long-term therapy in accordance with the legal conditions of prescription specified by the product licence (relative professional agreement).
5.1.
Recommendation 2.1
5.1.1.
Acetylcholinesterase inhibitors
The current data are insufficient for recommending acetylcholinesterase inhibitors (AChEI) in the treatment of cognitive impairment in MS. There is one single-centre, randomised, double-blind study available on donepezil in 69 patients (Krupp et al., 2004), which lacked external validation and had unequal groups due to the small population. There was also one single-centre, randomised, double-blind study on rivastigmine in 60 patients, which had negative results (Shaygannejad et al., 2008). As different review articles concluded (Amato et al., 2008; Christodoulou et al., 2008; Crayton and Rossman, 2006; Porcel and Montalban, 2006), additional studies must be done on larger cohorts. Considering the possible side effects of AChEI, it is recommended that these drugs should not be used in this situation without a sufficient level of proof of efficacy. Since this work, a new multicenter study, double-blind against placebo, has been published by Krupp et al. (2011). One hundred and twenty participants were enrolled and randomized and no significant treatment effect was found between groups.
Recommendation 1.3 5.1.2.
For this recommendation, atrophy does not require an automatic quantification but is led to the examinator’s appreciation. There is a correlation between cognitive impairment and increased volume of the third ventricle (Benedict et al., 2004, 2006; Tiemann et al., 2009), probably related to
Memantine
The current data are insufficient for recommending the use of memantine in the treatment of cognitive impairment related to MS. Two studies have been published: one on 60 patients (Villoslada et al., 2009), which was prematurely discontinued due to worsening of neurological symptoms in some of the
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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Recommendation No.
1.1
1.2
1.3
2.1
2.2
2.3
Quality criteria
Median
Opinion of the group
Maximum rating
Minimum rating
Degree of agreement
Easy to understand
9.0
Appropriate formulation
9
8
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
8
Strong agreement between group members
Sufficient
9.0
Sufficient recommendation
9
5
Relative agreement between group members
Easy to understand
9.0
Appropriate formulation
9
7
Strong agreement between group members
Useful
8.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
8.0
Sufficient recommendation
9
5
Relative agreement between group members
Easy to understand
9.0
Appropriate formulation
9
6
Relative agreement between group members
Useful
7.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
7.0
Sufficient recommendation
9
5
Relative agreement between group members
Number of discordant votes revue neurologique xxx (2012) xxx–xxx
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
Table 2 – Third rating of recommendation proposals. Troisie`me cotation des propositions de recommandations.
Easy to understand
9.0
Appropriate formulation
9
9
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
8
Strong agreement between group members
Sufficient
9.0
Sufficient recommendation
9
8
Strong agreement between group members
Easy to understand
9.0
Appropriate formulation
9
6
Relative agreement between group members
Useful
8.5
Appropriate recommendation
9
5
Relative agreement between group members
1 rating at 2
Sufficient
7.0
Sufficient recommendation
9
5
Relative agreement between group members
1 rating at 4
Easy to understand
9.0
Appropriate formulation
9
7
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
9.0
Sufficient recommendation
9
6
Relative agreement between group members
5
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Table 3 – Analysis of returns from the reading group. Analyse des retours du groupe de lecture. Recommendation No. 1.1 1.2 1.3 2.1 2.2 2.3
Number of agreements
Number of disagreements
Number of undecided
% agreements
Number of votes
20 19 17 20 16 17
0 1 1 0 0 1
0 0 2 0 4 2
100.0 95.0 85.0 100.0 80.0 85.0
20 20 20 20 20 20
treated patients; and the other, more recent, on 126 patients, with negative results (Lovera et al., 2010).
need for controlled studies. It is an open-label exploratory study (phase I/II) in eight patients with progressive MS.
5.1.3.
5.1.4.
Erythropoietin
The current data are insufficient for recommending the use of erythropoietin in the treatment of cognitive impairment related to MS. Only one pilot study is available (Ehrenreich et al., 2007), which demonstrates the feasibility of the treatment and the
Amphetamines
The current data are insufficient for recommending the use of amphetamines in the treatment of cognitive impairment related to MS. Only two studies were available at the time of this review: one pilot study on 19 patients (Benedict et al., 2008),
Table 4 – Criteria for attribution of the grade of each recommendation. Crite`res d’attribution du grade de chaque recommandation. Level of scientific proof
Grade of recommendation
Level 1 Randomised controlled trials with large sample size Meta-analyses
A
Level 2 Randomised controlled trials with small sample size
B
Level 3 Contemporary non-randomised controlled trials Cohort studies
C
Level 4 Controlled trials with historical controls Level 5 Case series Absence of scientific proof
Professional agreement
Determination of the degree of consensus in cases of professional agreement Rating
Degree of validation by the rating group
% of agreement within the reading group
Degree of professional agreement (synthesis of the opinions of the rating and reading groups)
Median between 7 and 9 for each of the 3 rating criteria Less than 2 ratings < 7 for each of the criteria Median between 7 and 9 for each of the 3 rating criteria 2 or more ratings < 7 Less than 2 ratings < 4
Strong consensus
90% Between 80 and 90%
Strong professional agreement Relative professional agreement
Relative consensus
Between 80 and 90%
Median < 7 2 or more ratings < 4
Regardless of the degree of consensus
< 80%
Either recommendation to remain and then new rating Or the working group does not give its opinion Or the working group decides to maintain the recommendation, while making clear the lack of consensus within the reading group
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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Table 5 – French version of the recommendations. Recommandations pour la de´tection et la prise en charge the´rapeutique des troubles cognitifs dans la scle´rose en plaques. Question clinique 1 : quels examens comple´mentaires permettent d’aider au de´pistage des troubles cognitifs au de´but de la maladie (hors examen clinique et tests neuropsychologiques) ? Recommandation 1.1. Aucun examen paraclinique ne remplace le bilan neuropsychologique pour de´pister les troubles cognitifs (accord professionnel fort) Recommandation 1.2. Une charge le´sionnelle importante a` l’IRM ce´re´brale doit inciter le clinicien a` s’interroger sur l’existence de troubles cognitifs dans la scle´rose en plaque (SEP) re´mittente. Pour autant, charge le´sionnelle et troubles cognitifs pour un individu ne sont pas force´ment lie´s (accord professionnel fort) Recommandation 1.3. L’existence d’une atrophie ce´re´brale, et en particulier un e´largissement du 3e ventricule a` l’IRM ce´re´brale, doit inciter le clinicien a` s’interroger sur l’existence de troubles cognitifs dans la SEP re´mittente (accord professionnel relatif) Question clinique 2 : quelle prise en charge proposer au patient SEP atteint de troubles cognitifs (traitements et neuro-reme´diation cognitive) ? ` ce jour, aucun traitement me´dicamenteux a` vise´e symptomatique n’a fait la preuve de son efficacite´ sur les Recommandation 2.1. A troubles cognitifs. En conse´quence, il n’est pas recommande´ de prescrire un traitement symptomatique lors du diagnostic de troubles cognitifs chez un patient atteint de SEP (accord professionnel fort) ` l’e´chelle individuelle, il peut y avoir un inte´reˆt a` proposer une technique de reme´diation cognitive Recommandation 2.2. A (accord professionnel relatif) Recommandation 2.3. L’existence de troubles cognitifs est un argument supple´mentaire dans le sens de l’instauration d’un traitement de fond, dans le respect des conditions fixe´es par l’AMM du produit (accord professionnel relatif)
which led the same team to perform a second single-centre study on 155 patients, with negative results (Morrow et al., 2009). In 2011, Sumowski et al. published a post-hoc reanalysis of this previous trial, which seems to demonstrate a beneficial effect on verbal and visuo-spatial memory for patients with baseline memory impairment. Other studies are therefore necessary.
5.1.5.
Methylphenidate
The current data are insufficient for recommending the use of methylphenidate in the treatment of cognitive impairment related to MS. Indeed, only one single-centre, double-blind pilot study versus placebo done on 26 patients is available (Harel et al., 2009). The patients, who presented with attention disorders, were tested before treatment and then 1 hour after treatment with the 3-second PASAT test. The patients on treatment had a 22.8% improvement of the PASAT score versus 4.5% on placebo (non-significant difference).
5.1.6.
Symptomatic treatments of fatigue
The current data are insufficient for recommending the use of symptomatic treatments of fatigue (amantadine, pemoline, 4AP, 3-4 DAP, modafenil) for treating cognitive impairment related to MS. Only small studies are available, the results of which are negative. Two pilot studies suggest an improvement in attention with amantadine (Amato et al., 2006; Pierson and Griffith, 2006).
5.1.7.
Naturopathy
The current data are insufficient for recommending the use of naturopathic medicine in the treatment of cognitive impairment related to MS. Only one study was published, the result of which was negative (Shinto et al., 2008).
5.2.
Recommendation 2.2
As for any rehabilitation technique, the evaluation of neurorehabilitation protocols are subject to many methodological difficulties: the difficulty in obtaining homogenous groups;
difficulty in working blinded; difficulties of evaluation (learning effect, evaluation in terms of tests and not in the real-life setting); and difficulties related to the unknown reproducibility of the methods. Most of the available studies appear promising in terms of efficacy but are not sufficient for establishing strong recommendations (Brenk et al., 2008; O’Brien et al., 2007; Tesar et al., 2005). The team from Nancy recently obtained promising results on memory and executive functions in 24 patients with a neurorehabilitation programme over 6 months (Brissart et al., 2010). This pilot study needs to be confirmed. Neurorehabilitation is a validated technique in patients with traumatic brain injuries (Carney et al., 1999; Lengenfelder et al., 2007; NIH consensus development panel on rehabilitation of persons with traumatic brain and injury, 1999; O’Brien et al., 2007) and in vascular diseases (Cicerone et al., 2000). It includes interventions that are known to improve the efficacy and abilities in activities of daily living, and includes two components. First, ‘‘compensation’’ measures that aim to modify the environment, with evaluation of needs in the real-life setting, of daily living, and the institution of assistive strategies such as keeping a planner, reduction of possible distractions, conversion of the work environment, etc. Second, ‘‘restorative’’, or more correctly rehabilitation, measures, which aim to improve performances by relying on the capacities of plasticity and cortical reorganization — in other words, either exercises targeting deficient domains, exercises that take advantage of preserved domains, or global practice of intellectual functions. Different methods are suggested using software or interviews with individuals or in groups. Several review articles have summarised the available studies and highlighted the interest generated by these methods, which remain to be confirmed by methodologically sound studies (Amato et al., 2008; Lensch et al., 2006; Thompson, 2005). In one of these review articles on the efficacy of neurorehabilitation in 19 selected studies, 16 were found to be of sufficient quality for evaluation (O’Brien et al., 2008). In the end, the authors did not obtain sufficient data for assessing their impact on attention disorders or executive functions. In the domains of learning
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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and memory, the techniques of ‘‘history recall’’ (contextualization, in association with emotional elements and mental imagery) and ‘‘self-generation’’ (self-production of items to remember) appear to have sufficient validation for use in clinical practice (Basso et al., 2006; Goverover et al., 2008). A Cochrane review examined the studies on psychological and neuropsychological interventions in MS (Thomas et al., 2006). The research strategy enabled three studies to be selected in the domain of cognitive impairment, but the authors noted few similarities between them with regard to population, intervention, objectives and the follow-up period. These were small-sized studies, which increased the risk of type II errors, and they focused on too many objectives, thus increasing the risk of type I errors. According to the authors, these works did not enable recommendations to be established. Since we did this review, Cochrane review has been re-actualized and on the basis of 14 studies (770 MS patients), authors conclude to low level of evidence for positive effects of neuropsychological rehabilitation in MS (Rosti-Otaja¨rvi and Ha¨ma¨la¨inen, 2011). With the exception of one discordant voice, this recommendation was validated by the rating group (Table 2). Despite 20% abstention rate, there was no opposition expressed within the reading group (Table 3). As a result, this recommendation, in accordance with that of the ‘‘Multiple Sclerosis Therapy Consensus Group of the German Multiple Sclerosis Society’’ (Henze et al., 2006), was maintained. In France, the lack of trained providers (neuropsychologists and speech therapists) is an obstacle to the application of these methods in practice.
5.3.
Recommendation 2.3
In the absence of validated data, this recommendation is drawn from the clinical expertise of the working group and from expert recommendations (Cohen, 2008; Crayton and Rossman, 2006; Defer et al., 2007; Patti, 2009; Tumani and Uttner, 2008; Winkelmann et al., 2007). The studies on interferons show a trend towards improvement of cognitive impairment, but they need to be confirmed. In the proof of principle studies of immunomodulators (Ebers, 1998; Jacobs et al., 1996; Johnson et al., 1995; The IFNB multiple sclerosis study group, 1993; Thompson, 2005), cognition was not included in the primary objectives. In the secondary objectives and in small studies, interferons seem to provide beneficial results on neuropsychological tests. Some open-label studies on immunosuppressants also appear to show a positive effect of these long-term treatments on cognitive impairment (Ze´phir et al., 2005, 2008). In addition, several recent studies (Deloire et al., 2010; Zipoli et al., 2010) confirm that the presence of cognitive impairment at the early stage of the disease is a negative prognostic factor with regard to clinical conversion and longterm disability. The detection of cognitive impairment in this case could be an additional argument for starting a long-term therapy. However, the prevention of long-term disability through the treatments has not been clearly demonstrated.
Acknowledgements We wish to gratefully acknowledge the members of the rating and reading groups (Table 1), for their contribution to the
present work, and Mrs. Guiquerro, Director of the university hospital library of Hoˆpital europe´en Georges-Pompidou (Paris), for her advice in documentary research.
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Recommendations
Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis Recommandations pour la de´tection et la prise en charge the´rapeutique des troubles cognitifs dans la scle´rose en plaques C. Bensa a,*, E. Bodiguel b,c, D. Brassat d, D. Laplaud e,f, L. Magy g, J.-C. Ouallet h, H. Zephir i, J. De Seze j,k, F. Blanc l,m a
Fondation Rothschild, service de neurologie, 25-29, rue Manin, 75019 Paris, France Poˆle urgences–re´seaux, hoˆpital europe´en Georges-Pompidou, 20, rue Leblanc, 75015 Paris, France c Service de neurologie, centre hospitalier Sainte-Anne, 1, rue Cabanis, 75014 Paris, France d Poˆle des neurosciences, Inserm U1043, universite´ Toulouse III, hoˆpital Purpan, place du Docteur-Baylac, BP 3028, 31024 Toulouse cedex 3, France e Service de neurologie, CHU de Nantes, 85, rue Saint-Jacques, 44093 Nantes cedex 1, France f Inserm UMR643, faculte´ de me´decine de Nantes, 30, boulevard Jean-Monnet, 44093 Nantes cedex 1, France g Service de neurologie, CHU de Limoges, 2, avenue Martin-Luther-King, 87042 Limoges cedex, France h Poˆle des neurosciences cliniques, universite´ de Bordeaux-Segalen, CHU de Bordeaux Pellegrin-Tripode, place Emilie-Raba-Le´on, 33076 Bordeaux cedex, France i Poˆle de neurologie, universite´ Lille Nord-de-France, hoˆpital Roger-Salengro, CHRU de Lille, rue E´mile-Laine 59037 Lille, France j Service de neurologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), CHU de Strasbourg, faculte´ de psychologie, 12, rue Goethe, 67000 Strasbourg, France k CNRS, centre d’investigation clinique (CIC) de Strasbourg, universite´ de Strasbourg, 1, place de l’Hoˆpital, 67091 Strasbourg cedex, France l Service de neuropsychologie, laboratoire d’imagerie et de neurosciences cognitives (LINC), de´partement de neurologie, CHU de Strasbourg, faculte´ de psychologie, 12, rue Goethe, 67000 Strasbourg, France m Service de neurologie, CNRS, centre me´moire de ressources et de recherche (CMRR), hoˆpital de Hautepierre, universite´ de Strasbourg, avenue Molie`re, BP 49, 67098 Strasbourg cedex, France b
info article
abstract
Article history:
The aim of the Multiple Sclerosis Think Tank (Groupe de re´flexion sur la scle´rose en plaques
Received 11 October 2011
[GRESEP]) is to prescribe recommendations following a systematic literature search and
Received in revised form
using a Rand Corporation and California University (RAND/UCLA) appropriateness derived
7 February 2012
method, in response to practical questions that are raised in the management of patients
Accepted 13 February 2012
with multiple sclerosis (MS). The topics of this working program were chosen because they were not addressed in the French recommendations and because of the few data in the literature that enabled practices to be based on validated data. Following the theme on useful serum testing with suspected multiple sclerosis, the subjects of the present work
Keywords :
concern the detection and management of cognitive impairment in the beginning stages of
Multiple sclerosis
the disease course. Two clinical questions were asked: which complementary exams
Cognitive disorders
(besides physical examination and neuropsychological tests) would help in the screening
Practice guideline
of cognitive impairment at the beginning of the disease? What care management should the
* Corresponding author. E-mail address : [email protected] (C. Bensa). 0035-3787/$ – see front matter # 2012 Publie´ par Elsevier Masson SAS. http://dx.doi.org/10.1016/j.neurol.2012.02.009 Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
NEUROL-881; No. of Pages 10
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revue neurologique xxx (2012) xxx–xxx
RAND/UCLA appropriateness
person with MS and cognitive impairment be offered (treatments and neurocognitive
method
rehabilitation)? The recommendations are the result of a consensus amongst a working
Review
group, a rating group and a reading group comprised of hospital neurologists involved in the management of patients with multiple sclerosis. Each recommendation is presented with
Mots cle´s :
the degree of consensus that it was accorded. # 2012 Published by Elsevier Masson SAS.
Scle´rose en plaques Troubles cognitifs Recommandations de pratique clinique Consensus formalise´ d’experts Revue
r e´ s u m e´ L’objectif du Groupe de re´flexion sur la scle´rose en plaques (GRESEP) est de formuler des recommandations, apre`s une analyse syste´matique de la litte´rature et en utilisant la me´thode du consensus formalise´ d’experts, en re´ponse a` des questions pratiques qui se posent dans la prise en charge des patients atteints de scle´rose en plaques. Les the`mes de ce programme de travail ont e´te´ choisis parce qu’ils n’e´taient pas traite´s dans les recommandations francophones. Le pre´sent article porte sur la de´tection et de la prise en charge des troubles cognitifs au de´but de l’e´volution de la maladie. Les recommandations re´pondent a` deux questions cliniques : quels examens comple´mentaires permettent d’aider au de´pistage des troubles cognitifs au de´but de la maladie (hors examen clinique et tests neuropsychologiques) ? Quelle prise en charge proposer au patient SEP atteint de troubles cognitifs (traitements et neuro-reme´diation cognitive) ? Les recommandations sont le fruit d’un consensus au sein d’un groupe de travail, d’un groupe de cotation et d’un groupe de lecture forme´s de neurologues hospitaliers implique´s dans la prise en charge de patients atteints de scle´rose en plaques. Chaque recommandation est expose´e avec le degre´ de consensus dont elle a fait l’objet. # 2012 Publie´ par Elsevier Masson SAS.
1.
Objectives
The Multiple Sclerosis Think Tank (Groupe de re´flexion sur la scle´rose en plaques [GRESEP]) is a working group made up of hospital neurologists that are involved in multiple sclerosis (MS). Its members were chosen by Jerome de Se`ze, on the criterion of expertise in managing this pathology. The general objective of GRESEP is to guide deliberation on questions raised in practice with regard to MS, some of which were slightly developed during the 2001 Consensus Conference (Fe´de´ration franc¸aise de neurologie, 2001) or which had conceptually evolved since this date. Following the theme of useful serumtestingwith suspected MS (Ouallet et al., in press), we present recommendations aiming to help in the detection and hospital management of cognitive impairment in the early course of MS in adult patients.
2.
Methods
The methodology used was that of the adaptation of recommendations (Haute Autorite´ de sante´, 2007), then a Rand Corporation and California University (RAND/UCLA) appropriateness derived method (Haute Autorite´ de sante´, 2006) (Table 1). It was explained in detail in our previous work on the theme of serum exams (Ouallet et al., in press). The aim of the recommendations is to respond to the following two clinical questions: which complementary exams (besides physical examination and neuropsychological tests) would help in the screening of cognitive impairment at the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)?
The documentary research strategy is outlined in Fig. 1. A systematic analysis of the literature was done in January 2010 and concerned referenced publications between 1st January 2005 and 31st December 2010. Collaborators in charge of the cognition theme (C. Bensa and F. Blanc) then drafted the recommendation proposals and arguments. The working document was subjected to three cycles of writing – rating – revision. The results of the last rating are summarised in Table 2. One discordant vote could be discarded from the analysis of this last rating. The opinions of the reading group are summarised in Table 3. The steering committee validated the final document that was submitted for publication. Each recommendation is followed by its argument and the degree of consensus amongst the rating and reading groups (Table 4). The French version of the recommendations appears in Table 5. The sponsor attended the working sessions but without possibility of intervention, and participated neither in the choice of the topics, nor in the bibliography selection process, nor in the consensus debates, nor in the rating sessions, nor in writing of the manuscript.
3.
Recommendations
The recommendations aim to respond to two clinical questions: Which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment at the beginning of the disease?
Please cite this article in press as: Bensa C, et al. Recommendations for the detection and therapeutic management of cognitive impairment in multiple sclerosis. Revue neurologique (2012), http://dx.doi.org/10.1016/j.neurol.2012.02.009
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Table 1 – Methodology of development of the recommendations. Me´thodologie de de´veloppement des recommandations. Participant
Action
Steering committee
Definition of the clinical questions Which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment in the beginning of the disease? What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? Monitoring of the project with assistance from the methodology group
Working group Cognition subgroup
Analysis of the literature provided by the methodology group Writing the recommendation proposals and arguments Consideration of the opinions of the rating and reading groups
Rating group
Critical reading of the recommendations and the arguments Rating the degree of agreement with the form and the content of each recommendation
Reading group
Critical reading of the recommendations and the arguments Vote (agreement, indecision or disagreement) on each consensual recommendation between the working and rating groups
Steering group: J. De Seze (Strasbourg, President), C. Bensa (Paris), F. Blanc (Strasbourg), D. Brassat (Toulouse), D. Laplaud (Nantes), L. Magy (Limoges), J.-C. Ouallet (Bordeaux), H. Zephir (Lille). Cognition working subgroup: C. Bensa (Paris), F. Blanc (Strasbourg). Rating group: A. Alkhedr (Amiens), O. Anne (La Rochelle), E. Berger (Besanc¸on), O. Casez (Grenoble), I. Coman (Bobigny), M. Coustans (Quimper), N. Derache (Caen), A. Fromont (Dijon), A.M. Guennoc (Tours), P. Lozeron (Paris), S. Pittion (Nancy), F. Rouhart (Brest), E. Thouvenot (Montpellier), S. Wiertlewski (Nantes). Reading group: B. Barroso (Pau), J.-M. Boulesteix (Cahors), C. Clerc (Montbe´liard), R. Colamarino (Vichy), T. De Broucker (Saint-Denis), J.M. Faucheux (Agen), D. Ferriby (Tourcoing), C. Gaultier (Colmar), E. Godet (Metz-Thionville), J. Grimaud (Chartres), O. Heinzlef (Poissy), C. Henry (Saint-Denis), O. Ille (Mantes-la-Jolie), P. Lejeune (La Roche-sur-Yon), E. Manchon (Gonesse), M. Marcel (Lens), M. Merienne (Saint-Malo), L. Nahum-Moscovici (Aulnay-sous-Bois), C. Renglewicz (Colmar), A. Verier (Valenciennes), M. Wagner (Metz-Thionville). Methodology group: E. Bodiguel (Paris), N. Charbonnier (Paris), N. Freynet (Paris).
What care management should the person with MS and cognitive impairment be offered (treatments and neurocognitive rehabilitation)?
4. Clinical question 1: which complementary exams (besides physical examination and neuropsychological testing) would help in the screening of cognitive impairment at the beginning of the disease? It’s necessary to follow three recommendations below: Recommendation 1.1. There is no complementary exam that replaces neuropsychological assessment for the screening of cognitive impairment (strong professional agreement); Recommendation 1.2. A significant lesion load on brain MRI must prompt the clinician to consider the existence of cognitive impairment in relapsing-remittent MS. Lesion load and cognitive impairment in an individual however are not necessarily related (strong professional agreement); Recommendation 1.3. The existence of cerebral atrophy, particularly enlargement of the third ventricle on brain MRI, must prompt the clinician to consider the existence of cognitive impairment in relapsing-remittent MS (relative professional agreement).
4.1.
Recommendation 1.1
On an individual level, there is no complementary exam that exhibits a sufficiently strong correlation with cognitive testing,
and there have been no studies specifically addressing this question. None of the following exams are sufficiently correlated to the results of neuropsychological testing to replace it: modification of focal or global cortical volume (Amato et al., 2007; Calabrese et al., 2009, 2010); modification of thalami volume (Houtchens et al., 2007); T1 hyposignal or T2 hypersignal lesion load; or focal or global cerebral volumetry (Benedict et al., 2004; Calabrese et al., 2009; Comi et al., 2000; Lazeron et al., 2005; Rao et al., 1989; Summers et al., 2008; Tiemann et al., 2009). Thus according to Lazeron et al. (2005), atrophy and lesion load only account for 10 to 25% of neuropsychological test variance. Several teams found significant relations between cortical lesion number and cognitive impairment (Nelson et al., 2011; Roosendaal et al., 2009). Other non-conventional MRI measures as magnetization transfer (MT) imaging may detect early tissue changes related to cognitive deficit (Deloire et al., 2011; Khalil et al., 2011). One objective of theses recommendations is their applicability in ordinary practice; so only routinely available MRI sequences (T1, T2, FLAIR–T2) have been retained for their writing.
4.2.
Recommendation 1.2
For this recommendation, lesion load does not require an automatic quantification but is led to the examinator’s appreciation. Several articles have found a correlation between lesion load on MRI and cognitive impairment. Rao et al. (1989) showed, in 53 patients with all types of MS, a link between total surface area of the lesions and memory, language, reasoning and visuo-spatial abilities. In 37 MS patients, Benedict et al. (2004) found a correlation between
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BIBLIOGRAPHIC RESEARCH ON INTERNET
FRANCOPHONE AND ANGLOPHONE RECOMMENDATIONS
Internet sites of publication of recommendations and consensus: 152 references
Medline document database: 43 references
PUBLICATIONS WITH PEER-REVIEWING
Medline document database : 361 references
First selection on title and clinical topics addressed: 34 references
First selection on title and abstract: 85 references
Selection on quality criteria: 1 reference
Selection on reading grid: 41 references
atrophy of the thalami (Houtchens et al., 2007). Visual measurement of the third ventricle however is not very reliable. Decreased cerebral volume at 1 year of progression is correlated with the existence of cognitive impairment at 5 years (Summers et al., 2008). In addition, there is a distinct correlation between overall cortical thickness and cognitive impairment (Amato et al., 2007; Calabrese et al., 2010).
5. Clinical question 2: what care management should the person with multiple sclerosis (MS) and cognitive impairment be offered (treatments and neurocognitive rehabilitation)? It’s necessary to follow three recommendations below:
Publications added by the experts: 24 references
Fig. 1 – Document selection strategy. 1: Keywords used: Clinical question 1: ‘‘Multiple Sclerosis’’ [Mesh] and ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ diagnosis’’ [Mesh] not ‘‘Psychological Tests’’ [Mesh]. Clinical question 2: ‘‘Multiple Sclerosis’’ [Mesh] and ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ drug therapy’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/prevention and control’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/ rehabilitation’’ [Mesh] or ‘‘Delirium, Dementia, Amnestic, Cognitive impairments/therapy’’ [Mesh] not ‘‘Terminal Care’’ [Mesh]. Strate´gie de se´lection documentaire. Date of Medline database search: 18th January 2010. Research of referenced publications between 1st January 2005 and 31st December 2010.
lesion load and the Symbol Digit Modalities Test ([SDMT] information processing speed). Other studies have had similar results, such as those of Arnett et al. (1994), Lazeron et al. (2005), Rovaris et al. (1998), and Swirsky-Sacchetti et al. (1992). In 56 patients in the early stage of the relapsing-remittent form, Deloire et al. (2005) showed that there was a correlation between lesion load, on the one hand, and SDMT and Paced Auditory Serial Addition Test ([PASAT] working memory, attention, processing speed) on the other, but not with memory tasks (Selective Reminding Test [SRT], 10/36) or tasks exploring inhibition abilities (Go-no-Go and Stroop). This correlation was not found by all the teams however, particularly in 92 patients with a clinically isolated syndrome (Glanz et al., 2007). Cognitive impairment is possible with a low lesion load, and such cases were found in most of the previously cited studies.
4.3.
Recommendation 2.1. There is no symptomatic drug treatment to date that has proven to be effective on cognitive impairment. Consequently, the prescription of symptomatic treatment is not recommended when cognitive impairment is diagnosed in patients with MS (strong professional agreement); Recommendation 2.2. On an individual basis, cognitive rehabilitation techniques may be beneficial (relative professional agreement); Recommendation 2.3. The existence of cognitive impairment is an additional argument for the establishment of long-term therapy in accordance with the legal conditions of prescription specified by the product licence (relative professional agreement).
5.1.
Recommendation 2.1
5.1.1.
Acetylcholinesterase inhibitors
The current data are insufficient for recommending acetylcholinesterase inhibitors (AChEI) in the treatment of cognitive impairment in MS. There is one single-centre, randomised, double-blind study available on donepezil in 69 patients (Krupp et al., 2004), which lacked external validation and had unequal groups due to the small population. There was also one single-centre, randomised, double-blind study on rivastigmine in 60 patients, which had negative results (Shaygannejad et al., 2008). As different review articles concluded (Amato et al., 2008; Christodoulou et al., 2008; Crayton and Rossman, 2006; Porcel and Montalban, 2006), additional studies must be done on larger cohorts. Considering the possible side effects of AChEI, it is recommended that these drugs should not be used in this situation without a sufficient level of proof of efficacy. Since this work, a new multicenter study, double-blind against placebo, has been published by Krupp et al. (2011). One hundred and twenty participants were enrolled and randomized and no significant treatment effect was found between groups.
Recommendation 1.3 5.1.2.
For this recommendation, atrophy does not require an automatic quantification but is led to the examinator’s appreciation. There is a correlation between cognitive impairment and increased volume of the third ventricle (Benedict et al., 2004, 2006; Tiemann et al., 2009), probably related to
Memantine
The current data are insufficient for recommending the use of memantine in the treatment of cognitive impairment related to MS. Two studies have been published: one on 60 patients (Villoslada et al., 2009), which was prematurely discontinued due to worsening of neurological symptoms in some of the
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Recommendation No.
1.1
1.2
1.3
2.1
2.2
2.3
Quality criteria
Median
Opinion of the group
Maximum rating
Minimum rating
Degree of agreement
Easy to understand
9.0
Appropriate formulation
9
8
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
8
Strong agreement between group members
Sufficient
9.0
Sufficient recommendation
9
5
Relative agreement between group members
Easy to understand
9.0
Appropriate formulation
9
7
Strong agreement between group members
Useful
8.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
8.0
Sufficient recommendation
9
5
Relative agreement between group members
Easy to understand
9.0
Appropriate formulation
9
6
Relative agreement between group members
Useful
7.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
7.0
Sufficient recommendation
9
5
Relative agreement between group members
Number of discordant votes revue neurologique xxx (2012) xxx–xxx
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Table 2 – Third rating of recommendation proposals. Troisie`me cotation des propositions de recommandations.
Easy to understand
9.0
Appropriate formulation
9
9
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
8
Strong agreement between group members
Sufficient
9.0
Sufficient recommendation
9
8
Strong agreement between group members
Easy to understand
9.0
Appropriate formulation
9
6
Relative agreement between group members
Useful
8.5
Appropriate recommendation
9
5
Relative agreement between group members
1 rating at 2
Sufficient
7.0
Sufficient recommendation
9
5
Relative agreement between group members
1 rating at 4
Easy to understand
9.0
Appropriate formulation
9
7
Strong agreement between group members
Useful
9.0
Appropriate recommendation
9
6
Relative agreement between group members
Sufficient
9.0
Sufficient recommendation
9
6
Relative agreement between group members
5
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Table 3 – Analysis of returns from the reading group. Analyse des retours du groupe de lecture. Recommendation No. 1.1 1.2 1.3 2.1 2.2 2.3
Number of agreements
Number of disagreements
Number of undecided
% agreements
Number of votes
20 19 17 20 16 17
0 1 1 0 0 1
0 0 2 0 4 2
100.0 95.0 85.0 100.0 80.0 85.0
20 20 20 20 20 20
treated patients; and the other, more recent, on 126 patients, with negative results (Lovera et al., 2010).
need for controlled studies. It is an open-label exploratory study (phase I/II) in eight patients with progressive MS.
5.1.3.
5.1.4.
Erythropoietin
The current data are insufficient for recommending the use of erythropoietin in the treatment of cognitive impairment related to MS. Only one pilot study is available (Ehrenreich et al., 2007), which demonstrates the feasibility of the treatment and the
Amphetamines
The current data are insufficient for recommending the use of amphetamines in the treatment of cognitive impairment related to MS. Only two studies were available at the time of this review: one pilot study on 19 patients (Benedict et al., 2008),
Table 4 – Criteria for attribution of the grade of each recommendation. Crite`res d’attribution du grade de chaque recommandation. Level of scientific proof
Grade of recommendation
Level 1 Randomised controlled trials with large sample size Meta-analyses
A
Level 2 Randomised controlled trials with small sample size
B
Level 3 Contemporary non-randomised controlled trials Cohort studies
C
Level 4 Controlled trials with historical controls Level 5 Case series Absence of scientific proof
Professional agreement
Determination of the degree of consensus in cases of professional agreement Rating
Degree of validation by the rating group
% of agreement within the reading group
Degree of professional agreement (synthesis of the opinions of the rating and reading groups)
Median between 7 and 9 for each of the 3 rating criteria Less than 2 ratings < 7 for each of the criteria Median between 7 and 9 for each of the 3 rating criteria 2 or more ratings < 7 Less than 2 ratings < 4
Strong consensus
90% Between 80 and 90%
Strong professional agreement Relative professional agreement
Relative consensus
Between 80 and 90%
Median < 7 2 or more ratings < 4
Regardless of the degree of consensus
< 80%
Either recommendation to remain and then new rating Or the working group does not give its opinion Or the working group decides to maintain the recommendation, while making clear the lack of consensus within the reading group
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Table 5 – French version of the recommendations. Recommandations pour la de´tection et la prise en charge the´rapeutique des troubles cognitifs dans la scle´rose en plaques. Question clinique 1 : quels examens comple´mentaires permettent d’aider au de´pistage des troubles cognitifs au de´but de la maladie (hors examen clinique et tests neuropsychologiques) ? Recommandation 1.1. Aucun examen paraclinique ne remplace le bilan neuropsychologique pour de´pister les troubles cognitifs (accord professionnel fort) Recommandation 1.2. Une charge le´sionnelle importante a` l’IRM ce´re´brale doit inciter le clinicien a` s’interroger sur l’existence de troubles cognitifs dans la scle´rose en plaque (SEP) re´mittente. Pour autant, charge le´sionnelle et troubles cognitifs pour un individu ne sont pas force´ment lie´s (accord professionnel fort) Recommandation 1.3. L’existence d’une atrophie ce´re´brale, et en particulier un e´largissement du 3e ventricule a` l’IRM ce´re´brale, doit inciter le clinicien a` s’interroger sur l’existence de troubles cognitifs dans la SEP re´mittente (accord professionnel relatif) Question clinique 2 : quelle prise en charge proposer au patient SEP atteint de troubles cognitifs (traitements et neuro-reme´diation cognitive) ? ` ce jour, aucun traitement me´dicamenteux a` vise´e symptomatique n’a fait la preuve de son efficacite´ sur les Recommandation 2.1. A troubles cognitifs. En conse´quence, il n’est pas recommande´ de prescrire un traitement symptomatique lors du diagnostic de troubles cognitifs chez un patient atteint de SEP (accord professionnel fort) ` l’e´chelle individuelle, il peut y avoir un inte´reˆt a` proposer une technique de reme´diation cognitive Recommandation 2.2. A (accord professionnel relatif) Recommandation 2.3. L’existence de troubles cognitifs est un argument supple´mentaire dans le sens de l’instauration d’un traitement de fond, dans le respect des conditions fixe´es par l’AMM du produit (accord professionnel relatif)
which led the same team to perform a second single-centre study on 155 patients, with negative results (Morrow et al., 2009). In 2011, Sumowski et al. published a post-hoc reanalysis of this previous trial, which seems to demonstrate a beneficial effect on verbal and visuo-spatial memory for patients with baseline memory impairment. Other studies are therefore necessary.
5.1.5.
Methylphenidate
The current data are insufficient for recommending the use of methylphenidate in the treatment of cognitive impairment related to MS. Indeed, only one single-centre, double-blind pilot study versus placebo done on 26 patients is available (Harel et al., 2009). The patients, who presented with attention disorders, were tested before treatment and then 1 hour after treatment with the 3-second PASAT test. The patients on treatment had a 22.8% improvement of the PASAT score versus 4.5% on placebo (non-significant difference).
5.1.6.
Symptomatic treatments of fatigue
The current data are insufficient for recommending the use of symptomatic treatments of fatigue (amantadine, pemoline, 4AP, 3-4 DAP, modafenil) for treating cognitive impairment related to MS. Only small studies are available, the results of which are negative. Two pilot studies suggest an improvement in attention with amantadine (Amato et al., 2006; Pierson and Griffith, 2006).
5.1.7.
Naturopathy
The current data are insufficient for recommending the use of naturopathic medicine in the treatment of cognitive impairment related to MS. Only one study was published, the result of which was negative (Shinto et al., 2008).
5.2.
Recommendation 2.2
As for any rehabilitation technique, the evaluation of neurorehabilitation protocols are subject to many methodological difficulties: the difficulty in obtaining homogenous groups;
difficulty in working blinded; difficulties of evaluation (learning effect, evaluation in terms of tests and not in the real-life setting); and difficulties related to the unknown reproducibility of the methods. Most of the available studies appear promising in terms of efficacy but are not sufficient for establishing strong recommendations (Brenk et al., 2008; O’Brien et al., 2007; Tesar et al., 2005). The team from Nancy recently obtained promising results on memory and executive functions in 24 patients with a neurorehabilitation programme over 6 months (Brissart et al., 2010). This pilot study needs to be confirmed. Neurorehabilitation is a validated technique in patients with traumatic brain injuries (Carney et al., 1999; Lengenfelder et al., 2007; NIH consensus development panel on rehabilitation of persons with traumatic brain and injury, 1999; O’Brien et al., 2007) and in vascular diseases (Cicerone et al., 2000). It includes interventions that are known to improve the efficacy and abilities in activities of daily living, and includes two components. First, ‘‘compensation’’ measures that aim to modify the environment, with evaluation of needs in the real-life setting, of daily living, and the institution of assistive strategies such as keeping a planner, reduction of possible distractions, conversion of the work environment, etc. Second, ‘‘restorative’’, or more correctly rehabilitation, measures, which aim to improve performances by relying on the capacities of plasticity and cortical reorganization — in other words, either exercises targeting deficient domains, exercises that take advantage of preserved domains, or global practice of intellectual functions. Different methods are suggested using software or interviews with individuals or in groups. Several review articles have summarised the available studies and highlighted the interest generated by these methods, which remain to be confirmed by methodologically sound studies (Amato et al., 2008; Lensch et al., 2006; Thompson, 2005). In one of these review articles on the efficacy of neurorehabilitation in 19 selected studies, 16 were found to be of sufficient quality for evaluation (O’Brien et al., 2008). In the end, the authors did not obtain sufficient data for assessing their impact on attention disorders or executive functions. In the domains of learning
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and memory, the techniques of ‘‘history recall’’ (contextualization, in association with emotional elements and mental imagery) and ‘‘self-generation’’ (self-production of items to remember) appear to have sufficient validation for use in clinical practice (Basso et al., 2006; Goverover et al., 2008). A Cochrane review examined the studies on psychological and neuropsychological interventions in MS (Thomas et al., 2006). The research strategy enabled three studies to be selected in the domain of cognitive impairment, but the authors noted few similarities between them with regard to population, intervention, objectives and the follow-up period. These were small-sized studies, which increased the risk of type II errors, and they focused on too many objectives, thus increasing the risk of type I errors. According to the authors, these works did not enable recommendations to be established. Since we did this review, Cochrane review has been re-actualized and on the basis of 14 studies (770 MS patients), authors conclude to low level of evidence for positive effects of neuropsychological rehabilitation in MS (Rosti-Otaja¨rvi and Ha¨ma¨la¨inen, 2011). With the exception of one discordant voice, this recommendation was validated by the rating group (Table 2). Despite 20% abstention rate, there was no opposition expressed within the reading group (Table 3). As a result, this recommendation, in accordance with that of the ‘‘Multiple Sclerosis Therapy Consensus Group of the German Multiple Sclerosis Society’’ (Henze et al., 2006), was maintained. In France, the lack of trained providers (neuropsychologists and speech therapists) is an obstacle to the application of these methods in practice.
5.3.
Recommendation 2.3
In the absence of validated data, this recommendation is drawn from the clinical expertise of the working group and from expert recommendations (Cohen, 2008; Crayton and Rossman, 2006; Defer et al., 2007; Patti, 2009; Tumani and Uttner, 2008; Winkelmann et al., 2007). The studies on interferons show a trend towards improvement of cognitive impairment, but they need to be confirmed. In the proof of principle studies of immunomodulators (Ebers, 1998; Jacobs et al., 1996; Johnson et al., 1995; The IFNB multiple sclerosis study group, 1993; Thompson, 2005), cognition was not included in the primary objectives. In the secondary objectives and in small studies, interferons seem to provide beneficial results on neuropsychological tests. Some open-label studies on immunosuppressants also appear to show a positive effect of these long-term treatments on cognitive impairment (Ze´phir et al., 2005, 2008). In addition, several recent studies (Deloire et al., 2010; Zipoli et al., 2010) confirm that the presence of cognitive impairment at the early stage of the disease is a negative prognostic factor with regard to clinical conversion and longterm disability. The detection of cognitive impairment in this case could be an additional argument for starting a long-term therapy. However, the prevention of long-term disability through the treatments has not been clearly demonstrated.
Acknowledgements We wish to gratefully acknowledge the members of the rating and reading groups (Table 1), for their contribution to the
present work, and Mrs. Guiquerro, Director of the university hospital library of Hoˆpital europe´en Georges-Pompidou (Paris), for her advice in documentary research.
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