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Multiple sclerosis

SHORT REPORT

Isolated cognitive relapses in multiple sclerosis Matteo Pardini,1,2,3 Antonio Uccelli,1 Jordan Grafman,4 Özgür Yaldizli,3,5 Gianluigi Mancardi,1,2 Luca Roccatagliata2,6,7 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2013-307275). 1

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy 2 Magnetic Resonance Research Centre on Nervous System Diseases, University of Genoa, Genoa, Italy 3 MS Centre, University College London Institute of Neurology, London, UK 4 Brain Injury Research, Rehabilitation Institute of Chicago, Chicago, Illinois, USA 5 Department of Neurology, University Hospital Basel, Basel, Switzerland 6 Department of Diagnostic and Interventional Neuroradiology, San Martino University Hospital, Genoa, Italy 7 Department of Health Sciences, University of Genoa, Genoa, Italy Correspondence to Dr Matteo Pardini, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Largo Daneo 3, Genoa 16143, Italy; [email protected] Received 18 November 2013 Revised 12 February 2014 Accepted 2 March 2014 Published Online First 31 March 2014

To cite: Pardini M, Uccelli A, Grafman J, et al. J Neurol Neurosurg Psychiatry 2014;85: 1035–1037.

ABSTRACT Objective While cognition can be affected during sensorimotor multiple sclerosis (MS) relapses, the relevance of isolated cognitive relapses (ICRs ie, those occurring in absence of new sensorimotor symptoms) remain poorly characterised. Here, we decided to explore the relationship between ICR, subjective evaluation of cognitive performance and long-term cognitive decline in a group of subjects with relapsing-remitting MS. Methods We analysed the cognitive performance of 99 clinically stable relapsing-remitting MS for whom data from four consequent clinical and cognitive evaluations were available, that is, a baseline evaluation (t0), followed in the subsequent 6 months by a second evaluation performed not later than 2 weeks after a routine brain scan positive for at least one area of gadolinium enhancement (t1) and two gadolinium enhancement-negative follow-up evaluations after 6 months (t2) and 1 year (t3) from t1. Based on published literature, we defined as a meaningful change in cognition a transient reduction of Symbol Digit Modalities Test score of at least four points at t1 compared with t0 and t2. Results ICRs were found in 17 patients and were not associated with subjective cognitive deficits or depression. Subjects who presented with an ICR at t1 presented with a significantly reduced cognitive performance at the follow-up evaluations compared with patients without ICR. Conclusions and relevance We showed that ICRs were not associated with changes in mood, fatigue levels or cognitive performance self-evaluations. Our study introduces an operational definition of ICRs and suggests to their role as a factor for cognitive decline in MS.

clinical practice, and so their possible relevance has tended to be overlooked. Indeed, while transient cognitive impairments have been described in association with other symptomatic neurological deficits during MS disease activity,4 the construct of isolated cognitive relapse (ICR), that is, a transient reduction in cognitive functioning not associated with other subjective or objective neurological symptomatology, albeit described in different single case reports,5 6 remains to date poorly characterised. Our main research questions were as follows: (1) Is it possible to evaluate ICR in the clinical setting? (2) What is the relationship between ICR and subjective cognitive evaluation, taking into account that transient changes in cognition are not a frequent complaint in MS? (3) What is the relationship between ICR and stable cognitive impairment?

METHODS ICR definition We applied the definition of relapse to the cognitive domain to operationally define ICR as (1) a transient significant (see below) cognitive decline in objective neuropsychological performance, (2) without clinical or subjective evidence of other new neurological signs and symptoms (3) associated with brain disease activity defined as a positive gadolinium enhancing scan (Gd+). We would like to point out that while the last criterion is not necessary for a clinical relapse per se, we still decided to apply it in this proof-of-concept study to ensure that enrolled subjects presented with current disease activity.

Patients’ population INTRODUCTION Relapses, one of the key features of relapsingremitting multiple sclerosis (RRMS), are defined as episodes of transient neurological disturbance due to disease activity, which last for at least 24 h and are not better accounted for by other clinical conditions.1 Relapses recovery can be full or with residual stable deficits.2 Relapses are protean in their clinical manifestations, ranging from optic neuritis to motor or sensory disturbances, making diagnosis challenging, especially for the less common presentations. Accurate and sensitive identification of relapses is important because they represent a major element of RRMS diagnostic criteria and because they are a widely used measure to assess treatment success.1 3 Among the different possible presentations of a multiple sclerosis (MS) relapse, cognitive relapses lack a clear operational definition applicable in

Pardini M, et al. J Neurol Neurosurg Psychiatry 2014;85:1035–1037. doi:10.1136/jnnp-2013-307275

Clinical and cognitive data were retrospectively collected from a group of patients with MS who underwent longitudinal cognitive and behavioural evaluations at our MS centre between 2008 and 2012. Our inclusion criteria were as follows: (1) a diagnosis of RRMS, (2) age range: 18–50 years, (3) EDSS score lower than 6, (4) at least 12 years of formal education and (5) no significant comorbidities or psychoactive drug use. For all time points described below we collected the following clinical and cognitive parameters: EDSS score, Symbol Digit Performance Test (SDMT) score,7 Hospital Anxiety and Depression Scale, depression score,8 Modified Fatigue Impact Factor Scale total score9 and MS Neuropsychological self-report score. Screening Questionnaire10 Cognitive reserve was evaluated with the Cognitive Leisure Activity Questionnaire, completed at the end of the observation period.11 Descriptions of all tests 1035

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Multiple sclerosis and baseline cut-off values for inclusion in the study are described in the supplementary online methods. To comply with our proposed operational definition of ICR, we focused on those subjects for whom data from four consequent clinical and cognitive evaluations were available, that is, a baseline evaluation (t0), followed in the subsequent 6 months by a second evaluation performed not later than 2 weeks after a routine brain scan positive for at least one Gd+ area (t1) and two gadolinium enhancement-negative follow-up evaluations after 6 months (t2) and 1 year (t3) from t1. We excluded from the analysis those subjects who presented with a change in Expanded Disability Status Scale (EDSS) score, novel subjective non-cognitive complaints or steroid use during the entire study period. Subjects consented to all procedures, which were performed according to the Helsinki declaration. All procedures were approved by the ethics committee.

location is reported in online supplementary table S2. The distribution of Gd+ lesions was different between the two groups with ICR subjects showing only frontoparietal Gd+ lesions (see online supplementary results).

Differences in cognitive performance over time Our model revealed a significant Time×Group interaction effect (F=45.116, p

Isolated cognitive relapses in multiple sclerosis.

While cognition can be affected during sensorimotor multiple sclerosis (MS) relapses, the relevance of isolated cognitive relapses (ICRs ie, those occ...
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