Luisa Pastò

Cognitive impairment in early stages of multiple sclerosis

Cognitive dysfunction involves 40–65% of multiple sclerosis patients and can have a great functional impact. It can be detected in all the disease phenotypes since the early stages of the disease, and tends to progress over time. Memory, complex attention, information-processing speed and executive functions are most commonly involved. The relationship between cognitive changes and magnetic resonance imaging (MRI) findings may involve changes in different areas, including white matter lesions, cortical and deep grey matter and normal appearing brain tissue on conventional MRI. The search for effective therapeutic strategies is a major undertaking, involving the use of both pharmacologic and rehabilitative approaches. Early treatment with disease-modifying drugs that can contain the disease burden in the brain seems to be highly advisable in order to prevent or delay the development of cognitive impairment.

Cognitive reserve and cortical atrophy in multiple sclerosis A longitudinal study

Objective: To test the cognitive reserve (CR) hypothesis in the model of multiple sclerosis (MS) by assessing the interactions among CR, brain atrophy, and cognitive efficiency in patients with relapsing-remitting MS. Methods: A Cognitive Reserve Index was calculated including education, premorbid leisure activities, and IQ. Brain atrophy was assessed through magnetic resonance quantitative parameters of normalized total brain volume and normalized cortical volume. Cognitive function was measured using Raos Brief Repeatable Battery. Results: Fifty-two patients with relapsing-remitting MS were evaluated at baseline and 35 of them were reassessed after a 1.6-year follow-up period. At baseline, higher CR predicted better performance on most of the Brief Repeatable Battery tests, independent of brain atrophy and clinical and demographic characteristics (p ≤ 0.021). An interaction between CRI and normalized cortical volume predicted better cognitive performance on tasks of verbal memory and attention/information processing speed (p < 0.005). However, at the follow-up examination, progressing cortical atrophy (β = 0.45; p = 0.008) and older age (β = −0.33; p = 0.044) were the only predictors of deteriorating cognitive performance. Conclusions: Our findings suggest that higher CR in individuals with MS may mediate between cognitive performance and brain pathology. CR-related compensation may, however, fail with progression of damage. The time window of opportunity for therapeutic approaches aimed at intellectual enhancement most likely lies in the earliest disease stages.

Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study

BackgroundOnly few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion.Materials and methodsWe recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons.ResultsData on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure.ConclusionsData in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.

Withdrawal of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six cases.

The objective of this article is to report our experience on fingolimod suspension in multiple sclerosis patients. We evaluated clinical and magnetic resonance (MR) outcomes in six patients after fingolimod discontinuation. Within three months from fingolimod suspension, five subjects returned to pre-treatment disease activity; one patient, however, exhibited a clear rebound of clinical and MR activity. Our findings suggest that clinical and MR outcomes after fingolimod suspension can vary among patients. Systematic collection of clinical, laboratory and imaging data is highly advisable to identify subjects who are at higher risk of rebound and to define effective management strategies in these subjects.

Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study

BackgroundFew studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS.MethodsIn the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis.ResultsWe collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005).ConclusionsOur findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study

BackgroundMost of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.MethodsStructured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.ResultsSeventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.ConclusionsOur data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Rebound after Fingolimod suspension in a pediatric-onset multiple sclerosis patient

Fingolimod is an oral agent approved for the treatment of relapsing-remitting Multiple Sclerosis (RRMS). Data about a possible reactivation of disease activity after Fingolimod withdrawal are limited [1–3]. We report a case of clinical and magnetic resonance (MR) rebound after Fingolimod discontinuation in a 19-year-old woman with pediatriconset MS (POMS). Case-report: A 19-year-old woman was diagnosed as RRMS in February 2004, when she was 11. Two relapses occurred before initiation of interferon beta in 2009. She experienced two new episodes of optic neuritis until 2011. In June 2011, brain MR showed ten new T2 lesions, five with Gadolinium (Gd) enhancement, in comparison with a scan of September 2010 which already showed a high lesion load ([9 T2-lesions). After a steroid course the EDSS score was 3.0. The patient was shifted to fingolimod treatment in December 2011. After 10 days from fingolimod initiation, she presented a severe relapse; the brain MR showed 10 new T2 lesions. She recovered after intravenous methyl-prednisolone (IVMP) therapy. Two new relapses occurred in March and May 2012, the latter treated with steroids. Brain MR, compared with the scan performed in June 2011, showed ten new T2 lesions with eight Gdenhancing lesions. After IVMP therapy the EDSS was 3.5. Fingolimod was discontinued due to lack of efficacy. The patient started laboratory, cardiologic and radiologic examinations preliminary to intravenous cyclophosphamide therapy. In June, she experienced a new relapse; brain and spinal cord MR, performed 50 days after Fingolimod discontinuation, showed a drastic increase of the brain lesion burden ([35 T2 lesions) with 25 Gd-enhancing lesions, suggesting a rebound phenomenon (Fig. 1). At that time the peripheral lymphocyte count had returned within the normal limits. Moreover, in August, the MR showed enlargement of some pre-existing brain lesions and the presence of a new lesion in the spinal cord. She underwent five plasmaexchange courses, followed by good recovery (EDSS 3.0). She then started intravenous cyclophosphamide therapy (800 mg/m of body surface every month). Over the sevenmonth follow-up no new relapse occurred, EDSS remained unchanged and no new MR lesion was documented. In conclusion, in our POMS patient, Fingolimod was not effective to contain the inflammatory process and the drug discontinuation resulted in a rebound phenomenon, although this was observed during a phase of continuing disease activity rather than in the context of quiescent disease. A systematic review of the patients coming off from the TRANSFORMS and the FREEDOMS studies did not demonstrate similar rebound [4]; however, other examples of rebound after Fingolimod suspension are reported in the literature suggesting that the phenomenon could be linked to immunological recovery [1–3]. Rebound can also occur after discontinuation of Natalizumab, a monoclonal antibody used in very active MS patients [5, 6]. There is no standardized management of rebound periods. We did not use natalizumab due to JC virus positivity and the associated risk of rebound in case of discontinuation. Mitoxantrone treatment was ruled out due to the risk of leukemia [7]. Using intensive immunosuppression with cyclophosphamide [8], we obtained clinical and MR remission over a 7-months follow-up, although this period is relatively short E. Piscolla B. Hakiki L. Pasto L. Razzolini E. Portaccio M. P. Amato (&) Department of Neurology, University of Florence, Largo Brambilla 3, 50134 Florence, Italy e-mail: mariapia.amato@unifi.it

No association between chronic cerebrospinal venous insufficiency and pediatric-onset multiple sclerosis

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) was hypothesized to play a causative role in multiple sclerosis (MS). The assessment of pediatric-onset MS (POMS) may provide a unique window of opportunity to study hypothesized risk factors in close temporal association with the onset of the disease. Methods: Internal jugular veins, vertebral veins and intracranial veins were evaluated with extracranial and intracranial ultrasound in 15 POMS and 16 healthy controls. Assessor’s blinding was maintained during the study. We considered subjects positive to CCSVI when at least two criteria were fulfilled. Results: CCSVI frequency was comparable between POMS and controls (p > 0.05). Clinical features were not significantly different between CCSVI-positive and CCSVI-negative patients. Conclusions: Our findings add to previous data pointing against a causative role of CCSVI in MS.

The cognitive reserve theory in the setting of pediatric-onset multiple sclerosis.

Background: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. Objectives: To assess the potential impact of CR on cognition in a cohort of POMS patients. Methods: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses. Results: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03–1.20; p = 0.006). Conclusion: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.

Cognitive rehabilitation in children and adolescents with multiple sclerosis

Cognitive impairment can be detected in a sizeable proportion of pediatric multiple sclerosis (MS) patients. It involves memory, complex attention, information processing speed, executive functions, linguistic abilities, and intelligent quotient. It has a great impact on school, everyday and social activities, and significantly progresses overtime in the great majority of the subjects. These findings highlight the importance of a comprehensive and systematic assessment of MS-related cognitive difficulties in pediatric cases. Moreover, despite the acknowledged relevance of cognitive impairment in this age range, specific interventions for pediatric MS are lacking. As for rehabilitative strategies, there is some evidence of efficacy in other diseases, in particular brain trauma, tumor, and stroke. The development of effective rehabilitative strategies tailored to the needs of young MS patients is a priority for future research in the field.