Sabrina Realmuto

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab: Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

IMPORTANCE The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Tumor Diagnosis Preceding Alzheimer's Disease Onset: Is There a Link Between Cancer and Alzheimer's Disease?

Studies reporting an inverse association between Alzheimers disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi-structured questionnaire. Tumors were categorized as benign, malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4-1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3-0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2-1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen.

Lesion Load May Predict Long-Term Cognitive Dysfunction in Multiple Sclerosis Patients

Background Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). Objectives To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients. Methods 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. Results AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12–1.97 p = 0.006), PASAT (OR 1.43, CI 1.14–1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35–2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28–2.03 p<0.001), MCST-category (OR 1.52, CI 1.2–1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2–1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02–1.55 p = 0.032). Conclusion In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.

EARLY AND LATE MORTALITY OF SPONTANEOUS HEMORRHAGIC TRANSFORMATION OF ISCHEMIC STROKE

BACKGROUND Hemorrhagic transformation (HT), a complication of ischemic stroke (IS), might influence patients prognosis. Our aim is to evaluate, in a hospital-based series of patients not treated with thrombolysis, the relationship between HT and mortality. METHODS We compared mortality of individuals with spontaneous HT with that of individuals without. Medical records of patients diagnosed with anterior IS were retrospectively reviewed. Outcome measures were 30- and 90-day survival after IS onset. Kaplan-Meier estimates were used to construct survival curves. Cox proportional hazards model was used to estimate hazard ratio (HR) for the main outcome measure (death). HT was stratified in hemorrhagic infarction and parenchymal hematoma (PH). We also evaluated the relationship between HT and the main mortality risk factors (gender, age, premorbid status, severity of stroke, and radiological features). RESULTS Thirty days from stroke onset, 8.1% (19 of 233) of patients died. At multivariate analysis, PH (HR: 7.7, 95% confidence interval [CI]: 2.1, 27.8) and low level of consciousness at admission (HR: 5.0, 95% CI: 1.3, 18.6) were significantly associated with death. At 3-month follow-up, mortality rate was 12.1% (28 of 232). At multivariate analysis, large infarct size (HR: 2.7, 95% CI: 1.2, 6.0) and HT (HR: 2.3, 95% CI: 1.0, 5.4) were independent risk factors for mortality. Parenchymal hematoma was, however, the strongest predictor of late mortality (HR: 7.9, 95% CI: 2.9, 21.4). CONCLUSIONS Neurological status and infarct size play a significant role, respectively, in early and late mortality after IS. Parenchymal hematoma independently predicts both early and late mortality.

VDBP, CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic demyelinating disease of central nervous system regarded as one of the most common causes of neurological disability in young adults. The exact etiology of MS is not yet known, although epidemiological data indicate that both genetic susceptibility and environmental exposure are involved. A poor vitamin D status has been proposed as the most attractive environmental factor. Several evidence have highlighted the importance of mutations in vitamin D-regulating genes for vitamin D status. The purpose of our study was to assess the genetic variants of VDBP and CYP27B1 in MS patients and in a control group. A total of 192 subjects, including 100 MS patients and 92 healthy controls, were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Serum 25-hydroxyvitamin D levels were measured in MS patients and controls by high-performance liquid chromatography. We did not observe any statically significant difference in the distribution of genotypic VDBP variants between the study groups. 25(OH)D plasma levels were significantly higher in the control group versus MS patients; MS patients who carried Gc2 showed lower 25(OH)D plasma levels and those who carried Gc1f showed higher levels. We observed only wild-type allele for CYP27B1 mutations analyzed both in MS patients and in the control group. In conclusion, our findings do not support a role of an independent effect of the investigated vitamin D-related gene variants, VDBP and CYP27B1, in the risk of MS.

A population-based survey of cognitive performance in a Sicilian elderly community.

Background: The global burden of neurodegenerative diseases is increasing. Previous studies reported differences related to age, gender and socioeconomic status. We calculated the cognitive performances of a Sicilian population aged 65 years or older, by means of a door-to-door population-based survey in Bagheria city, Sicily. Methods: A door-to-door survey was carried out in the city of Bagheria, Sicily (prevalence day September 30, 2006). A cohort of 2,200 persons was randomly stratified, obtaining a 25% sample of the whole population. Cognitive function was assessed by Mini Mental State Examination (MMSE). Percentile distributions by age, gender, education and working activity were calculated. Regression models were used to analyze the relationship between the investigated variables and cognitive performance. Results: A total of 1,837 persons agreed to participate (1,062 women and 775 men). Distribution of MMSE showed a highly significant inverse linear trend related to the increasing age (p < 0.0001) and to the degree of education (p < 0.0001), both in men and women. We observed a significant association between higher education and a better cognitive performance (OR 6.91; CI 3.24–14.76) and an inverse association between manual kind of occupation versus not manual and a poorer cognitive status (OR 0.82; CI 0.67–0.997). Height was associated with decreased cognitive performances in women (OR = 1.03; CI = 1.01–1.05) but not in men (OR = 0.997; CI = 0.993–1.002). Conclusions: These findings provide a feature of cognitive performances in Sicily, measured by MMSE scores in individuals aged 65 years or older.

Insidious onset of Pisa syndrome after rasagiline therapy in a patient with Parkinson’s disease

Pisa Syndrome (PS) is clinically defined as a pronounced lateral flexion of the trunk (at least 10 ), completely alleviated by passive mobilization or on lying supine [1]. PS has been described in patients with Parkinson’s disease (PD) and, until now, few studies have pointed out its possible relationship with either clinical evolution of disease and medical treatment. Although pathophysiology of PS still remains largely unexplained a dopaminergic impairment seems to play a major role in its onset. Accordingly, in some PD patients, PS may be triggered by starting of dopamine blocking agents, or by changes in dopaminergic medication (e.g., start of a new drug, and dose increase or decrease of existing medication). In addition, non-dopaminergic medications might also contribute for developing PS such as neuroleptics, lithium carbonate, valproic acid, antidepressants, anti-emetics, and cholinesterase inhibitors [1]. Here we describe the case of a 73-year-old woman with a 5-year PD history, who showed, during an outpatient visit, a lateral flexion of the trunk on the left side (10 on spine X-ray). This abnormal posture was not present at a previous clinical examination performed 6 months before. At current visit, the patient had not awareness of the abnormal posture that was made evident by the physicians. The patient’s past medical history was unremarkable and laboratory tests were normal. The patient denied assumption of neuroleptics, antiemetics, or cholinesterase inhibitors in the past years. Current treatment regimen was pramipexole (1.57 mg/day), levodopa (200 mg/day), and rasagiline (1 mg/day). Neurological examination showed a right hand rest tremor, a slight ipsilateral cogwheeling rigidity and bradykinesia, and a lateral flexion of the trunk to the left side (Fig. 1a). The patient underwent conventional EMG recordings in the paravertebral muscles at the thoracic-lumbar level T12L1 (longissimus thoracis muscle) [2]. Recordings, that were performed with the patient in stance position and during voluntary right and left lateral trunk flexion, showed a pattern of a co-contraction of agonist and antagonist muscles compatible with dystonia of paraspinal muscles (Fig. 2). As PS may be related to dopaminergic therapy [3], and according to recent observations that PS might be reversed after rasagiline withdrawal [4], we hypothesized that the onset of PS in our patient could be linked to the last modification in the antiparkinsonian treatment, that occurred nearly 1 year before when rasagiline was added in order to manage motor worsening and wearing-off phenomena. Based on these considerations, rasagiline was withdrawn and, within 4 weeks, an improvement of posture was observed (Fig. 1b). An EMG examination performed 4 weeks after rasagiline withdrawal showed disappearance of the abnormal dystonic pattern (Fig. 2). This report may further support the pathogenetic role of the dopaminergic therapy in the development of PS in PD, and its potential reversibility by optimizing the regimen of antiparkinsonian medications. It is noteworthy that, in our patient, the temporal interval between F. Valentino G. Cosentino B. Fierro S. Realmuto S. Mastrilli G. Savettieri M. D’Amelio (&) Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Università degli Studi di Palermo, Via Gaetano La Loggia 1, Palermo 90129, Italy e-mail: marco.damelio@unipa.it

Pisa syndrome after rasagiline therapy in a patient with Parkinson’s disease

We have read with interest comments by Solla et al. [1] regarding our Letter to the Editor published in Neurological Sciences titled ‘‘Insidious onset of Pisa Syndrome after rasagiline therapy in a patient with Parkinson’s Disease’’ [2]. We thank the authors for their interest in our paper, but we think it is necessary to make some clarifications regarding the temporal relationship between the onset of Pisa Syndrome (PS) and rasagiline therapy. PS occurred in fact after and not before rasagiline treatment as stated by Solla et al. In particular, PS occurred after a time interval of 6–12 months and anyway after rasagiline was added to patient’s therapy. This long time interval is one of the elements that makes the case interesting (time period longer than previously described). Temporal relationship is fundamental for the interpretation of clinical and electrophysiological findings in our case. Rasagiline is an inhibitor of monoamine oxidase type B, and although different mechanisms of action have been advocated, its effect is primarily dopamine mediated [3]. This means that occurrence of Pisa syndrome in our case was likely related not only to the specific mechanisms of action of the drug but also to increased dopamine extracellular levels at the striatal synapses, and thus to the total dopamine agonism load. To conclude, though it is likely that concomitant use of other antiparkinsonian drugs could have contributed to the onset of PS in our patient, it is noteworthy that PS was not evident before rasagiline was started, it became evident after rasagiline was initiated, and it was not anymore evident after rasagiline was stopped.

Clinical activity after fingolimod cessation: disease reactivation or rebound?

There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS.

Anodal transcranial direct current stimulation over the right hemisphere improves auditory comprehension in a case of dementia

BACKGROUND Noninvasive transcranial stimulation methods have been increasingly employed in order to improve cognitive performance in neurological patients. In previous studies with both stroke patients and healthy subjects, noninvasive stimulation of temporal-parietal regions and their homologue produced an improvement in linguistic tasks. OBJECTIVE The aim of the current study was to evaluate if anodal transcranial direct current stimulation (tDCS) over Brodmann areas 39/40 (angular and supramarginal gyri) could promote the recovery of linguistic functions, in particular comprehension and naming, in a single patient affected by dementia. METHODS Three preliminary explorative single sessions (right-side anodal, left-side anodal and sham tDCS) were carried out (Experiment 1). This procedure allows targeting the more effective site of stimulation for the treatment. Subsequently, we carried out a five-days tDCS treatment on the selected hemisphere (Experiment 2). RESULTS We report verb comprehension amelioration after 5 days of anodal tDCS over the right BAs 39/40 compared with the placebo tDCS. This result is maintained until two weeks after the end of the 5-days treatment. CONCLUSIONS Our findings provide new evidence for the therapeutic use of tDCS in degenerative diseases, suggesting that an explorative study can be useful for targeting the more appropriate stimulation site, and confirm the involvement of right-sided areas associated with language activities.