Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study.

BACKGROUND: The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant (IS) drugs. METHODS: We performed a cohort study including MS patients recruited at the Neurological Department of the University of Palermo. Mean follow-up period was ten years for the whole cohort. We calculated cancer incidence among patients treated with IS. Incidence rates were compared in the cohort by calculating the relative risk according to length and dose of exposure to IS. Cancer incidence among MS patients was compared to cancer incidence in the general population of Sicily in similar age groups. RESULTS: On an overall cohort of 531 MS patients (346 women and 185 men) exposed to IS, we estimated a crude incidence rate for cancer of 2.26% (2.02% in women, 2.7% in men). Cancer risk was higher compared to rates observed among an equal number of patients not exposed to IS, and to the risk in the general population in Sicily at similar age groups (adjusted HR: 11.05; CI 1.67-73.3; p = 0.013). CONCLUSION: The present study showed a higher cancer risk in MS patients associated only to previous IS exposure. Studies on long-term outcomes are essential to evaluate the possibility that treatment options that need to be considered for a long time-period may modify risk for life threatening diseases.

In patient's with Parkinson disease, autonomic symptoms are frequent and associated with other non-motor symptoms.

BACKGROUND: Autonomic symptoms and sleep disorders are common non-motor symptoms of Parkinson disease (PD), which are correlated with poor quality of life for patients. PURPOSE: To assess the frequency of autonomic symptoms in a consecutive series of PD patients and to correlate them with other motor and non-motor symptoms. METHODS: All consecutive non-demented PD patients who underwent an extensive evaluation including Hoehn and Yahr staging, Unified Parkinson's Disease Rating Scale, Beck's Depression Inventory, Neuropsychiatric Inventory, PDQ-39 Scale, the Parkinson's diseases Sleep Scale, the Epworth Sleepiness Scale and SCOPA-AUT scale were enrolled. Comorbidity has been also considered. Supine to standing position blood pressure and cardiac frequency changes were also measured. RESULTS: 135 PD patients were included (mean age at interview 67.7; mean disease duration: 5.3 years). Patients were stratified according to mean SCOPA-AUT scale score (13.1). Those with higher SCOPA-AUT scale score were significantly older, had longer disease duration, worse disease stage, worse quality of sleep, were more severely affected, and were also taking a higher dosage of levodopa. At multivariate analysis, older age, longer disease duration, and worse quality of sleep were independently associated with higher SCOPA-AUT scale scores. CONCLUSIONS: Our results remark the role of autonomic symptoms in PD. In our patient population, characterized by mild to moderate disease severity, most of the patients complained of autonomic nervous system involvement (84%). A significant association between autonomic symptoms and sleep disorders was also observed.

Transcranial direct current stimulation for treatment of freezing of gait: a cross-over study.

BACKGROUND AND OBJECTIVE: Progression of Parkinson's disease (PD) is frequently characterized by the occurrence of freezing of gait (FOG) representing a disabling motor complication. We aim to investigate safety and efficacy of transcranial direct current stimulation of the primary motor cortex of PD patients with FOG. METHODS: In this cross-over, double-blind, sham-controlled study, 10 PD patients with FOG persisting in "on" state underwent anodal and sham direct current stimulation for 5 consecutive days. Clinical assessment over a 1-month period was performed. RESULTS: A significant improvement of gait, as assessed by the Stand Walk Sit test, with reduction in number and duration of FOG episodes, along with a significant reduction in the Unified Parkinson's Disease Rating Scale score, were observed after anodal stimulation. Beneficial effects were more evident after the entire 5-day stimulation session, and persisted until the end of the observation period. CONCLUSIONS: Anodal transcranial direct current stimulation of the motor cortex is safe and has therapeutic potential in PD patients with FOG.

Early and late mortality of spontaneous hemorrhagic transformation of ischemic stroke.

BACKGROUND: Hemorrhagic transformation (HT), a complication of ischemic stroke (IS), might influence patient's 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.

Identification of biomarkers in cerebrospinal fluid and serum of multiple sclerosis patients by immunoproteomics approach.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. At present, the molecular mechanisms causing the initiation, development and progression of MS are poorly understood, and no reliable proteinaceous disease markers are available. In this study, we used an immunoproteomics approach to identify autoreactive antibodies in the cerebrospinal fluid of MS patients to use as candidate markers with potential diagnostic value. We identified an autoreactive anti-transferrin antibody that may have a potential link with the development and progression of MS. We found this antibody at high levels also in the serum of MS patients and created an immunoenzymatic assay to detect it. Because of the complexity and heterogeneity of multiple sclerosis, it is difficult to find a single marker for all of the processes involved in the origin and progression of the disease, so the development of a panel of biomarkers is desirable, and anti-transferrin antibody could be one of these.

Incidence of amyotrophic lateral sclerosis in Sicily: A population based study.

Our objective was to investigate incidence of amyotrophic lateral sclerosis (ALS) in Sicily, southern Italy, by means of a population based study. We included people with ALS resident in five Sicilian provinces, whose onset occurred in the two-year period 2005-2006 (population at 31 December 2006: 3,481,096 inhabitants). A multisource case-finding procedure was adopted and patients were classified as affected by ALS according to revised El Escorial criteria. During the two-year surveillance period, 97 patients meeting eligibility criteria included 57 males (58.8%) and 40 females (41.2%). Crude annual incidence rate was 1.4/100,000 person years (95% CI 1.33-1.47). The incidence rate was higher in males (1.71/100,000; CI 1.61-1.81) than in females (1.11/100,000; CI 1.01-1.21). Standardized incidence rate for the total population in the 45-74-years-old age group was 3.22 (CI 3.11-3.33). Prevalence rate was 6.0/100,000 (CI 5.97-6.03), higher in males (7.1/100,000; CI 7.02-7.18) than females (4.9/100,000; CI 4.86-4.94). In conclusion, ALS rates observed in the present study are higher in males than females, with a peak of incidence at 70 years of age in both genders. These findings are consistent with those of other population based European studies.

Sleep quality in caregivers of patients with Alzheimer's disease and Parkinson's disease and its relationship to quality of life.

BACKGROUND: Knowledge about sleep complaints of caregivers of patients with Alzheimer's disease (AD) and Parkinson's disease (PD) is limited, and we lack information about the relationship between caregivers' sleep problems and their quality of life (QoL). METHODS: We evaluated subjective sleep quality and its relationship to QoL in a group of 80 caregivers of patients with AD (ADCG, n = 40) and PD (PDCG, n = 40), and in 150 controls. Information about night-time complaints was collected using the Pittsburgh Sleep Quality Index (PSQI). QoL was measured using the McGill QoL Questionnaire. RESULTS: Eighteen ADCG (45%), 22 PDCG (55%), and 45 (30%) controls reported poor sleep quality. Mean global PSQI score of PDCG (6.25 ± 3.9) was not significantly different from that of ADCG (5.8 ± 3.5; p = 0.67). However, both PDCG and ADCG scored significantly higher than control group (4.3 ± 3.1; p < 0.01). ADCG frequently reported difficulties falling asleep (72.5%) and disturbed sleep (100%). PDCG reported reduced subjective sleep quality (80%) and increased sleep disturbances (100%). Poor sleep quality was associated with depressive symptoms and correlated with QoL in caregivers of both groups, particularly the psychological symptoms domain. CONCLUSIONS: Among caregivers of patients with AD and PD, poor sleep quality is frequent and significantly linked to QoL and depressive symptoms. Identifying the nature of sleep disturbances not only in patients but also in their caregivers is important as appropriate treatment may lead to a better management of the needs of families coping with these patients.

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.

Cholesterol levels and risk of hemorrhagic transformation after acute ischemic stroke.

BACKGROUND: The association between cholesterol levels and hemorrhagic transformation (HT) is still controversial. Studies investigating this issue are influenced by treatments as some are characterized by a higher risk of HT. The aim of our study was to evaluate, in a hospital-based series of patients not treated with thrombolysis, the relationship between cholesterol levels and HT. METHODS: We retrospectively collected information about total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) levels at admission in a consecutive series of 240 patients with anterior ischemic stroke (IS). The TC and LDLC levels were arranged in 3 groups according to their percentile distribution. RESULTS: TC levels were available for 215 patients (89.6%), while LDLC levels were available for 184 patients (76.7%). The risk of HT significantly increased with decreasing levels of TC (p for trend = 0.03) and LDLC (p for trend = 0.01). In multivariate analysis, the risk of HT was significantly higher in the groups of patients with the lowest TC (OR 2.8, 95% CI 1.0-8.9, p = 0.05) and LDLC (OR 5.0, 95% CI 1.2-20.1, p = 0.002) values compared to those with the highest ones. CONCLUSION: We confirm that lower TC and lower LDLC levels are associated with an increased risk of HT. As none of our patients received thrombolytic therapy, the results of our study provide baseline information about the natural history of HT.

Reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterised by fever, microangiopathic haemolytic anaemia, renal insufficiency, and thrombocytopenia. Neurological involvement, a prominent component of TTP, is characterised by a variety of brain lesions which include reversible cerebral oedema or magnetic resonance imaging (MRI) features of reversible posterior leukoencephalopathy syndrome (RPLS). TTP is frequently associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13.Here, we report a case of TTP with severe acute encephalopathy. Posterior leukoencephalopathy and brainstem oedema with triventricular hydrocephalus were observed on MRI. The low activity of ADAMTS13 was not observed and ADAMTS-13 antibodies were absent. Neurological symptoms and patient's condition were completely resolved by plasma exchange therapy in addition to high dose of methylprednisolone.

Protective role of heat shock proteins in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Despite a large amount of research, the pathogenetic mechanism of these diseases has not yet been clarified. Abnormal protein folding, oxidative stress, mitochondrial dysfunction, and apoptotic mechanisms have all been reported as causes of neurodegenerative diseases in association with neuroinflammatory mechanisms which, by generating deleterious molecules, could promote the cascade of events leading to neurodegeneration. Heat shock proteins (HSPs) play a central role in preventing protein misfolding and inhibiting apoptotic activity, and represent a class of proteins potentially involved in PD pathogenesis. The present review will focus on two HSPs, HSP70 and HSP90, with the aim of specifying their role in PD pathogenesis.

Leprosy: report of a case with severe peripheral neuropathy.

Leprosy (Hansen's disease) is a chronic granulomatous infectious disease, caused by Mycobacterium leprae, with cutaneous and neurological manifestations. Leprosy is very rare in Europe but some cases are reported, especially among people coming from endemic areas. Here, we report a case of Hansen's disease and emphasize the importance of a prompt diagnosis and treatment also in non-endemic areas.

Blood lipids, homocysteine, stress factors, and vitamins in clinically stable multiple sclerosis patients.

Multiple Sclerosis (MS) patients present a decrease of antioxidants and neuroprotective and immunoregulatory vitamins and an increase of total homocysteine (tHcy), cholesterol (CHL), HDL-cholesterol, and of cellular stress markers, variably associated with the different phases of the disease. We compared the blood levels of uric acid, folic acid, vitamins B12, A, and E, tHcy, CHL, HDL-cholesterol, and triglycerides in forty MS patients during a phase of clinical inactivity with those of eighty healthy controls, matched for age and sex. We found higher levels of tHcy (p = 0.032) and of HDL-cholesterol (p = 0.001) and lower levels of vitamin E (p = 0.001) and the ratio vitamin E/CHL (p = 0.001) in MS patients. In conclusion, modifications of some biochemical markers of cell damage were detected in MS patients during a phase of clinical inactivity.

Frequency and determinants for hemorrhagic transformation of cerebral infarction.

BACKGROUND: Frequency and associated risk factors for hemorrhagic transformation (HT), a worrying complication of ischemic stroke (IS), are not clearly defined. Our aim was to estimate the overall frequency and risk factors for HT in a hospital-based population. METHODS: A retrospective review of medical records of patients discharged from our department during the period 2004-2006 with a diagnosis of anterior IS. Demographic, clinical and hematological information was collected. Uni- and multivariate logistic regression analyses were used to estimate risk for spontaneous HT. RESULTS: We included 240 patients (125 males, 52%), mean age at admission was 72.5 years. HT was observed in 29 patients (12%). At univariate analysis, consciousness impairment at admission (OR 5.6, 95% CI 1.3-28.2), the presence of early CT signs (OR 2.4, 95% CI 1.1-5.3), infarcts of medium-large size (OR 11.3, 95% CI 4.1-30.8), cardioembolic stroke (OR 2.3, 95% CI 1.1-5.2) and low total cholesterol levels (OR 3.3, 95% CI 1.3-8.2) were significantly associated with HT. At multivariate analysis, only infarct size (OR 10.2, 95% CI 3.2-32.1) was still significantly associated with HT. CONCLUSIONS: Frequency of HT in our study was 12%. Consistently with previous results, HT was associated with the size of ischemic area. As patients included in our study did not receive thrombolytic therapy, our results are applicable to those patients whom clinicians, working in a hospital setting, usually deal with.

Predictors of caregiver burden in partners of patients with Parkinson's disease.

Aim of this study was to determine the predictors of caregiver burden among spouse caregivers of patients with Parkinson's disease (PD). Forty consecutive PD patients and their spouse caregivers were included. Patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr scale (HY), the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the Geriatric Depression Scale (GDS). Stress and depressive symptoms among caregivers were evaluated using the Caregiver Burden Inventory (CBI) scale and the GDS. Only PD severity (HY) and mental symptoms (NPI) were significantly associated to caregiver distress. A major attention must be given to the early identification of factors generating stress in caregivers in order to improve caregiver quality of life and patient's care.

Progressive necrotic encephalopathy following tacrolimus therapy for liver transplantation.

Previously described neurologic damage induced by immunosuppressive treatments includes transient or reversible central nervous system involvement. We describe a 57-year-old man who underwent liver transplantation and was started on immunosuppressive therapy with tacrolimus (FK506). Six months later, he started complaining of a progressive motor and sensory impairment of the left side, together with cognitive impairment. Brain MRI showed an enlarging lesion of the white matter with peripheral contrast enhancement. PET study indicated severe hypometabolism in the right hemisphere and spectroscopic MRI showed a peak of choline and relative reduction of other metabolites. Findings of CSF examinations and cultures, serology, and molecular techniques were normal. Tacrolimus treatment was stopped. A cerebral biopsy of the lesion showed a sub acute necrotizing process. In the following months, cognitive status of the patient tended to improve although he remained hemiplegic, while serial MRI confirmed the tendency to the recovery of the lesion that was still present 1 year after. The present observation describes a progressive encephalopathy associated with immune suppression with an unusual feature and permanent brain damage.

Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease.

Myocardial (123)Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ-1, PINK1, and leucine-rich repeat kinase 2 -LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin-associated Parkinsonisms, in 1 of the 2 patients with DJ-1 mutations, in 1 of the 2 brothers with PINK1 mutations, in 3 of the 6 unrelated patients with Gly2019Ser mutation in the LRRK2 gene, whereas it was impaired in all patients with idiopathic PD. MIBG was preserved in all control subjects. Our study shows that myocardial MIGB uptake was normal in 8 of 14 patients with genetic PD, suggesting that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. Our findings also demonstrate that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation.

Motor intracortical inhibition in PD: L-DOPA modulation of high-frequency rTMS effects.

Dopaminergic drugs and deep brain stimulation restore cortical inhibition in Parkinson disease (PD) patients. High-frequency rTMS was also found to increase cortical inhibition in PD but its therapeutic effect is still controversial. Here we hypothesize that, if dopaminergic drugs reverse to normal cortical excitability in M1, the effect of high-frequency (hf)-rTMS in PD patients could depend on whether they are in a medicated or unmedicated state. The present study aims to explore the lasting effects of sub-threshold hf rTMS trains over M1 on cortical inhibition in patients with "on" and without "off" L-DOPA treatment. Fourteen PD patients were examined twice while "on" and "off" medication. In both conditions, a paired-pulse paradigm was used to evaluate short intracortical inhibition (SICI) and long intracortical inhibition (LICI) that were evaluated before and after hf rTMS trains applied on the motor cortex. The results were compared with those obtained from normal controls. In baseline condition, SICI and LICI were significantly reduced in "off" compared to "on" patients and controls. hf-rTMS over the motor cortex significantly increased SICI and LICI in "off" medication PD patients. Magnetic stimulation proved to be ineffective when the same patients were in "on" state. The results showed that hf-rTMS affected intracortical inhibition (ICI) only in unmedicated patients. By restoring cortical inhibitory circuits dopaminergic drugs, normalize the excitability changes in M1 subsequent to motor rTMS. Whether patients are in a medicated or an unmedicated state would therefore appear to be critical for rTMS effects in PD patients. If a positive correlation exists between increased cortical inhibition and clinical improvement, hf-rTMS during the "off" state could be regarded as a potential add-on treatment to reduce the need of L-dopa and thus delay the adverse effects of its chronic use.

Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor.

We previously set a three-cell-type coculture system in which neurons and astrocytes synergistically induce brain capillary endothelial cells to form a monolayer with permeability properties resembling those of the physiological blood-brain barrier. Moreover, we recently found that neurons produce fibroblast growth factor-2 and vascular endothelial growth factor and secrete them at least in part by shedding extracellular vesicles. In this study, on the basis of immunofluorescence, scanner electron microscopy and Western blot analyses, we concluded that also astrocytes in culture shed extracellular vesicles that contain the same angiogenic factors, as well as beta1-integrin, a membrane protein that is considered a marker of shedding. Vesicles released by astrocytes are smaller than the ones produced by neurons and have an average size of 150-500 nm.