Hyperkinetic movement disorders in congenital disorders of glycosylation.

BACKGROUND AND PURPOSE: Congenital disorders of glycosylation (CDG) represent an increasing number of rare inherited metabolic diseases associated with abnormal glycan metabolism and disease onset in infancy or early childhood. Most CDG are multisystemic diseases mainly affecting the central nervous system. The aim of the current study was to investigate hyperkinetic movement disorders in patients affected by CDG and to characterize phenomenology based on CDG subtypes. METHODS: Subjects were identified from a cohort of patients with CDG who were referred to the University Hospital of Catania, Italy. Patients were evaluated by neurologists with expertise in movement disorders and videotaped using a standardized protocol. RESULTS: A variety of hyperkinetic movement disorders was detected in eight unrelated CDG patients. Involuntary movements were generally observed early in childhood, maintaining a clinical stability over time. Distribution ranged from a generalized, especially in younger subjects, to a segmental/multifocal involvement. In patients with phosphomannomutase 2 CDG, the principal movement disorders included dystonia and choreo-athetosis. In patients affected by other CDG types, the movement disorders ranged from pure generalized chorea to mixed movement disorders including dystonia and complex stereotypies. CONCLUSIONS: Hyperkinetic movement disorder is a key clinical feature in patients with CDG. CDG should be considered in the differential diagnosis of childhood-onset dyskinesia, especially when associated with ataxia, developmental delay, intellectual disability, autism or seizure disorder.

Late-onset and young-onset relapsing-remitting multiple sclerosis: evidence from a retrospective long-term follow-up study.

BACKGROUND AND PURPOSE: Late-onset multiple sclerosis (MS) has a prevalence of about 10-20% in natural history MS studies. Few data have been published about the long-term disease trajectory in the cohort of late-onset relapsing-remitting MS (LORRMS). The aim of this study was to identify the risk factors for reaching an Expanded Disability Status Scale (EDSS) score of 6.0 in LORRMS (onset at >40 years of age) and young-onset relapsing-remitting MS (YORRMS) (onset between 18 and 40 years of age). METHODS: Clinical and radiological [magnetic resonance imaging (MRI) of the brain] follow-up data were collected. Disability was assessed by EDSS score. A Cox proportional hazards model was used to evaluate the demographic and clinical predictors of reaching an EDSS score of 6.0 in the two cohorts. RESULTS: A total of 671 patients with relapsing-remitting MS were enrolled, 143 (21.3%) with LORRMS and 528 (78.7%) with YORRMS. In LORRMS, age at onset was 47.8 ± 5.3 (mean ± SD) years and duration of follow-up was 120.7 ± 52.7 months. In YORRMS, age at onset was 27 ± 2.7 years and duration of follow-up was 149.9 ± 92.7 months. The survival curve analyses showed a higher probability of reaching an EDSS score of 6.0 for LORRMS in a shorter time (months) than for YORRMS (94.2 vs. 103.2 months; log-rank 8.8; P < 0.05). On MRI, YORRMS showed more brain inflammatory features than LORRMS. In the multivariate Cox model, age at onset [Exp(B) value, 6.5; 95% confidence interval, 1.9-22.6; P < 0.001] and male gender [Exp(B) value, 1.7; 95% confidence interval, 1.0-2.8; P < 0.05] were the strongest predictors of reaching an EDSS score of 6.0. CONCLUSIONS: The male population with LORRMS reached severe disability faster than those with YORRMS, even when YORRMS showed more brain inflammatory features on MRI.

Blink reflex recovery cycle to differentiate progressive supranuclear palsy from corticobasal syndrome.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may share similar clinical findings and tests to distinguish between the two disorders could be useful. We evaluated the blink reflex and R2 blink reflex recovery cycle (R2BRRC), determining diagnostic sensitivity, specificity and positive and negative predictive value of R2BRRC in differentiating patients with PSP from those with CBS. METHODS: This was a prospective data collection study investigating blink reflex and R2BRRC at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in 12 patients with PSP, eight patients with CBS and 10 controls. RESULTS: Patients with PSP have earlier recruitment of R2BRRC as compared with patients with CBS (ISI: 100 ms, P = 0.002; 150 ms, P < 0.001; 200 ms, P < 0.001; 300 ms, P = 0.02) and controls (ISI: 100 ms, P < 0.001; 150 ms, P < 0.001; 200 ms, P < 0.001; 300 ms, P = 0.004). The presence of an early recovery of the R2 differentiated PSP from CBS with a specificity and sensitivity of 87.5% and 91.7%, respectively. CONCLUSIONS: The R2BRRC curve might be considered to be a useful tool in differentiating patients with PSP from those with CBS.

A rare case of Hoffa's fat pad herniation in a young patient: dynamic ultrasound and MRI diagnosis.

Hoffa's fat pad (HFP) is part of the knee structure interposed between the joint capsule and the synovium. Recent studies have classified infrapatellar fat pad (IFP) disorders on a pathogenesis-based classification: traumatic disorders, post-traumatic disorders, lesions secondary to adjacent disorders. Masses or pseudo-masses may also be found within the IFP, however these alterations are much less frequent. Diagnostic imaging plays an important role in the diagnosis of masses and pseudo-masses of IFP and the first choice exam is a dynamic ultrasound study. We presented a rare case of Hoffa's fat pad herniation through the joint capsule, in a young child without history of knee injuries that has never been described before in the literature.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.

BACKGROUND: The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. METHODS: We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0-10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. RESULTS: A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3-2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). CONCLUSIONS: Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

The epidemiology of amyotrophic lateral sclerosis in the Mount Etna region: a possible pathogenic role of volcanogenic metals.

BACKGROUND AND PURPOSE: Trace elements (TEs) may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and volcanic degassing is the major natural source of TEs. Mount Etna, in the province of Catania, is the largest active volcano in Europe. Our aim was to assess the incidence of ALS in the province of Catania during 2005-2010 and its spatial distribution with respect to volcanic gas deposition. METHODS: Cases from all neurological centres of the province of Catania and of the boundary provinces were retrospectively collected. Patients who had onset during 2005-2010 and fulfilled the El Escorial revised diagnostic criteria were included. The incidence of ALS was estimated for the entire province and separately for the population living on the eastern and western flank of Mount Etna, respectively, the most and least exposed areas to volcanogenic TEs, considered as a possible risk factor for ALS. RESULTS: One hundred and twenty-six (57 men) ALS patients were enrolled. The mean annual crude incidence rate was 2.0/100 000 person-years (95% confidence interval 1.7-2.4). A higher incidence rate was found in the population living on the eastern flank compared to the western flank (2.4/100 000 and 0.9/100 000 respectively) with a relative risk of 2.75 (95% confidence interval 1.64-4.89; P < 0.001). CONCLUSIONS: The incidence of ALS in the province of Catania is close to those reported worldwide. The incidence was higher amongst the population living on the eastern flank of Mount Etna, which could be interpreted as a possible role of volcanogenic TEs. Further research on TEs and genetic factors is necessary to support this assumption.

Restless legs syndrome and multiple sclerosis: a population based case-control study in Catania, Sicily.

BACKGROUND AND PURPOSE: A population-based case-control study in the city of Catania, Sicily, was carried out to determine restless legs syndrome (RLS) prevalence and its association with multiple sclerosis (MS). METHODS: Patients were randomly selected from a cohort of MS patients resident in the study area and a group of age and sex matched controls was enrolled from the general population. RLS was diagnosed according to the International Restless Legs Syndrome Study Group criteria. RESULTS: In total, 152 MS patients and 431 controls were included in the study. A significantly higher prevalence of RLS amongst MS patients (14.5%) compared with controls (6.0%) was detected, corresponding to an almost threefold increased risk (odds ratio 2.7, 95% confidence interval 1.4-5.0) of developing RLS. Spinal cord lesions in MS patients were associated with a higher risk of RLS (odds ratio 3.7, 95% confidence interval 1.1-13.5). CONCLUSION: RLS was strongly associated with MS, with a significantly higher risk in patients presenting spinal cord lesions.

Clinical and magnetic resonance imaging predictors of disease progression in multiple sclerosis: a nine-year follow-up study.

OBJECTIVE: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients. METHODS: A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4. RESULTS: We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)). CONCLUSIONS: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

Pregnancy outcomes in multiple sclerosis patients previously treated with cyclophosphamide.

BACKGROUND: Cyclophosphamide (Cyc) can induce ovarian failure and can have teratogenic effect. Few case reports of successful pregnancies after Cyc treatment in women with autoimmune diseases and malignancies have been described. To date, there are no data about Cyc effect on pregnancy outcomes in MS patients. AIM OF THE STUDY: To describe pregnancy outcomes in multiple sclerosis (MS) patients treated with Cyc before conception. METHODS: We reviewed retrospectively the medical records of all MS patients who received Cyc from 1st of January 1997 to 31st of March 2012, referring to the MS centre of the University of Catania. All pregnancies, occurred during the follow-up period after Cyc treatment, were recorded according to a computerized and standardized protocol (iMED). RESULTS: We found a total of 105 MS women of childbearing age; eleven patients experienced a pregnancy (10.4%); 10 of them had a successful delivery; and one experienced a voluntary abortion. Five women had a preterm delivery. One child was small for gestational age. CONCLUSIONS: Although the favourable pregnancy outcomes, Cyc should be avoided in young women planning a pregnancy. However, Cyc might be considered as a possible alternative to licensed therapies in few selected cases of very aggressive MS, including women of childbearing age.

Non-motor symptoms in PD evaluated during pharmacological ON state by a new tool: The NoMoS-ON scale. Is always the "ON" state beneficial?

OBJECTIVES: To evaluate non-motor symptoms (NMS) occurring during ON pharmacological state and validate a new questionnaire, the Non-motor symptoms-ON scale (NoMoS-ON), exploring ON NMS in Parkinson's disease (PD). MATERIAL AND METHODS: Patients with PD were evaluated by a new questionnaire, the NoMoS-ON scale, evaluating 17 items related to the main symptoms experienced during the ON state. PD patients who experienced at least one symptom in ON were defined ON-NMS+. Internal consistency and test-retest reliability of NoMoS-ON scale were also assessed. RESULTS: One-hundred and thirty-seven PD patients were consecutively enrolled (79 men and 58 women, age 69.4 ± 9.5 years (mean ± SD)). Seventy-seven patients were ON-NMS+ (56.6 %). PD patients with short disease duration (<7 years) showed the presence of unpleasant NMS: "sleepiness", "light-headedness", "nausea/vomiting". PD patients with longer disease duration experienced pleasant non-motor features including "feel lot of energy", "feel physical well-being". ON-NMS+ were also associated with female gender (OR 2.81, 95%CI 1.37-5.77, p-value 0.005) and with motor fluctuations (OR 2.41, 95%CI 1.20-4.83, p-value 0.013). Cronbach's alpha was 0.61 and 5 items had adequate item-to-total correlations (r ≥ 0.40). Test-retest reliability was acceptable (intraclass correlation coefficient, ICC = 0.77). CONCLUSIONS: The NoMoS-ON scale is a valid, reproducible and reliable questionnaire capturing the ON NMS in PD. PD patients with disease duration shorter than 7 years showed the presence of unpleasant NMS whereas those with longer disease duration experienced pleasant non-motor features. This could help the physician in the therapy management of PD patients in different phases of their disease.

Frequency and severity of headache is worsened by Interferon-ß therapy in patients with multiple sclerosis.

BACKGROUND: The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon-beta (IFNß) could induce or worsen HA. OBJECTIVE: To evaluate the impact of IFNß treatment on HA and the relationship between HA and the various commercial preparations of IFNß in mildly disabled patients with MS. METHODS: A specific questionnaire was administered to 357 relapsing-remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNß administration. RESULTS: One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNß-1a (Avonex(®)), 84 with subcutaneous injections of IFNß-1b (Betaferon(®)) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNß-1a (Rebif(®)) 22 mcg or IFNß-1a (Rebif(®)) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre-existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNß therapy; this was more frequently reported by patients treated with Avonex(®) and Rebif(®) 44. Ninety-five patients experienced new HA. CONCLUSION: IFNß treatment could worsen HA in patients with pre-existing HA or cause the appearance of new HA. Among different IFNß preparations, Rebif(®) 44 and Avonex(®) seemed to be more cephalalgic than the other drugs.

[(123) I]FP-CIT-SPECT asymmetry index to differentiate Parkinson's disease from vascular parkinsonism.

OBJECTIVES: Differential diagnosis between vascular parkinsonism (VP) and Parkinson's Disease (PD) is often difficult, due to the overlap in clinical presentation and the lack of specificity at neuroimaging. Aim of the study was to identify a possible reliable marker at SPECT imaging useful to distinguish the two conditions. MATERIAL AND METHODS: We studied 20 PD, 20 VP and 20 essential tremor (ET) patients as control group, who had undergone a cerebral [(123) I] FP-CIT SPECT. A semiquantitative analysis was performed on DaTSCAN SPECT imaging and to establish the degree of asymmetry of the ligand uptake the Striatal Asymmetry Index (SAI) was used. RESULTS: The binding of the ligand in the most affected side resulted significantly lower in VP than in ET patients but higher compared to PD patients. SAI was significantly higher in PD compared to VP (P < 0.001) and ET (P < 0.001) groups. We found that a cut-off of SAI greater than 14.08 could differentiate PD from VP with a 100% specificity and a 50% sensitivity. CONCLUSIONS: SAI detected using [(123) I]FP-CIT SPECT can be used to differentiate VP and PD with a good degree of certainty.

Variable effects of cyclophosphamide in rodent models of experimental allergic encephalomyelitis.

In this study, we have evaluated the effects of cyclophosphamide on the development of experimental allergic encephalomyelitis (EAE) in four EAE rodent models: monophasic EAE in Lewis rats, protracted relapsing (PR)-EAE in DA rats, myelin oligodendrocyte protein (MOG)-induced EAE in C57Bl/6 mice and proteolipid protein (PLP)-induced EAE in Swiss/Jackson Laboratory (SJL) mice. Cyclophosphamide, administered either prophylactically or therapeutically, suppressed most strongly the clinical symptoms of PR-EAE in DA rats. Treated rats in this group also exhibited the lowest degree of inflammatory infiltration of the spinal cord, as well as the lowest levels of nuclear factor kappa B, interleukin-12 and interferon-gamma. Cyclophosphamide prophylactically, but not therapeutically, also delayed significantly the onset of EAE in Lewis rats. In contrast, regardless of the treatment regimen used, was unable to influence the clinical course of EAE in either MOG-induced EAE in C57Bl/6 mice or PLP-induced EAE in SJL mice. This heterogeneous pharmacological response to cyclophosphamide suggests that significant immunopathogenic differences exist among these EAE rodent models that must be considered when designing preclinical studies. In addition, the effectiveness of cyclophosphamide in dark Agouti (DA) rats with PR-EAE suggests that this may be a particularly useful model for studying novel therapeutic approaches for refractory and rapidly worsening multiple sclerosis in human patients.