Evaluation of drivers of treatment switch in relapsing multiple sclerosis: a study from the Italian MS Registry.

BACKGROUND: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). METHODS: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. RESULTS: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. CONCLUSIONS: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.

Tremulous spastic ataxia in a patient with a homozygous truncating SYNE1 variant.

We describe a case of severe adult-onset progressive tremulous cerebellar ataxia with pyramidal signs associated with a rare homozygous truncating pathogenic variant in the SYNE1 gene (p.Arg5371*). This contrasts the initial views on SYNE1-related ataxia as a relatively benign, slowly progressive condition, with important implications for clinic-genetic counselling.

Visuospatial Deficits Are Associated with Pisa Syndrome and not Camptocormia in Parkinson's Disease.

Background: Pisa syndrome (PS) and camptocormia (CC) are postural abnormalities frequently associated with Parkinson's disease (PD). Their pathophysiology remains unclear, but the role of cognitive deficits has been postulated. Objectives: To identify differences in the neuropsychological functioning of patients with PD with PS or CC compared with matched patients with PD without postural abnormalities. Methods: We performed a case-control study including 57 patients with PD with PS (PS+) or CC (CC+) and 57 PD controls without postural abnormalities matched for sex, age, PD duration, phenotype, and stage. Patients were divided into four groups: PS+ (n = 32), PS+ controls (PS-, n = 32), CC+ (n = 25), and CC+ controls (CC-, n = 25). We compared PS+ versus PS- and CC+ versus CC- using a neuropsychological battery assessing memory, attention, executive functions, visuospatial abilities, and language. Subjective visual vertical (SVV) perception was assessed by the Bucket test as a sign of vestibular function; the misperception of trunk position, defined as a mismatch between the objective versus subjective evaluation of the trunk bending angle >5°, was evaluated in PS+ and CC+. Results: PS+ showed significantly worse visuospatial performances (P = 0.025) and SVV perception (P = 0.038) than their controls, whereas CC+ did not show significant differences compared with their control group. Reduced awareness of postural abnormality was observed in >60% of patients with PS or CC. Conclusions: Low visuospatial performances and vestibular tone imbalance are significantly associated with PS but not with CC. These findings suggest different pathophysiology for the two main postural abnormalities associated with PD and can foster adequate therapeutic and prevention strategies.

VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.

VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson's disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.

Continuous subcutaneous apomorphine infusion allowing awake deep brain stimulation in a Parkinson's disease patient.

BACKGROUND: Subthalamic Deep Brain Stimulation (DBS) have demonstrated in the last decades to determine an important clinical improvement in advanced and selected Parkinson's disease (PD) patients. However, only a minority of parkinsonian patients meet the criteria to undergo DBS, and the surgical procedure itself is often stressful, especially for patients experiencing severe OFF state. Subcutaneous Apomorphine continuous administration is suitable as an adjunctive therapy capable of improving a suboptimal DBS result. Here we hypothesize a possible role for subcutaneous apomorphine infusion to alleviate severe OFF state in parkinsonian patients undergoing DBS, thus allowing intraoperative microrecording and patient's collaboration during clinical testing. CASE PRESENTATION: A 68-year-old man, suffering from a very long PD-history, characterized by a severe akinetic status and dramatic non-motor features while in OFF, underwent Subthalamic-DBS keeping a slight but continuous apomorphine infusion (1.8 mg/hour), able to guarantee the right degree of patient's collaboration without interfering with microelectrode recordings. There were no intra or perioperative complications and after the procedure he experienced a marked clinical benefit, being able to stop apomorphine administration. CONCLUSIONS: Here we described the first Subthalamic DBS procedure performed with a low and stable dopaminergic stimulation guaranteed by subcutaneous Apomorphine continuous infusion. For its rapidity of action and prompt reversibility, apomorphine could be particularly suitable for use during difficult surgical procedures in PD, allowing more therapeutic opportunities for patients who would otherwise be excluded from the DBS option.

The Choice of Leg During Pull Test in Parkinson's Disease: Not Mere Chance.

Background: Parkinson's disease (PD) starts asymmetrically and it maintains a certain degree of asymmetry throughout its course. Once functional disability proceeds, people with PD can change their dominant hand due to the increased disease severity. This is particularly true for hand dominance, while no studies have been performed so far exploring the behavioral changes of lower limb utilization in PD according to the lateralized symptom dominance. In the current study, we aim to track the foot preference of participants with PD to respond to the Pull Test. Methods: Forty-one subjects suffering from PD, with a H&Y scale ≤ 2, were recruited. A motor evaluation was performed, including the motor part of the MDS-UPDRS, its axial and lateralized scores (for more and less affected side), two Timed Tests, namely Time to Walk a standard distance (TW, in seconds) and Time Up and Go Test (TUG, in seconds), and the Pull Test. The preferred foot (right or left) involved in the step backward was recorded. Thirty-seven healthy controls underwent a motor assessment which included the Pull Test and the Timed Tests. Both participants with PD and controls were right-handed. To evaluate the relationship between the response to Pull-Test and PD-symptoms, subjects with PD were further divided into two groups: (1) Right more affected side (Right-MAS), and (2) Left more affected side (Left-MAS). Results: Both groups of subjects with PD (Right-MAS and Left-MAS) during the Pull Test shifted significantly their leg use preference toward the opposite side than the more affected side: Right-MAS used preferentially their left leg (71%) and vice versa (p < 0.001). The limb preference shift was especially true for Left-MAS group that almost invariably used their right, dominant leg to respond to the Pull Test (95%). Similar results were obtained comparing people with PD and Controls. Conclusions: This study shows that the limb used to respond to the Pull Test generally predicts the contralateral side of worse PD involvement. As the disease takes place, it prevails over hemispheric dominance: right-handed subjects with left side PD-onset and worse lateralization tend to be hyper-right-dominant, while right-handed subjects with right side PD-onset and worse impairment tend to behave as left-handers. Lateralization of symptoms in PD is still a mysterious phenomenon; more studies are needed to better understand this association and to optimize tailored rehabilitation programs for people with PD.

Neurological Involvement in the Course of Scleromyxedema: A Case Report.

Scleromyxedema is a rare disease of unknown etiology primarily affecting the skin, characterized by generalized papular eruption, dermal fibroblast proliferation with mucin deposition, and a monoclonal gammopathy. Neurological impairment is a rare but sometimes fatal complication of scleromyxedema that should be rapidly identified to prevent significant morbidity and mortality. A 63-year-old Caucasian man had a 2-year history of scleromyxedema, and was under immunosuppressive treatment with ciclosporine and methotrexate. The patient came to our attention because of sudden neurological dysfunction with altered sensorium, confusion, and dysarthria. After a few hours since admission, the patient developed left hemiparesis, followed after 2 days by right hemiparesis. The brain computed tomography and cerebrospinal fluid examination results were normal. Brain magnetic resonance imaging (MRI) showed a bilateral cortical hyperintense signal on T2 sequences with leptomeningeal enhancement. Extensive serological and liquoral evaluations were performed without significant findings. After steroid initiation, a remarkable neurological improvement was noticed. The dramatic and immediate response of the patient's to steroid and MRI data strongly suggested a dysimmune etiology. Over the ensuing week, the patient's language, motor, and sensory functions continued to improve. Two weeks after admission, the patient was discharged to home without significant neurological sequelae.