Carlo Alberto Artusi

Transient effects of 80 Hz stimulation on gait in STN DBS treated PD patients: A 15 months follow-up study

BACKGROUND Subthalamic nucleus deep brain stimulation (STN DBS) is an effective therapeutic option for advanced Parkinsons disease (PD). Nevertheless, some patients develop gait disturbances despite a persistent improvement of PD segmental symptoms. Recent studies reported that stimulation of STN with low frequencies produced a positive effect on gait disorders and freezing episodes. OBJECTIVE To evaluate the effects of 80 Hz stimulation frequency on gait in PD patients undergoing STN DBS and to determine whether such effects are maintained over time. METHODS We evaluated 11 STN DBS treated PD patients who had developed gait impairment several years after surgery. Gait was assessed by means of the Stand-Walk-Sit (SWS) test. Motor symptoms and activities of daily living were evaluated through the Unified PD Rating Scale (UPDRS). The stimulation frequency was switched from 130 Hz to 80 Hz, adapting the voltage to maintain the same total delivered energy. Patients were assessed at baseline and 3 hours after switching the stimulation frequency to 80 Hz. Follow-up evaluations were carried out after 1, 5, and 15 months. The clinical global improvement scale was rated at every follow-up visit. RESULTS A significant improvement of gait (SWS test) was evident immediately after switching the stimulation frequency to 80 Hz, with no deterioration of PD segmental symptoms. However, gait improvement was no longer detectable by the SWS test at follow-up evaluations 1, 5, and 15 months later. Three patients were switched back to 130 Hz because of unsatisfactory control of motor symptoms. Of the eight patients maintained at 80 Hz up to 15 months, five showed a global improvement and three showed no change. CONCLUSIONS Stimulation frequency at 80 Hz has an immediate positive effect on gait in STN DBS treated patients; however, the objective gait improvement is not maintained over time, limiting the use of this frequency modulation strategy in the clinical setting.

Medical therapy and subthalamic deep brain stimulation in advanced Parkinson's disease: a different long-term outcome?

Objectives Few clinical trials reported the comparative short-term efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) versus medical therapy in advanced Parkinsons disease (PD). However, the comparative efficacy, safety and the potential disease-modifying effect of these treatments have not been investigated over a longer follow-up period. Methods In this study, we organised a ‘retrospective control group’ to compare medical and surgical therapies over a long-term period. We assessed a group of PD patients suitable for STN-DBS but successively treated with medical therapies for reasons not related to PD, and a group of similar consecutive STN-DBS patients. We thus obtained two groups comparable at baseline, which were re-evaluated after an average follow-up of 6 years (range 4–11). Results Patients treated with STN-DBS showed a long-lasting superior clinical efficacy on motor fluctuations, with a significant reduction in the average percentage of the waking day spent in ‘OFF’ and in the duration and disability of dyskinesia. Moreover, operated patients showed a better outcome in the activities of daily living in ‘Medication-OFF’ condition. On the other hand, a similar progression of motor score and cognitive/behavioural alterations was observed between the two groups, apart from phonemic verbal fluency, which significantly worsened in STN-DBS patients. Conclusions To our knowledge, this is the first long-term comparison between medical and surgical therapies; a superior efficacy of STN-DBS was observed on motor disability, while no significant differences were observed in the progression of motor symptoms and, apart from phonemic verbal fluency, of neuropsychological alterations.

80 Hz versus 130 Hz subthalamic nucleus deep brain stimulation: Effects on involuntary movements

BACKGROUND Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) represents a valid therapeutic option for advanced Parkinsons disease (PD), leading to a significant amelioration of motor fluctuations and levodopa-induced involuntary movements (IM). This study address the issue of whether stimulation frequency may influence the control of IM in STN-DBS treated patients, comparing the effects of 80 Hz and 130 Hz STN-DBS frequencies in 10 parkinsonian patients with residual IM (dyskinesia in 6 cases and dystonia in 4 cases). METHODS Patients were evaluated by means of the Rush Dyskinesias Rating Scale (blinded-video analysis) and Unified Parkinsons Disease Rating Scale at 4 different time-points: baseline, shortly after the switch of stimulation frequency from 130 Hz to 80 Hz, after 1 month and 12 months of chronic 80 Hz stimulation. RESULTS IM improved in most subjects after the switch of stimulation frequency: dyskinesias improved in 6/6 subjects and dystonic features in 3/4 subjects after one month of 80 Hz stimulation. However, the 130 Hz STN stimulation was restored in 4 subjects during the following months, because of a gradual worsening of parkinsonian symptoms. A sustained efficacy on motor features and IM was observed with 80 Hz stimulation frequency in the remaining patients. CONCLUSIONS In this limited cohort of STN-DBS patients, we observed an improvement of residual IM after the switch of stimulation frequency from 130 Hz to 80 Hz. However, a moderate worsening of parkinsonian symptoms was observed in a portion of patients, requiring to return at 130 Hz STN-DBS.

Subthalamic nucleus deep brain stimulation outcome in young onset Parkinson's disease: a role for age at disease onset?

Background Patients with young onset Parkinsons disease (YOPD) are often candidates for subthalamic nucleus–deep brain stimulation (STN–DBS). Nevertheless, few data have been reported on the long term STN–DBS clinical outcome of YOPD versus non-young onset Parkinsons disease (n-YOPD) patients. Aim In this study, the issue of whether YOPD might represent a long term positive predictive factor for STN–DBS was addressed, comparing follow-up data for 20 YOPD and 40 n-YOPD patients (20 treated after <15 years of disease duration and 20 treated after ≥15 years of disease duration). Materials and methods Mean scores for the Unified Parkinsons Disease Rating Scale (UPDRS) sections were compared 1 year, 5 years and, for 34 patients (12 YOPD and 22 n-YOPD), ≥7 years after surgery. Furthermore, a Cox proportional hazard regression model was used to determine the influence of age at PD onset, clinical phenotype, disease duration and duration of motor complications on the development of stimulation and medication resistant symptoms. Results YOPD patients showed a lower incidence of stimulation and medication resistant symptoms and a lower mortality rate; also, the tremor dominant clinical phenotype was associated with a lower risk of developing dementia, hallucinations and constipation. No significant differences in UPDRS scores were observed between n-YOPD patients treated after <15 years of PD and those treated after ≥15 years of PD. Conclusion In this series of STN–DBS treated patients, YOPD was associated with a medium to long term lower incidence of stimulation and medication resistant symptoms.

Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab

Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta–treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.

Natalizumab in Multiple Sclerosis: Long-Term Management

Natalizumab is a monoclonal antibody highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Despite its effectiveness, there are growing concerns regarding the risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCV), particularly after 24 doses and in patients who previously received immunosuppressive drugs. Long-term natalizumab treated, immunosuppressive-pretreated, and JCV antibody-positive patients are asked to rediscuss natalizumab continuation or withdrawal after 24 doses. Until now, there has not been a clear strategy that should be followed to avoid PML risk and in parallel reduce clinical and radiological rebound activity. In this review, we analyzed the results of clinical trials and case reports in relation to the following situations: natalizumab continuation, natalizumab discontinuation followed by full therapeutic suspension or switch to other first or second line MS treatments. Quitting all MS treatment after natalizumab increases MS activity occurrence. The results regarding the therapeutic switch are not homogeneous, so at the moment there are no established guidelines regarding natalizumab treatment after 24 administrations; the choice is currently based on the professional experience of the neurologist, and on patients’ clinical features and preferences.

Prevalence and burden of dysautonomia in advanced Parkinson's disease

We sought to examine the prevalence and burden of dysautonomia in patients with advanced Parkinson’s disease (PD) treated with subthalamic deep brain stimulation (STNDBS) and levodopa-carbidopa intestinal gel infusion (LCIG). Using a standardized battery of autonomic tests, blood pressure measurement protocol, and the Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), 60 consecutive PD patients treated with STN-DBS (n 5 30) and LCIG (n 5 30) were classified according to the presence or absence of dysautonomia. We evaluated the impairment in activities of daily living/instrumental activities of daily living (ADL/iADL), adjusting for cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA), age, and motor severity using the motor subscale of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III). Additional measures included SCOPA-AUT, Orthostatic Hypotension Symptom Assessment, and the PD Quality-of-Life Questionnaire (PDQ-8). Binary logistic regression was used to estimate the impact (odds ratio [OR]) of dysautonomia on ADL/iADL, adjusting for cognitive impairment, age, and motor severity. A multiple linear regression model was used to estimate the correlation between SCOPA-AUT and PDQ-8. In addition, analysis of covariance was used to estimate the extent to which the dependent variables, ADL/iADL, adjusted for MoCA, age, and MDS-UPDRS-III, were influenced by (1) symptomatic state (symptomatic vs asymptomatic orthostatic hypotension); and (2) therapy (STN-DBS vs LCIG). Mann-Whitney and Fisher’s tests were used for comparisons between groups. The overall prevalence of dysautonomia in this unselected population was 48.3% (29 of 60 patients), similar to that in the STN-DBS (50%) and LCIG (46.7%) cohorts (P 5 0.796). Adjusted analysis showed that dysautonomia was independently associated with a threefold impairment in ADL/iADL (OR, 2.850; 95% CI, 1.044-10.326; P 5 0.042). There was a robust correlation between autonomic symptoms (SCOPA-AUT) and quality-of-life impairment (P< 0.001). The strongest correlation was for gastrointestinal (P< 0.001), urinary/sexual (P 5 0.01), and cardiovascular (P 5 0.017) domains. Adjusted ADL/iADL scores differed between patients with and without orthostatic hypotension (P 0.047). In post hoc analyses, symptomatic (15.0%) and asymptomatic (11.7%) orthostatic hypotension worsened ADL/iADL to a similar extent (P 0.045) compared with patients without orthostatic hypotension (Fig. 1). The adjusted ADL/iADL scores was similar in the STN-DBS and LCIG cohorts (P 0.473). Subanalysis of autonomic domains (Fig. 1) revealed worse cardiovascular impairment in the LCIG cohort (P 5 0.039), potentially because of higher dopaminergic dosage (Supplementary Table) and worse pupillomotor impairment in the STN-DBS cohort (P 5 0.026), plausibly associated with electrical spread to the optic tract.

Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis

ABSTRACT Introduction: Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti–JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies.

Effects of intestinal Levodopa infusion on freezing of gait in Parkinson disease

OBJECTIVE To determine the impact of levodopa-carbidopa intestinal gel (LCIG) infusion on different subtypes of freezing of gait (FoG) classified according to levodopa responsiveness in advanced Parkinson disease (PD) patients. METHODS We retrospectively assessed the presence and severity of FoG in 32 advanced PD patients based on the Unified PD Rating Scale (UPDRS) item 14 score. Different FoG subtypes were inferred from the score variation with oral dopaminergic medications. Modifications following long-term LCIG infusion were analysed. Motor symptoms and motor complications were assessed by UPDRS part III and IV respectively. RESULTS FoG related UPDRS score varied from 2.6±0.9 in OFF condition to 0.9±0.8 in the ON condition at baseline and improved to 0.6±0.7 with LCIG infusion (p=0.027). After a mean of 2.59±1.12years of continuous LCIG infusion, Pseudo-ON-FoG improved to a greater extent with LCIG infusion than with oral therapy in 12 patients (38%) and equally well in 8 patients (25%), OFF-type-FoG was controlled equally well in 8 patients (25%) and worsened slightly in 3 patients (9%). Unresponsive-FoG, present in one patient (3%), was unmodified by LCIG infusion. CONCLUSIONS Even though limited by the subjective simple measure of FoG, this study suggests that patients undergoing LCIG infusion maintain a good long-term control of FoG. Pseudo-on-FoG improves in a considerable percentage of patients and OFF-type-FoG remains well controlled with LCIG infusion. Further studies with a larger number of patients and objective measures of FoG are needed to confirm these findings.

Ultrasound-guided Botulinum Toxin-A Injections: A Method of Treating Sialorrhea.

Neurological diseases can be complicated by sialorrhea, an excessive flow of saliva. Patients suffering from moderate to severe sialorrhea have an impaired quality of life, often worsened by correlated complications such as aspiration pneumonia, oral infections, dental caries, and maceration of the skin. Diverse therapeutic approaches have been proposed for the treatment of sialorrhea, including surgery and the use of anticholinergic agents, with limited results and the possible occurrence of serious adverse events. Recently, botulinum toxin (BoNT) injection within the major salivary glands has been proposed in patients refractory to anticholinergic therapy, with the aim of inhibiting local acetylcholine release and gland activity. In order to obtain a better outcome in terms of reduction of saliva production, efficacy, duration, and avoidance of major adverse events, we developed an ultrasound-guided BoNT-type A injection technique accurately described in the text. Here we present a method of treating sialorrhea with bilateral parotid and submandibular gland BoNT-type A injections under ultrasound guidance. Four quadrants of the parotid gland and two quadrants of the submandibular gland are visualized and injected using two accesses and one access, respectively. The ultrasound-guided procedure provides a simple, non-invasive, real-time visualization of the muscular and glandular tissues and their surrounding structures, optimizing treatment efficacy and safety.