Does Temporary Externalization of Electrodes After Deep Brain Stimulation Surgery Result in a Higher Risk of Infection?

OBJECTIVES: Deep brain stimulation (DBS) is a well-established surgical therapy for movement disorders that comprises implantation of stimulation electrodes and a pacemaker. These procedures can be performed separately, leaving the possibility of externalizing the electrodes for local field potential recording or testing multiple targets for therapeutic efficacy. It is still debated whether the temporary externalization of DBS electrodes leads to an increased risk of infection. We therefore aimed to assess the risk of infection during and after lead externalization in DBS surgery. MATERIALS AND METHODS: In this retrospective study, we analyzed a consecutive series of 624 DBS surgeries, including 266 instances with temporary externalization of DBS electrodes for a mean of 6.1 days. Patients were available for follow-up of at least one year, except in 15 instances. In 14 patients with negative test stimulation, electrodes were removed. All kinds of infections related to implantation of the neurostimulation system were accounted for. RESULTS: Overall, infections occurred in 22 of 624 surgeries (3.5%). Without externalization of electrodes, infections were noted after 7 of 358 surgeries (2.0%), whereas with externalization, 15 of 252 infections were found (6.0%). This difference was significant (p = 0.01), but it did not reach statistical significance when comparing groups within different diagnoses. The rate of infection with externalized electrodes was highest in psychiatric disorders (9.1%), followed by Parkinson's disease (7.3%), pain (5.7%), and dystonia (5.5%). The duration of the externalization of the DBS electrodes was comparable in patients who developed an infection (6.1 ± 3.1 days) with duration in those who did not (6.0 ± 3.5 days). CONCLUSIONS: Although infection rates were relatively low in our study, there was a slightly higher infection rate when DBS electrodes were externalized. On the basis of our results, the indication for electrode externalization should be carefully considered, and patients should be informed about the possibility of a higher infection risk when externalization of DBS electrodes is planned.

Serologic immunogenicity and safety of Herpes Zoster subunit vaccine in patients with Rheumatoid Arthritis receiving Janus Kinase inhibitors.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with Janus Kinase inhibitors (JAKi) are at increased risk of Herpes Zoster (HZ). The objective of this study was to investigate serological immunogenicity and safety of the HZ subunit (HZ/su) vaccine in RA patients treated with JAKi, for which little is known. METHODS: RA patients treated with JAKi (n = 82) at the Department of Rheumatology, Skåne University Hospital, Sweden, and healthy controls (n = 51) received two doses of the HZ/su vaccine (Shingrix). Vaccine-specific antibody responses were analysed using indirect enzyme-linked immunosorbent assay (ELISA). Post-vaccination antibody levels were compared between patients and controls using analysis of covariance. Potential predictors for vaccine response were investigated using a multivariable linear regression analysis. Self-reported adverse events (AEs) and changes in RA disease activity were analysed. RESULTS: Following vaccination, vaccine-specific antibody levels increased significantly in both patients and controls (p< 0.0001). 80.5% of patients and 98.0% of controls achieved a ≥ 4-fold increase in antibody levels. Post-vaccination antibody levels were lower in patients than controls (ratio 0.44, 95% CI 0.31-0.63), and lower in patients receiving JAKi+Methotrexate than JAKi monotherapy (ratio 0.43, 95% CI 0.24-0.79). AEs, mostly mild/moderate, were common. One patient developed HZ and six patients (6.5%) had increased RA disease activity following vaccination. CONCLUSION: The HZ/su vaccine was serologically immunogenic in most RA patients treated with JAKi. Moreover, the vaccine had an acceptable safety profile. These results support recommendations for usage of the HZ/su vaccine in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03886038.

Immunogenicity and safety of pneumococcal vaccination in patients with systemic sclerosis.

Objective: To study the impact of disease and treatment with DMARDs on antibody response elicited by either pneumococcal conjugate vaccine (PCV13) or pneumococcal polysaccharide vaccine (PPV23) in patients with SSc. Methods: Forty-four SSc patients and 49 controls received a dose of either PCV13 or PPV23. Twelve patients were treated with DMARDs. Antibody levels to pneumococcal polysaccharides 6B and 23 F were measured before and 4-6 weeks after vaccination using ELISA. Antibody functionality was studied using opsonophagocytic assay performed on serotype 23 F. Results: Number of patients, percentage female and mean age (years) at vaccination were: 32, 94%, 57.5 years in SSc without DMARDs; 12, 100%, 55.5 years in SSc on DMARDs and 49, 63% and 50.6 years in controls. Post-vaccination antibody levels for both serotypes increased significantly in SSc without DMARDs and controls (P < 0.001), but in SSc on DMARDs only for 6B (P = 0.041). Compared with the other groups, patients with SSc receiving DMARDs had lower post-vaccination antibody levels for both serotypes. Opsonophagocytic assay increased significantly in all three groups. No significant difference in immunogenicity between PCV13 and PPV23 was seen. Conclusion: Pneumococcal vaccination using either PCV13 or PPV23 yielded satisfactory antibody response in SSc patients without DMARD treatment, but a lower response in patients treated with synthetic DMARDs. Type of pneumococcal vaccine (conjugate or polysaccharide) did not significantly influence antibody response. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02240888.

Effects of Digital Physical Health Exercises on Musculoskeletal Diseases: Systematic Review With Best-Evidence Synthesis.

BACKGROUND: Musculoskeletal diseases affect 1.71 billion people worldwide, impose a high biopsychosocial burden on patients, and are associated with high economic costs. The use of digital health interventions is a promising cost-saving approach for the treatment of musculoskeletal diseases. As physical exercise is the best clinical practice in the treatment of musculoskeletal diseases, digital health interventions that provide physical exercises could have a highly positive impact on musculoskeletal diseases, but evidence is lacking. OBJECTIVE: This systematic review aims to evaluate the impact of digital physical health exercises on patients with musculoskeletal diseases concerning the localization of the musculoskeletal disease, patient-reported outcomes, and medical treatment types. METHODS: We performed systematic literature research using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was conducted using the PubMed, BISp, Cochrane Library, and Web of Science databases. The Scottish Intercollegiate Guidelines Network checklist was used to assess the quality of the included original studies. To determine the evidence and direction of the impact of digital physical health exercises, a best-evidence synthesis was conducted, whereby only studies with at least acceptable methodological quality were included for validity purposes. RESULTS: A total of 8988 studies were screened, of which 30 (0.33%) randomized controlled trials met the inclusion criteria. Of these, 16 studies (53%) were of acceptable or high quality; they included 1840 patients (1008/1643, 61.35% female; 3 studies including 197 patients did not report gender distribution) with various musculoskeletal diseases. A total of 3 different intervention types (app-based interventions, internet-based exercises, and telerehabilitation) were used to deliver digital physical health exercises. Strong evidence was found for the positive impact of digital physical health exercises on musculoskeletal diseases located in the back. Moderate evidence was found for diseases located in the shoulder and hip, whereas evidence for the entire body was limited. Conflicting evidence was found for diseases located in the knee and hand. For patient-reported outcomes, strong evidence was found for impairment and quality of life. Conflicting evidence was found for pain and function. Regarding the medical treatment type, conflicting evidence was found for operative and conservative therapies. CONCLUSIONS: Strong to moderate evidence was found for a positive impact on musculoskeletal diseases located in the back, shoulder, and hip and on the patient-reported outcomes of impairment and quality of life. Thus, digital physical health exercises could have a positive effect on a variety of symptoms of musculoskeletal diseases.

Microelectrode recording and hemorrhage in functional neurosurgery: a comparative analysis in a consecutive series of 645 procedures.

OBJECTIVE: Functional stereotactic neurosurgery including deep brain stimulation (DBS) and radiofrequency lesioning is well established and widely used for treatment of movement disorders and various other neurological and psychiatric diseases. Although functional stereotactic neurosurgery procedures are considered relatively safe, intracranial hemorrhage resulting in permanent neurological deficits may occur in 1%-3% of patients. Microelectrode recording (MER) has been recognized as a valuable tool for refining the final target in functional stereotactic neurosurgery. Moreover, MER provides insight into the underlying neurophysiological pathomechanisms of movement disorders and other diseases. Nevertheless, there is an ongoing controversy on whether MER increases the risk for hemorrhage. The authors aimed to compare the risk of hemorrhage in functional stereotactic neurosurgical procedures with regard to the use of MER. METHODS: The authors performed a comparative analysis on a consecutive series of 645 functional neurosurgery procedures, including 624 DBS surgeries and 21 radiofrequency lesionings, to evaluate whether the use of MER would increase the risk for hemorrhage. MER was performed in 396 procedures, while no MER was used in 249 cases. The MER technique involved the use of a guiding cannula and a single trajectory when feasible. Postoperative CT scans were obtained within 24 hours after surgery in all patients and screened for the presence of hemorrhage. RESULTS: Twenty-one intracranial hemorrhages were detected on the postoperative CT scans (3.2%). Of the 21 intracranial hemorrhages, 14 were asymptomatic and 7 were symptomatic. Symptoms were transient except in 1 case. There was no statistically significant correlation between hemorrhage and the use of MER at any site (subdural, ventricle, trajectory, target, whether asymptomatic or symptomatic). There were 4 cases of symptomatic hemorrhage in the MER group (1%) and 3 cases in those without MER (1.2%). CONCLUSIONS: Intraoperative MER did not increase the overall risk of hemorrhage in the authors' experience using primarily a single MER trajectory and a guiding cannula.

Case report: Pallidal deep brain stimulation for treatment of tardive dystonia/dyskinesia secondary to chronic metoclopramide medication.

Objectives: Tardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal deep brain stimulation (DBS) has become an accepted treatment for TDD secondary to neuroleptic medication, there is much less knowledge about its effects on metoclopramide-induced TDD. Methods: We present the case of a woman with metoclopramide-induced TDD, whose symptoms were initially misjudged as "functional." After 8 years of ineffective medical treatments, she received bilateral implantation of quadripolar electrodes into the posteroventral lateral globus pallidus internus (GPi). Results: GPi DBS led to significant symptom reduction [Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score 24/44 at admission and 7/44 at discharge]. Chronic stimulation led to full recovery from TDD symptoms 9 years after surgery. The BFMDRS motor score decreased to 0.5 (98% improvement). Discussion: Pallidal DBS may result in sustained improvement of TDD secondary to chronic metoclopramide intake in the long term.

Are Transventricular Approaches Associated With Increased Hemorrhage? A Comparative Study in a Series of 624 Deep Brain Stimulation Surgeries.

BACKGROUND: Deep brain stimulation (DBS) surgery has advanced tremendously, for both clinical applications and technology. Although DBS surgery is an overall safe procedure, rare side effects, in particular, hemorrhage, may result in devastating consequences. Although there are certain advantages with transventricular trajectories, it has been reasoned that avoidance of such trajectories would likely reduce hemorrhage. OBJECTIVE: To investigate the possible impact of a transventricular trajectory as compared with a transcerebral approach on the occurrence of symptomatic and asymptomatic hemorrhage after DBS electrode placement. METHODS: Retrospective evaluation of 624 DBS surgeries in 582 patients, who underwent DBS surgery for movement disorders, chronic pain, or psychiatric disorders. A stereotactic guiding cannula was routinely used for DBS electrode insertion. All patients had postoperative computed tomography scans within 24 hours after surgery. RESULTS: Transventricular transgression was identified in 404/624 DBS surgeries. The frequency of hemorrhage was slightly higher in transventricular than in transcerebral DBS surgeries (15/404, 3.7% vs 6/220, 2.7%). While 7/15 patients in the transventricular DBS surgery group had a hemorrhage located in the ventricle, 6 had an intracerebral hemorrhage along the electrode trajectory unrelated to transgression of the ventricle and 2 had a subdural hematoma. Among the 7 patients with a hemorrhage located in the ventricle, only one became symptomatic. Overall, a total of 7/404 patients in the transventricular DBS surgery group had a symptomatic hemorrhage, whereas the hemorrhage remained asymptomatic in all 6/220 patients in the transcerebral DBS surgery group. CONCLUSION: Transventricular approaches in DBS surgery can be performed safely, in general, when special precautions such as using a guiding cannula are routinely applied.

Rechargeable Pacemaker Technology in Deep Brain Stimulation: A Step Forward, But Not for Everyone.

BACKGROUND: Rechargeable implantable pulse generator (IPG) technology has several advantages over non-rechargeable systems and is routinely used now in deep brain stimulation (DBS). Little is known about the occasional need and the circumstances for switching back to non-rechargeable technology. CASES: Out of a cohort of 640 patients, 102 patients received a rechargeable IPG at first implantation or at the time of replacement surgery. Out of these, 3 patients underwent preemptive replacement with non-rechargeable devices for the following reasons: dissatisfaction with handling and recharge frequency (pallidal DBS in advanced Parkinson's disease/dystonia), severe DBS OFF status subsequent to missed recharging (subthalamic DBS in Parkinson's disease) and twiddler's syndrome (nucleus accumbens DBS in alcohol dependency). CONCLUSIONS: Although rechargeable IPG technology has been received well and is used widely, there are unexpected scenarios that require replacement surgery with non-rechargeable IPGs.

Predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression.

BACKGROUND: Many depressed patients do not achieve response or remission despite adequate treatment. Identifying predictors of outcome can contribute to developing therapeutic algorithms for difficult-to-treat depression. Therefore, we examined clinical predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression. METHODS: Three hundred and fifty-one consecutive inpatients admitted to a tertiary care university hospital (specialized psychiatry unit for treatment of unipolar and bipolar depression) between January 2014 and December 2016 were characterized by a set of sociodemographic and clinical variables. The predictive value of these variables for response (≥ 50% decrease from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score) and remission (MADRS score at discharge < 10) were explored using bivariate analysis and logistic regression. RESULTS: Greater symptom severity and fewer psychotropic medications at the time of admission predicted response. Remission rates were higher for patients with non-chronic depression, higher number of previous depressive episodes, fewer psychotropic medications and less severe depression at admission. LIMITATIONS: This was a retrospective study without a control group. The sample was drawn from a single inpatient ward specialized for difficult-to-treat depression. CONCLUSIONS: Greater baseline depression severity might be a proxy for a less chronic course of depression thereby explaining its association with greater response rates. Fewer episodes in the past and polypharmacy could indicate treatment-resistance and chronicity, contributing to lower remission rates. Therefore, preventing chronicity should be a central aim of depression treatment.

Immune response to pneumococcal conjugate vaccine in patients with systemic vasculitis receiving standard of care therapy.

AIM: To study the effect of standard of care therapy on antibody response and functionality following immunization with 13-valent pneumococcal conjugate vaccine (PCV13) in patients with primary systemic vasculitis compared to healthy controls. METHODS: 49 patients with vasculitis and 49 controls received a single dose (0.5ml) PCV13 intramuscularly. Ongoing treatments: azathioprine (AZA; n=11), cyclophosphamide (CYC; n=6), methotrexate (MTX; n=9), rituximab (n=3); anti-TNF (n=2), mycophenolate mofetil (n=2), prednisolone alone (n=15) and no active treatment (n=2). Specific antibody concentrations for serotypes 6B and 23F were determined using ELISA and opsonophagocytic activity (OPA) assay (23F) was performed, on serum samples taken immediately before and 4-6weeks after vaccination. Proportion of individuals with putative protective antibody concentration (≥1.0µg/mL) and positive antibody response (≥2-fold increase from prevaccination concentration) for both serotypes were calculated and groups were compared. RESULTS: At baseline, 6 patients (12%) and 12 controls (24%) had protective antibody levels for both serotypes. After vaccination, antibodies increased for both serotypes in patients and controls (p<0.001), 32 patients (65%) and 35 controls (71%) reached protective level for 6B, and 32 patients (65%) and 37 controls (76%) for 23F. Compared to controls, patients had lower prevaccination geometric mean concentration (23F, p=0.01) and a numerical trend towards lower prevaccination level (6B) and postvaccination levels (both serotypes). Patients with prednisolone alone had lower prevaccination OPA (p<0.01) compared to controls. OPA increased after vaccination in both patients and controls (p<0.001), but improvement was better in controls (p=0.001). AZA, CYC or MTX, but not prednisolone alone, tended towards a lower proportion of patients reaching protective antibody levels (p=0.06), compared to controls. CONCLUSIONS: Pneumococcal conjugate vaccine was safe and immunogenic in patients with established vasculitis. Treatment with DMARDs, mostly AZA, CYC and MTX but not systemic prednisolone may impair antibody response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02240888. Registered 4 September, 2014.

Methotrexate reduces vaccine-specific immunoglobulin levels but not numbers of circulating antibody-producing B cells in rheumatoid arthritis after vaccination with a conjugate pneumococcal vaccine.

BACKGROUND: Treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) leads to decreased total immunoglobulin (Ig) levels and impairs vaccine-specific IgG antibody levels following pneumococcal vaccination. The mechanisms by which MTX exerts these effects in RA are unknown. We aimed to evaluate whether MTX reduces vaccine-specific serum Ig levels and their functionality in RA patients following vaccination with pneumococcal conjugate vaccine, and if numbers of antigen-specific circulating plasmablasts are affected. METHODS: Ten patients with RA on MTX and 10 RA patients without disease modifying anti-rheumatic drug (DMARD) were immunized with a dose 13-valent pneumococcal conjugate vaccine (Prevenar13). Circulating plasmablasts producing total IgG and IgA as well as specific IgG and IgA against two pneumococcal capsular serotypes (6B and 23F) were enumerated using ELISPOT 6days after vaccination. IgG levels against both these serotypes were determined with ELISA before and 4-6weeks after vaccination. Positive antibody response was defined as ⩾2-fold increase of pre-vaccination antibody levels. The functionality of vaccine specific antibodies to serotype 23F was evaluated by measuring their ability to opsonize bacteria using opsonophagocytic assay (OPA) in 4 randomly chosen RA patients on MTX and 4 RA patients without DMARD. RESULTS: After vaccination, RA patients on MTX showed significant increase in pre- to postvaccination antibody levels for 6B (p<0.05), while patients without DMARD had significant increases for both 6B and 23F (p<0.05 and p<0.01, respectively). Only 10% of RA on MTX and 40% of RA patients without DMARD showed positive post-vaccination antibody responses for both serotypes. Increased opsonizing ability after vaccination was detected in 1 of 4 RA patients on MTX and 3 of 4 patients on RA without DMARD. However, numbers of circulating total and vaccine-specific IgG- or IgA-producing plasmablasts did not differ between RA patients with or without MTX. CONCLUSIONS: MTX treatment in RA leads to reduced vaccine-specific antibody responses and their functionality compared to untreated RA following pneumococcal vaccination using polysaccharide-protein conjugate vaccine. However, since there was no reduction in numbers of circulating total or vaccine-specific antibody-producing plasmablasts after vaccination this effect is probably not due to reduced activation of B cells in lymphoid tissue. CLINICAL TRIAL REGISTRATION: NCT02240888.

The association between antibody levels before and after 7-valent pneumococcal conjugate vaccine immunization and subsequent pneumococcal infection in chronic arthritis patients.

INTRODUCTION: The aim of present study is to inverstigate the association between antibody levels after vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) and subsequent serious pneumococcal infections in rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients. METHODS: A cohort of 497 patients (RA=248 and SpA=249) received a single dose of PCV7. At vaccination, patients were treated with methotrexate (MTX; n=85), anti-tumour necrosis factor (anti-TNF) + MTX (n=169), anti-TNF monotherapy (n=158) and non-steroidal anti-inflammatory drugs (NSAIDs)/analgesics (n=85). Antibody levels of serotypes 6B and 23B were analyzed before and 4 to 6 weeks after vaccination using standard enzyme-linked immunosorbent assay (ELISA). Serious pneumococcal infections (pneumonia/lower respiratory tract infection, meningitis, sepsis, septic arthritis) occurring within 4.5 years after vaccination were identified in the Skåne Healthcare Register using the International Classification of Diseases, tenth revision (ICD-10) codes. The association between post-vaccination antibody levels and protection against infections and determination of protective cutoff levels was explored using receiver operating characteristic (ROC) curves. Predictors of infection were studied using regression analyses. RESULTS: Eighteen infections were registered in 15 patients before vaccination and 27 infections in 23 patients after vaccination. Patients with serious infections after vaccination had significantly lower post-vaccination antibody titres for both 6B (P=0.04) and 23 F (P=0.04). Post-vaccination antibody levels of at least 1.29 mg/L and 1.01 mg/L for 6B and 23, respectively, were associated with better protection from serious infections. Higher age, concomitant prednisolone but not MTX or anti-TNF were associated with such infections. CONCLUSIONS: Patients with more robust antibody responses after vaccination with pneumococcal conjugate vaccine were less likely to suffer from serious infections. High age and prednisolone at vaccination were associated with putative serious pneumococcal infections in this cohort. TRIAL REGISTRATION NUMBER: EudraCT EU 2007-006539-29 and NCT00828997 . Registered 23 January 2009.