Repetitive transcranial magnetic stimulation of the primary motor cortex in management of chronic neuropathic pain: a systematic review.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) with frequencies 5-20 Hz is an expanding non-invasive treatment for chronic neuropathic pain (NP). Outcome data, however, show considerable inhomogeneity with concern to the levels of effect due to the great diversity of treated conditions. The aim of this review was to survey the literature regarding the efficacy and safety of M1 rTMS, and the accuracy to predict a positive response to epidural motor cortex stimulation (MCS) which is supposed to give a more longstanding pain relief. METHODS: A systematic literature search was conducted up to June 2019 in accordance with the PRISMA guidelines. We used the PICO Model to define two specific clinical questions: (1) Does rTMS of M1 relieve NP better than sham treatment? (2) Can the response to rTMS be used to predict the effect of epidural MCS? After article selection, data extraction, and study quality assessment, the certainty of evidence of treatment effect was defined using the GRADE system. RESULTS: Data on 5-20 Hz (high-frequency) rTMS vs. sham was extracted from 24 blinded randomised controlled trials which were of varying quality, investigated highly heterogeneous pain conditions, and used excessively variable stimulation parameters. The difference in pain relief between active and sham stimulation was statistically significant in 9 of 11 studies using single-session rTMS, and in 9 of 13 studies using multiple sessions. Baseline data could be extracted from 6 single and 12 multiple session trials with a weighted mean pain reduction induced by active rTMS, compared to baseline, of -19% for single sessions, -32% for multiple sessions with follow-up <30 days, and -24% for multiple sessions with follow-up ≥30 days after the last stimulation session. For single sessions the weighted mean difference in pain reduction between active rTMS and sham was 15 percentage points, for multiple sessions the difference was 22 percentage points for follow-ups <30 days, and 15 percentage points for follow-ups ≥30 days. Four studies reported data that could be used to evaluate the accuracy of rTMS to predict response to MCS, showing a specificity of 60-100%, and a positive predictive value of 75-100%. No serious adverse events were reported. CONCLUSIONS: rTMS targeting M1 can result in significant reduction of chronic NP which, however, is transient and shows a great heterogeneity between studies; very low certainty of evidence for single sessions and low for multiple sessions. Multiple sessions of rTMS can maintain a more longstanding effect. rTMS seems to be a fairly good predictor of a positive response to epidural MCS and may be used to select patients for implantation of permanent epidural electrodes. More studies are needed to manifest the use of rTMS for this purpose. Pain relief outcomes in a longer perspective, and outcome variables other than pain reduction need to be addressed more consistently in future studies to consolidate the applicability of rTMS in routine clinical practice.

Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures.

Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of drug-resistant epilepsy. A new VNS system ("FitNeS"; manufactured by BioControl Medical (B.C.M.) Ltd., Yehud, Israel) was implanted in 5 patients with refractory focal epilepsy. The system is composed of a programmable pulse generator and a cuff electrode that is able to provide unidirectional stimulation, both of which are implanted in the left chest and in the neck, respectively. FitNeS is based on the CardioFit vagus nerve stimulation system, which is intended for the treatment of heart failure and which is currently in a randomized controlled phase III clinical trial. Long-term stimulation in the 5 patients resulted in a 50% seizure reduction in 2 patients, 25% in 2 patients, and no effect in one patient, with few reports concerning side effects. There were no complaints of hoarseness at levels of stimulation below 2mA nor were there any reports of dysphagia or cough. The lack of perceived stimulation effects might finally allow for the design of a truly blinded randomized controlled study to evaluate the efficacy of VNS compared to placebo.

Vagus nerve stimulation in patients with Alzheimer's disease: Additional follow-up results of a pilot study through 1 year.

BACKGROUND: Cognitive-enhancing effects of vagus nerve stimulation (VNS) have been reported during 6 months of treatment in a pilot study of patients with Alzheimer's disease (AD). Data through 1 year of VNS (collected from June 2000 to September 2003) are now reported. METHOD: All patients (N = 17) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD. Responder rates for the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental State Examination (MMSE) were measured as improvement or absence of decline from baseline. Global change, depressive symptoms, and quality of life were also assessed. Cerebrospinal fluid (CSF) levels for total tau, tau phosphorylated at Thr181 (phosphotau), and Abeta42 were measured by standardized enzyme-linked immunosorbent assay (ELISA). RESULTS: VNS was well tolerated. After 1 year, 7 (41.2%) of 17 patients and 12 (70.6%) of 17 patients improved or did not decline from baseline on the ADAS-cog and MMSE, respectively. Twelve of 17 patients were rated as having no change or some improvement from baseline on the Clinician Interview-Based Impression of Change (CIBIC+). No significant decline in mood, behavior, or quality of life occurred during 1 year of treatment. The median change in CSF tau at 1 year was a reduction of 4.8% (p = .057), with a 5.0% increase in phosphotau (p = .040; N = 14). CONCLUSION: The results of this study support long-term tolerability of VNS among patients with AD and warrant further investigation.

Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study.

BACKGROUND: Vagus nerve stimulation (VNS) is an established treatment method for therapy-refractory epilepsy and, in Europe, for treatment-resistant depression also. Clinical and experimental investigations have also shown positive effects of VNS on cognition in epilepsy and depression. The purpose of the present pilot study was to investigate the effect of VNS on cognition in patients with Alzheimer's disease. METHOD: All the included patients (N = 10) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for the diagnosis of Alzheimer's disease. Before the implantation of the vagus stimulator (NeuroCybernetic Prosthesis), the patients underwent neuropsychological tests (e.g., Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-cog] and Mini-Mental State Examination [MMSE]), computerized tomography of the brain, medical/neurologic and psychological examinations (status evaluation), and lumbar puncture with investigation of the cerebrospinal fluid. The presence of depressive symptoms was rated using the Montgomery-Asberg Depression Rating Scale. The VNS was initiated 2 weeks after the implantation, and the patients were followed up with regular investigations and tests over 6 months. Response was defined as improvement or absence of impairment in ADAS-cog and MMSE scores after 3 and 6 months. RESULTS: After 3 months of treatment, 7 of 10 patients were responders according to the ADAS-cog (median improvement of 3.0 points), and 9 of 10 patients were responders according to the MMSE (median improvement of 1.5 points). After 6 months of treatment, 7 patients were responders on the ADAS-cog (median improvement of 2.5 points), and 7 patients were responders on the MMSE (median improvement of 2.5 points). VNS was well tolerated, and its side effects were mild and transient. CONCLUSION: The results of this open-label pilot study suggest a positive effect of VNS on cognition in patients with Alzheimer's disease. Further studies are warranted.

Force measurements of postural sway and rapid arm lift in seated children with and without MMC.

OBJECTIVE: The aim was to investigate the horizontal ground reaction forces of seated postural sway and rapid arm lift in children with and without myelomeningocele. BACKGROUND; It is unclear whether children with myelomeningocele have limited control of body posture entirely caused by the impairment in the legs or also by other dysfunction. METHODS: 11 children with myelomeningocele, 10-13 years, and 20 children without physical impairment were investigated. Data were collected by force plate measurements during quiet sitting and during rapid arm lift. The forces were expressed as the corresponding acceleration of the centre of mass. The amplitude and the frequency of the centre of mass acceleration quantified the sway. Movement time, onset and anteroposterior peak acceleration were analysed during arm lift. RESULTS: The children with myelomeningocele had a low sway frequency under both conditions: eyes open and eyes closed. The movement time was longer for these children compared to the controls. The onset of initial anteroposterior centre of mass acceleration preceded the arm lift and was directed forward in both groups. The peak centre of mass acceleration was usually directed backward. CONCLUSIONS: The control of postural sway was different in children with myelomeningocele compared to children without disabilities and this could not be explained by the cele level. The children with myelomeningocele had a slow motor performance of the seated sway and during arm lift. RELEVANCE: Slow motor performance involves functional limitations in the individual child and is important for the therapy program.