Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy

PURPOSE: The open-label phase 3 ‘Treatment with IncobotulinumtoxinA in Movement Open-Label’ (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12–16 weeks’ observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

Comparison of Spinal Cord Stimulation vs. Dorsal Root Ganglion Stimulation vs. Association of Both in Patients with Refractory Chronic Back and/or Lower Limb Neuropathic Pain: An International, Prospective, Randomized, Double-Blinded, Crossover Trial (BOOST-DRG Study)

While spinal cord stimulation (SCS) is a well-established therapy to address refractory persistent spinal pain syndrome after spinal surgery (PSPS-T2), its lack of spatial selectivity and reported discomfort due to positional effects can be considered as significant limitations. As alternatives, new waveforms, such as burst stimulation and different spatial neural targets, such as dorsal root ganglion stimulation (DRGS), have shown promising results. Comparisons between DRGS and standard SCS, or their combination, have never been studied on the same patients. “BOOST DRG” is the first prospective, randomized, double-blinded, crossover study to compare SCS vs. DRGS vs. SCS+DRGS. Sixty-six PSPS-T2 patients will be recruited internationally in three centers. Before crossing over, patients will receive each stimulation modality for 1 month, using tonic conventional stimulation. After 3 months, stimulation will consist in switching to burst for 1 month, and patients will choose which modality/waveform they receive and will then be reassessed at 6 and 12 months. In addition to our primary outcome based on pain rating, this study is designed to assess quality of life, functional disability, psychological distress, pain surface coverage, global impression of change, medication quantification, adverse events, brain functional imaging and electroencephalography, with the objective being to provide a multidimensional insight based on composite pain assessment.

Efficacy and safety of medical cannabinoids in children: a systematic review and meta-analysis

Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical cannabinoids (tetrahydrocannabinol, cannabidiol and other cannabis derivatives) versus control in children, independently assessed by two reviewers. Eight studies were included, all of which are randomized controlled trials. Cannabidiol is associated with 50% reduction in seizures rate (Relative Risk (RR) = 1.69, 95% CI [1.20–2.36]) and caregiver global impression of change (Median Estimated difference = (− 1), 95%CI [− 1.39–(− 0.60)]) in Dravet syndrome, compared to placebo. While cannabidiol was associated with a reduction in reported seizure events (RR = 0.59, 95% CI [0.36–0.97]), no association was found in products contained also tetrahydrocannabinol (RR = 1.35, 95% CI [0.46–4.03]). Higher dose of cannabidiol was associated with decreased appetite (RR = 2.40, 95% CI [1.39–4.15]). A qualitative assessment suggests that medical cannabinoids might be associated with adverse mental events. In conclusion, cannabidiol is associated with clinical improvement in Dravet syndrome. However, cannabidiol is also associated with decreased appetite. Adverse mental events were reported as well, however, more research should be performed to assess well this outcome.

Distal biceps repair through a single incision with the use of a knotless cortical button device: Mid-term results

Background Distal biceps rupture presents with an increasing incidence and evidence suggests that although a surgical repair is not mandatory, it results in superior functional outcomes when compared to non-operative management. As implant technology has advanced, several devices have been utilised and studied in managing this pathology. We present our single-centre experience with the use of the ToggleLoc Ziploop reattachment device, a knotless cortical button implant, using a single-incision technique. Methods Retrospective series of 70 consecutive distal biceps tendon repairs, at a mean follow-up of 45.6 months after surgery, using a standardised single implant, single-incision technique, and post-operative rehabilitation programme. Results There was one (1.4%) re-rupture in our patient cohort. The range of motion was complete in all patients except for one patient who had symptomatic heterotopic ossification, causing limitation in pronation. Complications were minor with the commonest being transient neuropraxia of the lateral cutaneous nerve of the forearm. The mean Oxford elbow score was 46.9 out of 48, and the patient global impression of change scale was 7 out of 7 in 77% of cases. Conclusion Our data support this technique and implant combination when dealing with acute and chronic distal biceps tendon rupture.

Efficacy and Safety of Gabapentine and Duloxetine in Diabetic Peripheral Neuropathic Pain

Introduction: Diabetic peripheral neuropathy (DPNP) is not uncommon now a days. As the pathophysiology is not completely understood, symptoms relief is still the main goal of treatment. Gabapentine and Duloxetine are being using around the world for this purpose. But clinical data regarding its efficacy and safety are not sufficiently available. Materials and Methods: This prospective comparative clinical study conducted in Sylhet MAG Osmani Medical College and Sylhet Diabetic Hospital, Bangladesh from January 2013 to December 2013. Diagnosis of DPNP confirmed by Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathic en-4 (DN4). Patients were treated by Gabapentine (Group-A) and Duloxetine (Group-B); and followed up at 4th, 8th and 12th week of treatment using 11-point numerical pain rating scale (NRS), clinical global impression of change (CGIC) score and patient’s global impression of change (PGIC) score. Results: A total of 72 patients with DPNP were recruited. Final comparison was done in 64 patients – 33 in Group-A and 31 in Group-B. Changes in NRS (p = <0.001), CGIC (p = <0.001) and PGIC (p = <0.001) were statistically significant during the course of treatment. However, inter-group variation of NRS, CGIC and PGIC were not statistically significant at the beginning and 4th, 8th and 12th week of treatment. Insignificant adverse effects were noted between the groups in this study except constipation (p = 0.022) and nausea-vomiting (p = 0.01) of Duloxetine taking group. Conclusion: Gabapentine and Duloxetine are equally effective in the treatment of DPNP with good safety profile. Medicine Today 2021 Vol.33(2): 108-113

The Effect of Voxelotor on Exercise Capacity of Youths with Sickle Cell Anemia

Background/Hypothesis: Children and adults with sickle cell anemia (SCA) exhibit decreased cardiopulmonary fitness. Anemia is directly related to oxygen carrying capacity and is one factor that affects cardiopulmonary fitness. The new sickle cell drug voxelotor raises hemoglobin in patients with SCA treated or untreated with hydroxyurea. We hypothesized that voxelotor improves exercise capacity in youths with SCA. Methods: A single-center, open-label, single-arm longitudinal interventional pilot study was conducted for patients with SCA age &gt; 12. Participants performed baseline Cardiopulmonary Exercise Testing (CPET#1), took 1500mg voxelotor for 2 months, then CPET was repeated (CPET#2). A modified Bruce Protocol using 2-minute stages was performed on a motorized treadmill, for a goal of 8-12 minutes of exercise. Breath by breath gas exchange data were collected and analyzed using a VMax Encore 29C metabolic cart. The metabolic test included standard monitoring of heart rate, EKG ST changes, arrhythmias, and O2 saturation. A respiratory quotient &gt;1.1 was used as evidence of participant effort. Peak oxygen consumption (peak VO2), anaerobic threshold (AT), O2 pulse, VE/VCO2 slope, and time exercised in CPET#1 and CPET#2 were compared for each participant. The primary endpoint was peak VO2. Hemoglobin (Hgb), reticulocyte count, and bilirubin were measured before CPET#1 and CPET#2. Pill count was used to monitor medication adherence and left shift of the P50 oxygen dissociation curve was used to document biochemical effect of voxelotor. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected at the end of the study. Statistical analysis was performed using Student's paired T-test. Results: Nine SCA patients ages 12-20, including 4 males and 5 females, completed the study. All had Hgb SS and were stably maintained on hydroxyurea, which was continued without dose change during the study. After 2 months of voxelotor, all participants demonstrated expected hematologic changes, including mean rise in Hgb +1.3 g/dL (95% C.I.= 0.8, 1.7), mean decrease in reticulocyte count -2.4% (95% C.I.= -4.1, -0.8), and mean decrease in bilirubin -0.4 mg/dL (95% C.I.= -0.8, -0.1). All participants demonstrated voxelotor adherence and leftward shift of p50 (Table 1). Oxygen consumption, measured as percent predicted peak VO2 (ml/kg/min), ranged from 52% to 80% in CPET#1 and from 55% to 71% in CPET#2. The changes in peak VO2 for individual participants ranged from -10% to +10% of predicted peak VO2, with a mean difference of -2.2% (95% CI = -7.1, 2.7), which is insignificant (p=0.3). Using +/- 6% as variability in peak VO2 measurement, 5 participants exhibited no change, 3 participants had decrease in peak VO2 of -7%, -9%, and -10%, while peak VO2 increased by +10% for a single participant, who started to exercise on his own after starting voxelotor. Changes in individuals' anaerobic threshold, O2 pulse, VE/VCO2 slope, and time exercised were not significant and did not correlate with changes in peak VO2. All participants achieved respiratory quotient &gt;1.1, assuring participant effort during CPET (Table 2). On the 7-point PGIC questionnaire evaluating activity limitations, symptoms, emotions, and overall quality of life, 7 out of 9 participants reported positive change, including "a great deal better," "definite," and "moderate" improvements. Two participants reported minimal to no change, and no participants reported worsening. In comparison, clinicians reported "minimal" to "much" improvement on CGIC for all participants. Overall, patient impression of improvement was higher than clinician impression of improvement. Conclusion: This pilot study demonstrated the feasibility of using CPET to evaluate exercise capacity longitudinally in youths with SCA. After addition of voxelotor to hydroxyurea for 2 months, all patients perceived global improvement. Peak VO2 did not change in 8 out of 9 participants and improved for 1 participant who exercised between the 2 CPETs. To increase peak VO2, higher Hgb increase, concurrent regular exercise, and longer exposure to voxelotor may be necessary. This study was funded by Global Blood Therapeutics Figure 1 Figure 1. Disclosures Larkin: Forma Therapeutics, Inc.: Research Funding. Dulman: Pfizer: Other: own stock. Kuypers: Forma Therapeutics, Inc.: Research Funding.

Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study

Background A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Methods Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. Results In triptan insufficient responders, lasmiditan was superior to placebo ( p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. Conclusions Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174)

The Effect and Safety of 5-HT1F Receptor Agonist Lasmiditan on Migraine: A Systematic Review and Meta-Analysis

Background. Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. Objective. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. Methods. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration’s risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. Results. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75 , 95% CI (0.61, 0.92), P = 0.007 ; 200 mg: RR = 0.81 , 95% CI (0.66, 0.99), P = 0.04 ) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs ( RR = 2.75 , 95% CI (0.81, 9.37), P = 0.11 ). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose ( RR = 0.83 , 95% CI (0.74, 0.94), P = 0.004 ) but associated with a higher risk of reporting at least one TEAE ( RR = 0.88 , 95% CI (0.81, 0.96), P = 0.006 ). Conclusions. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Injectable amniotic membrane/umbilical cord particulate for facet joint syndrome: A retrospective, single-center study

BACKGROUND: Facet joint syndrome (FJS) pain is a significant contributor to back pain and has a high rate of opioid prescription. Unfortunately, there are a limited number of therapeutic options for these patients. OBJECTIVE: To evaluate the safety and effectiveness of amniotic membrane/umbilical cord particulate (AM/UC) in managing FJS pain. METHODS: A single-center, investigator-initiated, retrospective study was performed on consecutive patients with FJS pain who received intra- or peri-articular injection of AM/UC between July 1, 2018 and July 26, 2019. Primary outcome was change in Patient Global Impression of Change (PGIC) at 6 weeks, 3 months, 6 months, and 12 months to assess the self-reported percent improvement relative to baseline. Safety was assessed by AM/UC- and procedure-related complications. Paired t-tests were used to determine whether there is a statistically significant improvement of pain post-injection compared to baseline. RESULTS: There were a total of 54 patients (69.7 ± 13.4 years; 31 female) presenting baseline pain score of 9.2 ± 1.0 despite prior treatments of activity modification (66.7%), NSAIDs (61.1%), opioids (37.0%), and physical therapy (35.2%). Mean GPIC improvement was 65.3%, 67.5%, 56.9%, and 56.7% among responders30, respectively. There were no complications. CONCLUSION: This study supports the safety and effectiveness of AM/UC particulate injection in managing FJS pain.

Personalized Repetitive Transcranial Magnetic Stimulation for Primary Progressive Aphasia

Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome for which no effective treatment is available. Objective: We aimed to assess the effect of repetitive transcranial magnetic stimulation (rTMS), using personalized targeting. Methods: We conducted a randomized, double-blind, pilot study of patients with PPA receiving rTMS, with a subgroup of patients receiving active- versus control-site rTMS in a cross-over design. Target for active TMS varied among the cases and was determined during a pre-treatment phase from a list of potential regions. The primary outcome was changes in spontaneous speech (word count). Secondary outcomes included changes in other language tasks, global cognition, global impression of change, neuropsychiatric symptoms, and brain metabolism using FDG-PET. Results: Twenty patients with PPA were enrolled (14 with nonfluent and 6 with semantic variant PPA). For statistical analyses, data for the two variants were combined. Compared to the control group (n = 7), the group receiving active-site rTMS (n = 20) showed improvements in spontaneous speech, other language tasks, patient and caregiver global impression of change, apathy, and depression. This group also showed improvement or stabilization of results obtained in the baseline examination. Increased metabolism was observed in several brain regions after the therapy, particularly in the left frontal and parieto-temporal lobes and in the precuneus and posterior cingulate bilaterally. Conclusion: We found an improvement in language, patient and caregiver perception of change, apathy, and depression using high frequency rTMS. The increase of regional brain metabolism suggests enhancement of synaptic activity with the treatment. Trial registration: NCT03580954 (https://clinicaltrials.gov/ct2/show/NCT03580954)