Botulinum Toxin Can Abolish and/or Quiet Tinnitus Associated with Chronic Migraine: Serendipidous Observations.

INTRODUCTION: It is well established that treatment of head and neck myofascial dysfunction can alleviate both tinnitus and chronic migraine (CM). Onabotulinumtoxin A (OnaA) has become a standard treatment for CM. In a recent systematic study a subject reported tinnitus improvement. This prompted a survey of the tinnitus in all study participants. METHODS: Fifty-seven patients with CM at a tertiary headache referral center received intramuscular Onabotulinumtoxin A (OnaA) injections into craniocervical muscles using the "follow-the-pain" protocol for headache. Effectiveness of OnaA was assessed by changes in (i) tinnitus loudness and (ii) number of headache days. RESULTS: Of the five patients with pre-existing tinnitus OnaA abolished the tinnitus in two, including one whose tinnitus of ten years' duration resolved permanently with one treatment. The tinnitus loudness of the other four was attenuated between 70 to 100 percent for about three months, which paralleled their headaches response. All were women who had (i) a significant improvement of their CM and (ii) headaches located fronto-temporally. None of the CM non-responders reported tinnitus. Analysis of injection sites revealed that the temporalis muscle injections were likely accounting for the tinnitus attenuation. CONCLUSION: Tinnitus associated with chronic migraine is abolished/quieted by intramuscular craniocervical Onabotulinumtoxin A injections. These results are consistent with the dorsal cochlear nucleus hypothesis for craniocervical somatic tinnitus, as well as the association between migraine and tinnitus. This serendipitous result warrants further study of botulinum toxin for tinnitus.

Increased Risk of Parkinson's Disease in Women after Bilateral Oophorectomy.

BACKGROUND: Results regarding the association between hormonal exposure and risk of Parkinson's disease (PD) are heterogeneous. OBJECTIVES: To investigate the association of reproductive life characteristics with PD among postmenopausal women. METHODS: The PARTAGE case-control included 130 female cases and 255 age-matched female controls. Information on gynecological history was obtained from a standardized questionnaire and PD was validated by neurological examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. RESULTS: After adjustment for education level, smoking status, professional exposure to pesticides, and coffee and alcohol drinking, bilateral oophorectomy (OR = 3.55, 95%CI = 1.75-7.20), but neither menopause before age 50 years (OR = 1.24, 95%CI = 0.74-2.09) nor hormone therapy (HT; OR = 1.07, 95%CI = 0.62-1.86), was associated with PD. CONCLUSION: Our findings suggest that bilateral oophorectomy is associated with increased risk of PD. © 2021 International Parkinson and Movement Disorder Society.

How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p < 0.0001). CONCLUSION: The ESTIMET study confirms the significant benefit experienced on chronic BP by patients implanted with multicolumn SCS, independently from multicolumn lead programming. These good clinical outcomes might result from the specific architecture of the multicolumn lead, giving the opportunity to select initially the best column on a multicolumn grid and to optimize neural targeting with low-energy requirements. However, involving more columns than one does not appear necessary, once initial spatial targeting of the "sweet spot" has been achieved. Our findings suggest that this spatial concept could also be transposed to cylindrical leads, which have drastically improved their capability to shape the electrical field, and might be combined with temporal resolution using SCS new modalities.

Delayed-onset post-craniotomy headache responsive to botulinum toxin A: a case series.

We report here the case of four patients presenting with delayed-onset temporal pain after pterional craniotomy. They reported similar symptoms: attacks of pain over the temporal region, ipsilateral to the operative site, irradiating around the eye and lasting from 10 min to 1 h. All patients had hypertrophy of at least one part of the temporalis muscle. All responded dramatically to botulinum toxin A injection (25 to 50 Botox® units) into the temporalis muscle. We suggest that the headaches were caused by aberrant nerve regeneration following surgical injury to the frontal branch of the facial nerve.

OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study.

BACKGROUND: OnabotulinumtoxinA has proven its efficacy in reducing the number of headache days in chronic migraine (CM) patients. The usual paradigm includes 31 pericranial injection sites with low dose (5 U) per site. The aim of this study is to present the results obtained using a simpler injection protocol of onabotulinumtoxinA, with injection sites targeted to pericranial myofascial sites of pain. METHODS: Observational, open label, real-life, cohort study. We enrolled 63 consecutive patients fulfilling the diagnostic criteria of CM, and refractory to conventional treatments. The patients were injected using a "follow-the-pain" pattern into the corrugator and/or temporalis and/or trapezius muscles. The doses per muscle were fixed. According to the number of muscles injected, the total dose could vary from 70 to 150 U per session. Patients were considered responders if they had a ≥ 50% decrease in number of headache days in at least two consecutive injection cycles. RESULTS: Forty one patients (65.1% in intention to treat analysis) responded to treatment. In 70.7% of responders, the effect size was even higher, with a reduction ≥70% in the number of headache days. The associated cervical pain and muscle tenderness, present in 33 patients, was reduced by ≥50% in 31 patients (94%). Triptan consumption dramatically decreased (81%) in responders. The trapezius was the most frequently injected muscle. We observed no serious adverse event. The mean patient satisfaction rate was 8.5/10. CONCLUSIONS: This study provides additional robust evidence supporting the efficacy of onabotulinumtoxinA injections in CM. Furthermore, the paradigm we used, with reduced number of injection sites targeted to pericranial myofascial sites of pain, may provide evidence in favor of the implication of myofascial trigger points in migraine chronicization. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Record I17022 ClinicalTrials.gov Identifier: NCT03175263 . Date of registration: June 7, 2017. Retrospectively registered.

A systematic review of studies on anatomical position of electrode contacts used for chronic subthalamic stimulation in Parkinson's disease.

BACKGROUND: The dorso-lateral part of the subthalamic nucleus (STN) is considered as the usual target of deep brain stimulation for Parkinson's disease. Nevertheless, the exact anatomical location of the electrode contacts used for chronic stimulation is still a matter of debate. The aim of this study was to perform a systematic review of the existing literature on this issue. METHOD: We searched for studies on the anatomical location of active contacts published until December 2012. RESULTS: We identified 13 studies, published between 2002 and 2010, including 260 patients and 466 electrodes. One hundred and sixty-four active contacts (35 %) were identified within the STN, 117 (25 %) at the interface between STN and the surrounding structures, 184 (40 %) above the STN and one within the substantia nigra. We observed great discrepancies between the different series. The contra-lateral improvement was between 37 and 78.5 % for contacts located within the STN, between 48.6 and 73 % outside the STN, between 65.3 and 66 % at the interface. The authors report no clear correlation between anatomical location and stimulation parameters. CONCLUSIONS: Post-operative analysis of the anatomical location of active contacts is difficult, and all the methods used are debatable. The relationship between the anatomical location of active contacts and the clinical effectiveness of stimulation is unclear. It would be necessary to take into account the volume of the electrode contacts and the diffusion of the stimulation. We can nevertheless assume that the interface between dorso-lateral STN, zona incerta and Forel's fields could be directly involved in the effects of stimulation.

Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain.

OBJECTIVE: Botulinum toxin type A (BTX-A) has been reported to have analgesic effects independent of its action on muscle tone, possibly by acting on neurogenic inflammation. Such a mechanism may be involved in peripheral neuropathic pain. METHODS: A possible direct analgesic effect of BTX-A pain processing was investigated in 29 patients with focal painful neuropathies and mechanical allodynia using a randomized, double-blind, placebo-controlled design. Patients received a one-time intradermal administration of BTX-A (20-190 units) into the painful area. Outcome measures, evaluated at baseline, then at 4, 12, and 24 weeks, included average spontaneous pain intensity, quantified testing of thermal and mechanical perception and pain, allodynia to brushing (area, intensity), neuropathic symptoms, clinical global impression, and quality of life. RESULTS: BTX-A treatment, relative to placebo, was associated with persistent effects on spontaneous pain intensity from 2 weeks after the injection to 14 weeks. These effects correlated with the preservation of thermal sensation at baseline (p < 0.05). BTX also improved allodynia to brush and decreased pain thresholds to cold, without affecting perception thresholds. There were sustained improvements in the proportion of responders (number needed to treat for 50% pain relief: 3.03 at 12 weeks), neuropathic symptoms, and general activity. Most patients reported pain during the injections, but there were no further local or systemic side effects. INTERPRETATION: These results indicate for the first time that BTX-A may induce direct analgesic effects in patients with chronic neuropathic pain independent of its effects on muscle tone and suggest novel indications for BTX-A in analgesia.

Efficacy of Intra-Articular Botulinum Toxin in Osteoarticular Joint Pain: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: This study was conducted with the aim of evaluating the efficacy of intra-articular injections of botulinum toxin type A (BT-A) into the painful joint diseases through a systematic review of the literature and a meta-analysis of controlled randomized trials. Intra-articular therapies (corticosteroids, hyaluronic acid) have limited efficacy and run a risk of toxicity in patients with joint pain. New therapeutic options are needed to treat painful osteoarticular disease. METHODS: We searched via Pubmed, American College of Rheumatology, and European League Against Rheumatism congresses, and gray literature for the studies reported until June 2016 and addressing the issue of BT intra-articular injections in patients with refractory joint pain. Randomized trials were included. For the meta-analysis, we compared a numeric rating scale (NRS) from 0 to 10 before treatment and at 1 or 2 months and 6 months after in the BT-A and the control groups for each study. We also compared separately low dose and high dose of BT at 1 or 2 months' evaluation. RESULTS: In a total of 269 selected articles, 8 were analyzed and 6 studies were included in the meta-analysis involving a total of 382 patients. On comparing the NRS rating for 5 trials, at 1 or 2 months irrespective of the dose of BT, 4 trials showed a positive effect of BT compared with the control on the NRS and 1 found no effect; the overall weighted mean difference [95% confidence interval (CI)] was -1.10 (-1.62, -0.58) (P<0.0001, I=63%). Among the 4 trials with a low dose of BT (100 U), comparing NRS at 1 or 2 months, 3 trials showed significant results with a positive effect of BT-A injection compared with the control on the NRS; the fourth study failed to find any effect. The overall weighted mean difference (95% CI) was -0.95 (-0.02, -1.88) (P=0.05, I=67%). In the 2 trials using a high dose of BT (200 U) comparing NRS at 1 or 2 months, there was an almost zero effect of BT, with an overall weighted mean difference (95% CI) of 0.13 (-0.55, 0.81) (P=0.71, I=0%). In the 3 trials comparing NRS at 6 months there was an overall weighted mean difference (95% CI) of -0.57 (-1.98, 0.83) (P=0.42, I=73%). CONCLUSIONS: BT-A intra-articular injections have short-term benefits with a statistically significant decrease in the NRS pain score of around 1 point in patients with refractory joint pain. A decrease in the pain score was also observed at 6 months but with a nonsignificant result.

Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain. METHODS: We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, and Neurological Centre, Hôpital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clínicas da FMUSP, São Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211. FINDINGS: Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0·77, 95% CI -0·95 to -0·59; p<0·0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1·0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0·8). INTERPRETATION: Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further. FUNDING: Institut National de la Santé et de la Recherche Médicale (INSERM) and Fondation CNP (France).

Impact of recommendations on the initial therapy of Parkinson's disease: a population-based study in France.

Levodopa induces long-term motor complications in Parkinson's disease (PD). Therapeutic strategies that prevent motor complications are needed. Our aim was to evaluate the impact of recommendations of a French consensus conference published in 2000 on initial PD therapy. We identified 308 PD patients as part of a population-based study performed within the Mutualité Sociale Agricole in five French districts (2007). Neurologists confirmed PD diagnosis. We compared initial therapy in 102 patients treated before 12/31/2000 to that of 206 patients treated afterwards. Initial treatment was in agreement with the recommendations if dopamine agonists were used in patients <60 years (n = 49) and levodopa in patients ≥70 years (n = 133). Agreement with the recommendations increased after 2000 (66.0%) compared to before (46.3%, p = 0.025). For patients <60 years, agreement increased (64.0% vs 20.2%, p = 0.017) while it remained stable (66.4% vs 70.6%, p = 0.73) in patients ≥70 years. The publication of recommendations has influenced initial treatment choices for PD in France.

Dose equivalence of two commercial preparations of botulinum neurotoxin type A: time for a reassessment?

BACKGROUND: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice. METHODS: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A--Dysport (Dp) and Botox (Bx). RESULTS: Four key areas of evidence were identified: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Nonclinical data indicate that the principal reasons for differences in unit potency between the two products are dilution artefacts in the mouse assay. Use of saline as a diluent, at high dilutions, results in significant loss of potency in the Bx assay, whereas use of gelatin phosphate buffer in the Dp assay procedure protects the toxin during dilution. The published data on mouse assays show a Dp : Bx unit ratio range of 2.3-2.5 : 1 in saline and 1.8-3.2 : 1 in gelatin phosphate buffer. Data indicate that complexing proteins or size of the complex, which is highly pH sensitive, play no role in toxin diffusion and that Dp and Bx have similar diffusion characteristics when used at comparable doses. Randomized, controlled clinical studies indicate that 3 : 1 is more appropriate than 4 : 1, but the two products are not equivalent at this ratio. Comparative human experimental studies using the extensor digitorum brevis test, facial lines and anhidrotic action halo tests support dose-conversion ratios less than 3 : 1. LIMITATIONS: Data comparing dose equivalence ratios from the non-clinical setting should be extrapolated into the clinical setting with some caution. CONCLUSIONS: Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a mitochondrial disease caused by point mutations in mitochondrial DNA. It usually presents as severe bilateral visual loss in young adults. We report on a neurological disorder resembling Leigh syndrome, which complicated Leber's hereditary optic neuropathy in three unrelated male patients harboring mitochondrial DNA mutations at nucleotide positions 3460, 14459, and 14484, respectively. This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy.