Onabotulinum Toxin Type Research Articles

Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: an organ culture study.

BackgroundOnabotulinumtoxin type A (BoNT-A) has been found to reduce pain in chronic migraine. The aim of the present study was to ask if BoNT-A can interact directly on sensory mechanisms in the trigeminal ganglion (TG) using an organ culture method.MethodsTo induce inflammation, rat TGs were incubated for 24 hrs with either the mitogen MEK1/2 inhibitor U0126, BoNT-A or NaCl. After this the TGs were prepared for immunohistochemistry. Sections of the TG were then incubated with primary antibodies against CGRP (neuronal transmitter), iNOS (inflammatory marker), IL-1β (Interleukin 1β), SNAP-25 (synaptic vesicle docking protein) or SV2-A (Botulinum toxin receptor element).ResultsWe report that CGRP, iNOS, IL-1β, SNAP-25 and SV2-A were observed in fresh TG with a differential distribution. Interestingly, NaCl organ culture of the TG resulted in enhanced expression of CGRP and SNAP-25 in neurons and iNOS in SGCs. Co-incubation with U0126 or BoNT-A retained the increased expression of SNAP-25, while it decreased the IL-1β immunoreactivity in neurons. The iNOS expression in SGCs returned to levels observed in fresh specimens. Moreover, we observed no alteration SV2-A expression in SGCs. Thus, the overall picture is that both U0126 and BoNT-A have the ability to modify the expression of certain molecules in the TG.ConclusionWe hypothesize that chronic migraine might be associated with some degree of inflammation in the TG that could involve both neurons and SGCs. It is clinically well recognized that treatment with corticosteroids will reduce the symptoms of chronic migraine; however this remedy is associated with long-term side effects. Understanding the mechanisms involved in the expressional alterations may suggest novel ways to modify the changes and indicate novel therapeutics. The results of the present work illustrate one way by which BoNT-A may modify these expressional alterations.

Treatment of lateral canthal rhytides with a medium depth chemical peel with or without pretreatment with onabotulinum toxin type A: A randomized control trial

Treatment of lateral canthal rhytides with a medium depth chemical peel with or without pretreatment with onabotulinum toxin type A: A randomized control trial

Therapeutic outcome of onabotulinum toxin type A in patients with upper limb spasticity

Onabotulinum toxin type A treatment for post-stroke upper limb spasticity was investigated to contribute to establishing a standard dosage for Japanese patients. A total of 100 patients participated in the study. The outcome one month (33.6±6.5 days) after the treatment was assessed by the Modified Ashworth Scale (MAS) to estimate the mean effect with a 10-unit injection and the standard dosage expected to improve MAS 1 degree. Average improvement of 263 muscles treated with a higher concentration of 10 units diluted in 0.2 ml was 0.207±0.414 degrees, and that of 231 muscles treated with a lower concentration of 10 units in 0.4 ml was 0.149±0.244 degrees without significant difference among diluted concentrations. To improve MAS 1 degree, 64.6±31.1 units were required for the pectoralis major, 51.2±21.3 units for the teres major, 111.7±48.0 units for the biceps brachii, 51.6±26.8 units for the brachioradialis, 54.1±23.2 units for the brachialis, 34.4±10.7 units for the pronator teres, 64.6±27.9 units for the flexor carpi radialis, 62.4±26.8 units for the flexor carpi ulnalis, 58.5±31.1 units for the flexor digitorum profundus, 69.7±35.1 units for the flexor digitorum superficialis, 24.6±13.4 units for the flexor pollicis longus, and 15.6±11.3 units for the adductor pollicis. Although the results shown here had no significant differences among concentrations, increasing the volume would disturb injection into small muscles, so we considered that a lower volume with a higher concentration should assure larger benefits. It is difficult to make effective injections into all spastic muscles within the officially permitted health insurance dosage of 240 units. Hence, it is advisable to increase the applicable upper limit based on safely achieved cumulative experience.

EHMTI-0270. Experience with onabotulinumtoxin type a in high-frequency episodic migraine

To analyse the efficacy of onabotulinumtoxin type A (OnabotA) in High Frequency Episodic Migraine (HFEM) after two treatment cycles. Twenty-three consecutive patients (22 women, 1 man) diagnosed with HFEM and with an inadequate response or intolerance to oral preventatives were included. Data regarding frequency and intensity of headache attacks, analgesic use and migraine disability assessment scale (MIDAS) before and after OnabotA was collected. The current oral preventive therapy was continued in all patients. Good responders were those who after treatment improved from HFEM to low-frequency episodic migraine, presented with a reduction in 75% of headpain intensity, had a reduction of the oral analgesic/triptans use to one or less per week, and improved from a severe to a mild disability measured using the MIDAS scale (improvement in four categories). This was achieved in 16 patients (69.6%). Six other patients (26%) presented with a partial reponse to OnabotA, this was measured by an improvement from severe to moderate or minimal disability measured using the MIDAS scale and a reduction in the analgesic use (improvement in two categories). One patient did not improve after treatment. In our clinical practice, treatment of refractory HFEM with OnabotA reduces the frequency and the intensity of the migraine attacks, reduces the consumption of symptomatic treatments and, improves the disability related with migraine. This makes it a good preventive therapeutic option.

EHMTI-0283. Predictors of early response to onabotulinumtoxin type a in chronic migraine

To analyse predictors of early response after two treatment cycles with Onabotulinumtoxin type A (OnabotA) in patients with chronic migraine (CM). Thirty-one patients (24 women, 7 men) with IHS criteria for CM and an inadequate response or intolerance to other oral preventatives were included. Data regarding the frequency and intensity of headache attacks, analgesic use and migraine disability assessment scale (MIDAS) before and after OnabotA treatment was collected; as well as, headache location and the presence of allodynia or bruxism. The current oral preventive therapy was continued in all patients. Good responders were patients who after treatment improved in all of these four categories: headache frequency (CM to low-frequency episodic migraine), headpain intensity (reduction of >75%), analgesic/triptan use (reduction to a use of two days or less per week), and disability (from severe to a mild disability measured using the MIDAS scale). Partial responders were those who only improved in two of the four categories. Patients were classified into 3 categories: good responders (58.1%), partial responders (29%), and non-responders (12.9%). The age (younger subjects) and the presence of a shorter migraine history are the two indicators of a better response to the treatment (p=0.04; p=0.04 respectively). Unilateral headache, presence of allodynia and/or bruxism appears not to be predictors of response to OnabotA in our study. Age and the years of migraine history are predictors of early response to OnabotA in our experience. The younger the patient and less years of migraine chronification are good predictors of early response.

EHMTI-0273. Onabotulinotoxin type A is a therapeutic option in chronic cluster headache

To analyse the efficacy of Onabotulinumtoxin type A (OnabotA) in chronic cluster headache patients. Six patients (5 men and 1 woman) diagnosed with refractory chronic cluster headache were included. Data regarding the characteristics of the headache, the frequency and the duration of the attacks, the presence of family history of migraine and the analgesic use were collected. The patients continued with their usual preventative treatment. In 4 of the 6 patients included (66.6%), we have observed a clear improvement in the frequency of the headache with a change in the pattern (from chronic to episodic). All of these had family history of migraine. In one of the patients no improvement was observed, and one patient was lost during follow-up. The use of OnabotA could be considered as a therapeutic option in those patients with chronic cluster headache which are intolerant or refractory to the known and used preventative treatments, before using more invasive treatments. Larger series are needed to confirm these findings.

EHMTI-0105. CGRP and VIP levels as predictors of efficacy of onabotulinumtoxin type A in chronic migraine

The mechanism of action of Onabotulinumtoxin type A (onabotA) in chronic migraine (CM) is unknown.

CGRP and VIP Levels as Predictors of Efficacy of Onabotulinumtoxin Type A in Chronic Migraine

Onabotulinumtoxin type A (onabotA) has shown efficacy in chronic migraine (CM). Its precise mechanism of action, however, is unknown. To analyze a potential relationship between calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) levels and response to onabotA in CM. Adult patients with CM were recruited. Matched healthy subjects with no headache history served as controls. CGRP and VIP levels were determined in samples obtained from the right antecubital vein by ELISA outside of a migraine attack and having taken no symptomatic medication prior to treatment with onabotA. OnabotA was administered according to the PREEMPT protocol every 12 weeks for at least two treatment cycles. A patient was considered as a moderate responder when both: (1) moderate-severe headache episodes were reduced by between 33 and 66%; (2) subjective benefit in a visual scale of 0-100 was recorded by the patient of between 33-66%. Patients were considered as excellent responders when both items improved >66%. Those without improvement of at least one-third in the two items were considered as nonresponders. We assessed plasma samples from 81 patients with CM and 33 healthy controls. CGRP and VIP levels were significantly increased in CM population vs controls. CGRP and, to a lesser degree, VIP levels were significantly increased in responders vs nonresponders. For CGRP, a threshold of 72 pg/mL positively correlated with 95% of nonresponders. The probability of being a responder to onabotA was 28 times higher in patients with a CGRP level above the threshold of 72 pg/mL. Even though the sensitivity for the calculated threshold for VIP was poor, the probability that CM patients with low CGRP levels will respond to onabotA was significantly higher in those patients with high VIP levels. Interictal CGRP and, to a lesser degree, VIP levels measured in peripheral blood are of great help in predicting response to onabotA.

Onabotulinumtoxin type A (Botox®) versus Incobotulinumtoxin type A (Xeomin®) in the treatment of focal idiopathic palmar hyperhidrosis: results of a comparative double-blind clinical trial

Focal hyperhidrosis often has a substantial psychological and social impact on quality of life, since it interferes with daily activities. To date, for the treatment of focal hyperhidrosis, the botulinum toxin type A is an effective second line tool. The purpose of this study was to compare Onabotulinumtoxin A (Botox(®)) and Incobotulinumtoxin A (Xeomin(®)) administration in the treatment of palmar hyperhidrosis. In a double-blind clinical trial, 25 patients with moderate or severe palmar hyperhidrosis received in the same session intradermal injections of Onabotulinumtoxin A on one hand and Incobotulinumtoxin A on the other. Several measures of efficacy and safety were evaluated: disease severity improvement, sweat reduction, hand-grip strength decrease, pain/discomfort during the treatment, and patient's global satisfaction. All patients were responsive to the treatments (HDSS at T4 vs HDDs at T0; p < 0.0001), and no significant difference between Onabotulinumtoxin A and Incobotulinumtoxin A in terms of anhidrotic effect (Minor's test at T4; p = 0.51), long-term efficacy (Minor's test at T12; p = 0.76), (Minor's test at T24; p = 0.58), subjective pain related to the injections (p = 0.88), muscle strength reduction after treatment (p = 0.56), and global satisfaction with the treatment (p = 0.26). Onabotulinum toxin A and Incobotulinumtoxin A seem to be comparable in terms of anhidrotic effect (short-term results), duration of benefits (long-term efficacy), muscle strength reduction (safety), pain related to injections (tolerability), and treatment satisfaction expressed by patients.

Targets for botulinum toxin in the lower urinary tract

Botulinum toxin type A (BoNT/A), one of the seven subtypes of Botulinum toxin, is commercially available naked or complexed to other proteins. Onabotulinum toxin type A is the most extensively studied BoNT/A brand. Dose equivalence studies between the different brands have never been carried out. BoNT/A is internalized by nerve fibers after binding synaptic vesicle proteins, and the final target of action is synaptosome-associated protein 25 kDa (SNAP-25), a membrane protein essential for synaptic vesicle fusion with the neuronal membrane. The current literature about botulinum toxin mechanisms was reviewed to provide an up to date knowledge about the topic. Immunoreactivity to cleaved SNAP-25, the end product of BoNT/A activity, has been identified in parasympathetic (pre- and postganglionic), sympathetic, and afferent fibers. A consistent decrease in the release of acetylcholine from parasympathetic, norepinephrine from sympathetic, and glutamate and neuropeptides from sensory neurons follows BoNT/A administration. Immunoreactivity to cleaved SNAP-25 was not identified in the urothelium or in myofibroblasts. Nevertheless, a decreased release of ATP and neurotrophins from the urothelial cells has been consistently observed after BoNT/A. The toxin does not cause apoptosis in the bladder. However, injection in rat and dog prostates was shown to induce apoptosis in acinar and stromal cells. There is now robust information to support that the mechanism of action of BoNT/A in the bladder involves neurotransmitter release from nerve fibers and urothelial cells. Which neurotransmitter is more relevant is, however, unclear. Likewise, the long duration of effect, the importance of the volume of vehicle injected and the selection of specific injection sites, like the trigone, needs further evaluation.

Electrophysiological correlates of cervical dystonia therapy with onabotulinum toxin type A

Electrophysiological correlates of cervical dystonia therapy with onabotulinum toxin type A

627 Effect of onabotulinum toxin type A intraprostatic injection on the outcome of BPH patients refractory to medical therapy: A 2-year study

627 Effect of onabotulinum toxin type A intraprostatic injection on the outcome of BPH patients refractory to medical therapy: A 2-year study

Increasing Interval between Injections after Prolonged Onabotulinum Toxin Type A Use for Blepharospasm (P02.260)

Objective: To determine the change in in dosing interval after prolonged onabotulinum toxin A use for blepharospasm. Background We have been using onabolulinum toxin type A (BTA) to treat blepharospasm (BEB) for over 25 years and noted that some patients seem to have an increase in efficacy over time as seen by longer intervals between injections. The change in duration of response to therapy has been described in cervical dystonia and hemifacial spasm. There is limited data regarding changes in dosing intervals after prolonged BTA use in patients with BEB. Design/Methods: We retrospectively reviewed the charts of patients that continued to follow in our clinic and were receiving BTA for BEB. Clinical information from the initial and most recent injections were recorded into a database including: sex, age at the start of treatment, current age, initial frequency of injections, current frequency of injections. Results: We identified 9 cases where the interval between injections had changed. The average age at first injection was 59.8 years and average current age was 74.4 years. Two patients were male and 7 were female. Average duration of toxin use was 15 years (range=8-26 years). The average dosing interval at the start of treatment was 2.8±0.4 months, which increased to 5.0±1.3 months (p Conclusions: The dosing interval for BTA may increase over time in patients treated for BEB. The change in dosing interval may occur more readily in BEB patients treated with BTA for approximately10 years. Disclosure: Dr. DeLott has nothing to disclose. Dr. Cornblath has received research support for the Case Crossover Study.

997 Urinary levels of noradrenaline are increased in patients with bladder pain syndrome/interstitial cystitis and are decreased by intratrigonal onabotulinum toxin type A injection

997 Urinary levels of noradrenaline are increased in patients with bladder pain syndrome/interstitial cystitis and are decreased by intratrigonal onabotulinum toxin type A injection

Poster 419 Dosing Patterns of Canadian Physicians Administering Onabotulinum Toxin Type A for Therapeutic Use in the MOBILITY Project (MDs on BOTOX Utility)

Poster 419 Dosing Patterns of Canadian Physicians Administering Onabotulinum Toxin Type A for Therapeutic Use in the MOBILITY Project (MDs on BOTOX Utility)

New therapeutic developments in chronic migraine

Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine.