Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure

Recently, it was reported that botulinum toxin type B complex (BoNT/B) (NeuroBloc®, Elan Pharmaceuticals) can produce an adequate therapeutic response in patients with antibody induced failure of botulinum toxin type A complex (BoNT/A) therapy. We wanted to study whether this effect is transient or sustained. For this, 10 consecutive patients (6 males, 4 females, age 54.6 ± 14.3 years, duration of illness 15.8 ± 7.0 years) with complete BoNT/A therapy failure and BoNT/A antibody titres in excess of 10mU/ml in the mouse diaphragm assay (MDA) received BoNT/B in an initial dose of 12370 ± 1804MU. After the first BoNT/B application the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) improved from 20.1 ± 3.0 to 11.9 ± 3.4. In all patients systemic anticholinergic side effects occurred. Three patients had stable continuous responses to two, three and five subsequent BoNT/B applications. Six patients showed complete secondary therapy failure to the second or third subsequent BoNT/B applications. Side effects did no longer occur. In four of them the BoNT/B doses were doubled without producing any therapeutic benefit or any side effects. In five of them MDA testing was performed and revealed BoNT/B antibody titres in excess of 1mU/ml. One patient lost half of her initial BoNT/B responsiveness indicating partial secondary BoNT/B therapy failure. This partial therapy failure was seen on two consecutive application series and has not proceeded to complete therapy failure so far. BoNT/B seems to be only temporarily effective in the majority of patients with BoNT/A antibody induced therapy failure. Whether the formation of BoNT/B antibody points to a high antigenic potency of BoNT/B, to an increased immunoreactivity in BoNT/A antibody carriers or whether it is due to the large amount of protein applied in BoNT/B therapy needs to be studied.     

Botulinum toxin type B (Myobloc®) in subjects with hemifacial spasm: Results from an open‐label,dose‐escalation safety study

Ojbective

Evaluate the safety of botulinum toxin type B (BoNT‐B) in subjects with hemifacial spasm (HFS).

Methods

This open‐label, sequential dose‐escalation study evaluated BoNT‐B in subjects with HFS. Eligible subjects were enrolled and received a single injection of one of four sequential BoNT‐B doses (100, 200, 400, or 800 U). Following injection, subjects were evaluated in person at Weeks 2 and 8 and by phone at Weeks 1, 4, and 10 and every 2 weeks thereafter until benefit was lost. Safety was assessed by adverse events (AEs), vital signs and clinical laboratory evaluation. The severity of HFS was assessed using a patient social impairment visual analog scale (VAS), subject severity of contraction VAS, the HFS physician assessment, and subject HFS frequency and severity assessment.

Results

Nineteen predominately Caucasian (92%) and female (67%) subjects (aged 36–80 years) with HFS participated in this study. Subjects remained in the study an average of 88 days (range of 41–332 days) after receiving a single dose of BoNT‐B. No deaths, serious AEs or AEs leading to trial discontinuation occurred during the study period. Two subjects in the 400 U dose group requested early withdrawal, whereas all other subjects completed the study. A reduction in HFS severity was observed in subjects treated with doses of 200 U or more. Improvements in subject HFS assessments tended to return to baseline values by 8 weeks following injection.

Conclusion

BoNT‐B was well‐tolerated and reduced HFS severity in subjects who received injections of 200 to 800 U. Additional investigation is necessary to confirm the findings from this open‐label study. © 2007 Movement Disorder Society     

Botulinum toxin A versus B in sialorrhea: A prospective,randomized, double‐blind,crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease

Background: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions. Methods: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT‐A) or B (BoNT‐B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re‐treated with the other serotype. Ultrasound‐guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT‐A (Dysport) and 2500 U BoNT‐B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline. Results: Twenty‐seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT‐A and BoNT‐B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT‐B treatments (3.2 ± 3.7 days) compared to BoNT‐A (6.6 ± 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT‐A and BoNT‐B, respectively (P = NS). The only toxin‐related side effect was a change to saliva thickness. Conclusions: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT‐B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT‐B treatment. © 2011 Movement Disorder Society     

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with type A-resistant cervical dystonia (CD). Background: Local intramuscular injections of BoNT are an effective therapy for CD. After repeated use, some patients become resistant to therapy. BoNT/B, effective in type A toxin-responsive patients, is proposed as an alternative therapy for type A-resistant patients. METHODS: The authors performed a 16-week, double-blind, placebo-controlled trial of BoNT/B in type A-resistant patients with CD. After resistance to therapy was confirmed with the frontalis-type A test, placebo or 10,000 U BoNT/B was administered in a single session into two to four clinically involved muscles. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was the primary efficacy measurement. TWSTRS-Total, three visual analog scales (Patient Global Assessment of Change, Principal Investigator Global Assessment of Change, Patient Analog Pain Assessment), and adverse events were assessed at baseline and weeks 2, 4, 8, 12, and 16. RESULTS: A total of 77 patients participated (38 placebo, 39 active). Improvements in severity, disability, and pain were documented in the BoNT/B-treated group. TWSTRS-Total scores were improved in the BoNT/B-treated group at weeks 4 (p = 0.0001), 8 (p = 0.0002), and 12 (p = 0.0129). All three visual analog scales demonstrated improvements at week 4 (p < 0.0001, 0.0001, and 0.001). A Kaplan-Meier analysis supported a duration of effect of 12 to 16 weeks in the active group. Dry mouth and dysphagia were self-limited adverse effects, reported more commonly in the BoNT/B group. CONCLUSIONS: Botulinum toxin type B (BoNT/B) (NeuroBloc) is safe and efficacious for the management of patients with type A-resistant cervical dystonia with an estimated duration of treatment effect of 12 to 16 weeks.     

Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia.

OBJECTIVE: To determine the safety and efficacy of botulinum toxin type B (BoNT/B) in patients with cervical dystonia (CD). BACKGROUND: BoNT/B is a form of chemodenervation therapy for the treatment of patients with CD. METHODS: The authors performed a 16-week, randomized, multicenter, double-blind, placebo-controlled trial of BoNT/B in patients with CD who continue to respond to botulinum toxin type A. Placebo, or 5,000 U or 10,000 U of BoNT/B was administered in two to four muscles involved clinically in CD. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 was the primary efficacy measure. Clinical assessments and adverse events were recorded for treatment day 1 and at weeks 2, 4, 8, 12, and 16. RESULTS: A total of 109 patients were enrolled randomly across all three treatment groups. The mean improvement in the TWSTRS-Total scores in each group at week 4 was 4.3 (placebo), 9.3 (5,000 U), and 11.7 (10,000 U). For the prospectively defined primary contrast (10,000 U versus placebo), highly significant differences were noted for the primary (TWSTRS-Total, baseline to week 4, p = 0.0004) and supportive secondary (Patient Global Assessment, baseline to week 4, p = 0.0001) outcome measures. Improvement in pain, disability, and severity of CD occurred for patients who were treated with BoNT/B when compared with placebo-treated patients. Overall, improvements associated with BoNT/B treatment were greatest for patients who received the 10,000-U dose. The duration of treatment effect for BoNT/B was 12 to 16 weeks for both doses. CONCLUSION: Botulinum toxin type B (NeuroBloc) is safe and efficacious at 5,000 U and 10,000 U for the management of patients with cervical dystonia.     

Prolonged vastus lateralis denervation after botulinum toxin type A injection

Intramuscular injection of botulinum toxin (BoNT) produces reversible blockade of neuromuscular transmission. In animal experimental models, recovery begins within four weeks and is usually complete by twelve weeks. We present evidence of prolonged denervation following BoNT injection of the vastus lateralis (VL) muscle to correct quadriceps muscle imbalance in patients with chronic anterior knee pain. Needle electromyography data were obtained from 10 subjects who had received a single BoNT treatment 5 to 19 months earlier as part of a clinical trial. Insertional and spontaneous activity, recruitment, and motor unit action potentials were examined. Clear differences between the injected and non‐injected VL muscles, which correlated with the time since injection, were identified in all subjects. All 10 subjects studied with needle EMG showed evidence of persisting denervation in the BoNT‐A injected VL muscle beyond the period of neuromotor recovery expected from animal experimental studies. © 2010 Movement Disorder Society     

Botulinum toxin A (Botox) and sweating-dose efficacy and comparison to other BoNT preparations

BACKGROUND: Botulinum toxin type A (BoNT/A) is 20-50 times more effective than Botulinum toxin type B (BoNT/B) concerning the treatment of muscular hypercontractions [Sloop, R.R., Cole, B.A., Escutin, R.O., 1997. Human response to botulinum toxin injection: type B compared with type A. Neurology 49, 189-194]. Botulinum toxins block motor nerves as well as autonomic fibres [Rand, M.J., Whaler, B.C., 1965. Impairment of sympathetic transmission by botulinum toxin. Nature 206, 588-591]. OBJECTIVE: Purpose of this study was to analyse the dose dependent reduction of sweating using the BoNT/A preparation Botox and to compare the results with our earlier results analysing Dysport [Braune, C., Erbguth, F., Birklein, F., 2001. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: measured by sudometry. Br. J. Dermatol. 144, 111-117] and Neurobloc (BoNT/B) [Birklein, F., Eisenbarth, G., Erbguth, F., Winterholler, M., 2003. Botulinum toxin type B blocks sudomotor function effectively: a 6 month follow up. J. Invest. Dermatol. 121, 1312-1316]. METHODS: Different doses of Botox were injected subcutaneously (n=27 healthy subjects). Planimetrical analyses of the area of anhidrosis and quantitative sudomotor-axon-reflex testing (QSART) were done after 3 weeks, 3 and 6 months. RESULTS: A threshold dose of 1.25 MU Botox led to anhidrotic skin spots after 3 weeks. The duration of anhidrosis was prolonged for 3 months when 17.5 MU and for 6 months when 50 MU were injected. Anhidrotic area size decreased with time (p=0.001), indicating partial recovery at the edges. After 3 weeks, QSART had significantly decreased to 29% of baseline. With doses of 70 MU or more it decreased to zero. After 3 months, QSART had returned to 68% of baseline and after 6 months to 87%. CONCLUSIONS: Botox dose-dependently suppressed sweating. Comparison to Dysport and Neurobloc revealed a strikingly similar efficacy after 3 weeks and 3 months for all preparations. BoNT/A in general induced a more sustained anhidrosis than BoNT/B.     

Botulinum toxin type A and cervical dystonia: a seven-year follow-up

Most cases of cervical dystonia (CD) are idiopathic, and focal injections of botulinum toxin A (BoNT/A) are the treatment of choice. The objective of our study was to document the effects of long-term BoNT/A treatment in idiopathic CD patients. Fifty-eight patients with idiopathic CD were recruited from March 2001 to May 2002. Twenty-eight of the subjects were available for reassessment after seven years. During this period, all had received regular treatment with BoNT/A injections. Clinical information about patients and the severity of CD (TWSTRS and VAPS) at baseline assessment (2001-2002) and follow-up (2008-2009) was compared. Significant motor improvement was detected based on TWSTRS scale scores, which were used to analyze clinical severity (19.6 ± 6.6 and 17.7 ± 4.8; p<0.05). There was no improvement in the severity of cervical pain (p=0.43). In conclusion, BoNT/A was a safe and effective long-term therapy for CD.     

Botulinum neurotoxins for post‐stroke spasticity in adults: A systematic review

The aim of this systematic review was to determine whether botulinum neurotoxin (BoNT) reduce spasticity or improve function in adult patients after stroke. Eleven double‐blind randomized placebo‐controlled trials met inclusion criteria. They encompassed 782 patients, 767 (98%) of whom received BoNT/A, and 15 (2%) BoNT/B. Most studies used the Ashworth scale as primary outcome measure. Differences between treated and control groups were assessed as categorical or continuous comparisons. The overall effect on upper limb spasticity was in favor of BoNT/A. A significantly higher number of patients had a reduction of upper limb spasticity at 4‐week and 8‐week evaluations in the treatment group compared with placebo. Mean changes in joint spasticity revealed improvement 3 to 6 weeks and 9 to 12 weeks after treatment. There were insufficient data to establish BoNT/A efficacy on lower limb spasticity or the effect of BoNT/B on the upper and lower limbs. Because of inconsistency and heterogeneity of the available data, it was not possible to perform a meta‐analysis on disability and patients' reported outcomes. There was an overlapping safety profile between the treatment and the placebo groups. BoNT/A reduces upper limb spasticity in patients post‐stroke, but the improvement in functional ability remains to be established. This gap needs to be filled by new studies to assess the effect of BoNT in the context of multidisciplinary patient management. © 2009 Movement Disorder Society     

Efficacy and safety of repeated doses of botulinum toxin type B in type A resistant and responsive cervical dystonia.

Efficacy of botulinum toxin type B (BoNT B) for the treatment of type A-resistant (AR) and non-A-resistant (NAR) cervical dystonia (CD) has been demonstrated in several single injection studies. There is little data available on long-term therapy with repeated injection sessions and it is unknown if AR and NAR patients respond in a similar manner over time. To evaluate the long-term efficacy and safety of BoNT B in AR and NAR CD patients, we carried out a prospective, open-label study examining 10 repeated dosing sessions of BoNT B in 34 patients with CD (15 AR and 19 NAR). Dosing was started at 10,000 units and could be increased to 25,000. Assessments included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and a patient global assessment at each baseline (injection) and Week 4 (peak effect) visit. Change in TWSTRS total was the primary efficacy end point. Data was analyzed using repeated-measures analysis of variance. BoNT B therapy resulted in an overall significant improvement of CD (P<0.001) and improvement was seen in all 10 individual sessions (2.5 years). The magnitude of response decayed over time (P<0.001). There was no difference between AR and NAR patients with regard to dose, treatment effect, or decay in response. The AR group perceived (patient global) treatment as being less effective (P=0.047). Dry mouth frequency decreased with each session despite increasing doses whereas flu-like syndrome and weakness increased. BoNT B therapy provides long-term benefit for CD patients but the magnitude of response diminishes over time. The cause of this decay is probably multifactorial. AR and NAR CD patients respond in a similar fashion.     

Split‐screen video demonstration of sonography‐guided muscle identification and injection of botulinum toxin

A standardization of injection procedures for the various botulinum toxin (BoNT) indications has not been achieved to date. One established option to guide the therapist's needle is sonography guidance. It provides real‐time visualization of the injection process, which is quick, allows perfect precision, and the procedure as such is painless. To demonstrate these qualities, we have recorded six split‐screen video segments that show the handling of the probe and the needle during BoNT injections concurrently with the respective cross‐sectional sonography recordings. The video sequences show differentiation of the pollicis longus muscle and individual finger flexor fascicles, needle tracking, and real‐time sonography‐guided injection of the gastrocnemius, rectus femoris, and iliopsoas muscles. We hope this short presentation will help to encourage a more widespread use of the technique as well as further research on sonography guidance for precise delivery of BoNT injections to various target muscles. © 2010 Movement Disorder Society     

Safety and efficacy of botulinum toxin type B for treatment of sialorrhea in Parkinson's disease: a prospective double-blind trial

Sialorrhea (drooling) is a common symptom of Parkinson's disease (PD) that can significantly impair a patient's health and quality of life. Fifty-four PD subjects with troublesome sialorrhea were enrolled using a multicenter, randomized, double-blind, sequential-dose escalation design in which subjects received a single intraglandular treatment with botulinum toxin type B (doses of 1,500 Units [0.3 mL]; 2,500 Units [0.5 ml]; or 3,500 Units [0.7 ml]) or placebo. Postinjection, subjects were followed acutely for 4 weeks and long-term for up to 20 weeks. Safety/tolerability, as assessed by adverse events, was the primary outcome measure. Efficacy, as assessed by the Drooling Frequency and Severity Scale and unstimulated salivary flow rate, was secondary. Gastrointestinal-related adverse events occurred more frequently in the active groups versus placebo group (31% vs 7%), with dry mouth being most common (15%). There were no serious adverse events attributed to botulinum toxin type B or discontinuations due to adverse events from treatment. At 4 weeks postinjection, Drooling Frequency and Severity Scale scores significantly improved versus placebo (-1.3 ± 1.3) in a dose-related manner (-2.1 ± 1.2, P = 0.0191; -3.3 ± 1.4, P < 0.0001; -3.5 ± 1.1, P < 0.0001, respectively) and unstimulated salivary flow rates significantly decreased in all active groups versus placebo (P ≤ 0.0009). Furthermore, treated subjects appeared to have more sustained improvement in sialorrhea than placebo subjects. We conclude that intraglandular injection of botulinum toxin type B was safe, tolerable, and efficacious in treating sialorrhea in PD patients. Additional studies are warranted to further confirm the drug's robust efficacy, as well as evaluate its effect with repeated dosing.     

The impact of the initial severity on later outcome: retrospective analysis of a large cohort of botulinum toxin naïve patients with idiopathic cervical dystonia

Journal of Neurology - The aim of study was to demonstrate that the first three injections of botulinum neurotoxin type A (BoNT/A) appear to be less effective in botulinum toxin naïve patients...     

Behavioral and structural effects of unilateral intrastriatal injections of botulinum neurotoxin a in the rat model of Parkinson's disease

Botulinum neurotoxin (BoNT) inhibits the release of acetylcholine from presynaptic vesicles through its proteinase activity cleaving the SNARE complex. Parkinson's disease (PD) is associated with locally increased cholinergic activity in the striatum. Therefore, the present study investigates the effect of unilateral intrastriatal BoNT‐A injection in naïve rats on striatal morphology; i.e., the total number of Nissl‐stained neurons and the volume of caudate‐putamen (CPu) were estimated. Furthermore, stainings for markers of gliosis (glial fibrillary acidic protein) and microglia (Iba1) were performed. In addition, the potential beneficial effects of a unilateral intrastriatal injection of BoNT‐A on motor activity in the rat model of hemi‐PD were evaluated. Hemi‐PD was induced by unilateral injection of 6‐hydroxydopamine (6‐OHDA) into the right medial forebrain bundle. Six weeks later, rats received an ipsilateral intrastriatal injection of BoNT‐A. Behaviorally, motor performance was tested. The total number of CPu neurons and the striatal volume were not significantly different between the BoNT‐A‐injected right and the intact left hemispheres of naïve rats. In hemi‐PD rats, intrastriatal BoNT‐A abolished apomorphine‐induced rotations, increased amphetamine‐induced rotations, and tended to improve left forelimb usage. Forced motor function in the accelerod test was not significantly changed by BoNT‐A, and open field activity was also unaltered compared with sham treatment. Thus, intrastriatal BoNT‐A affects spontaneous motor activity of hemi‐PD rats to a minor degree compared with drug‐induced motor function. In the future, tests assessing the cognitive and emotional performance should be performed to ascertain finally the potential therapeutic usefulness of intrastriatal BoNT‐A for PD. © 2013 Wiley Periodicals, Inc.     

Comparative electrophysiological study of response to botulinum toxin type B in Japanese and Caucasians

Ethnic differences in the muscle‐relaxing effect of botulinum toxin type B (BTX‐B) were examined by means of electrophysiological measurements in Japanese and Caucasian volunteers. This was a randomized, single‐blinded, single‐center study of 24 Japanese and 24 Caucasian healthy adult male subjects in Japan. BTX‐B (20 U, 100 U, or 500 U/0.2 mL) or placebo was administered to the extensor digitorum brevis (EDB) muscle in the left lower limb as a single dose (in each dose group, 6 subjects received the test drug and two received placebo). The inhibitory effect of BTX‐B on the M wave amplitude of EDB muscle generated by stimulation of the deep peroneal nerve was measured frequently during 2 weeks after administration, and then at weeks 4 (day 28) and 12 (day 84). The inhibitory effect of BTX‐B on the M wave amplitude of EDB muscle was dose‐dependent in both Japanese and Caucasian subjects, and the dose‐response curves were similar. These findings demonstrate that the muscle‐relaxing effect of BTX‐B in Japanese subjects is electrophysiologically similar to that in Caucasians. © 2007 Movement Disorder Society     

Muscle biopsy substantiates long‐term MRI alterations one year after a single dose of botulinum toxin injected into the lateral gastrocnemius muscle of healthy volunteers

Despite numerous clinical and experimental studies on botulinum toxin type A (BoNT/A), long‐term alterations of muscle texture and fine structure following BoNT/A treatment have thus far not been studied in normal human skeletal muscle. After obtaining institutional review board approval, we performed a prospective, placebo‐controlled, double‐blinded follow‐up study on two healthy adults using magnetic resonance imaging (MRI) and muscle biopsy to visualize long‐term alterations after a single BoNT/A injection into the lateral head of the gastrocnemius muscle. MRI disclosed a high‐signal‐intensity pattern in short tau inversion recovery sequences, and a reduction of the cross‐sectional area in the BoNT/A‐injected, but not in the saline‐injected contralateral control muscle (at 6 to 9 months in volunteer A: 73%, in B: 62%; at 12 months in A: 88%, and in B: 78%). Enzyme histochemistry, 12 months after injection, confirmed neurogenic atrophy of muscle fibers only in the BoNT/A‐injected muscle. Electron microscopy revealed additional degenerative changes at the neuromuscular junction. The data confirm that MRI is a suitable tool to monitor the long‐term effect of BoNT/A on skeletal muscle. Neurogenic muscle atrophy following a single BoNT/A injection should be taken into consideration when repeated BoNT/A injections into the same muscles are proposed. © 2009 Movement Disorder Society     

Effects of intraplantar botulinum toxin‐B on carrageenan‐induced changes in nociception and spinal phosphorylation of GluA1 and Akt

Increasing evidence suggests that botulinum neurotoxins (BoNTs) delivered into the skin and muscle in certain human and animal pain states may exert antinociceptive efficacy though their uptake and transport to central afferent terminals. Cleavage of soluble N‐methylaleimide‐sensitive attachment protein receptor by BoNTs can impede vesicular mediated neurotransmitter release as well as transport/insertion of channel/receptor subunits into plasma membranes, an effect that can reduce activity‐evoked facilitation. Here, we explored the effects of intraplantar botulinum toxin‐ B (BoNT‐B) on peripheral inflammation and spinal nociceptive processing in an inflammatory model of pain. C57BL/6 mice (male) received unilateral intraplantar BoNT (1 U, 30 μL) or saline prior to intraplantar carrageenan (20 μL, 2%) or intrathecal N‐methyl‐D‐aspartate (NMDA), substance P or saline (5 μL). Intraplantar carrageenan resulted in edema and mechanical allodynia in the injected paw and increased phosphorylation of a glutamate subunit (pGluA1ser845) and a serine/threonine‐specific protein kinase (pAktser473) in spinal dorsal horn along with an increased incidence of spinal c‐Fos positive cells. Pre‐treatment with intraplantar BoNT‐B reduced carrageenan evoked: (i) allodynia, but not edema; (ii) pGluA1 and pAkt and (iii) c‐Fos expression. Further, intrathecal NMDA and substance P each increased dorsal horn levels of pGluA1 and pAkt. Intraplantar BoNT‐B inhibited NMDA, but not substance P evoked phosphorylation of GluA1 and Akt. These results suggest that intraplantar toxin is transported centrally to block spinal activation and prevent phosphorylation of a glutamate receptor subunit and a kinase, which otherwise contribute to facilitated states.     

Botulinum toxin therapy of migraine and tension‐type headache: comparing different botulinum toxin preparations

Most of the initial reports on botulinum toxin in tension‐type headache (TTH) and in migraine were positive. Unfortunately, these results were not reproduced in well‐designed, randomized controlled trials. So far, doses from 20 U (Botox®) to 500 U (Dysport®) have been studied in patients with chronic TTH, and doses from 16 to 200 U (Botox®) in patients with migraine. Overall, there is no evidence for a beneficial effect of botulinum toxin, although trends favoring botulinum toxin were reported. Experience with botulinum toxin type B (Myobloc®/NeuroBloc®) is limited and similar to the experience with the type A. Thus, a widespread use of botulinum toxin therapy in headache can currently not be recommended.     

Antidepressant medication exposure and 5‐HT1A autoreceptor binding in major depressive disorder

Objective: We have previously reported higher brain serotonin 1A (5‐HT_1A) autoreceptor binding in antidepressant‐naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5‐HT_1A receptor binding after medication discontinuation. Methods: Positron emission tomography (PET) imaging with the 5‐HT_1A receptor radioligand [¹¹C]WAY‐100635 was performed in 66 individuals with current DSM‐IV MDD to examine relationships between 5‐HT_1A binding and time since most recent antidepressant treatment. All subjects were medication‐free for at least 2 weeks prior to scanning. Thirty‐two additional MDD comparison subjects were antidepressant naïve. Results: No differences in [¹¹C]WAY‐100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [¹¹C]WAY‐100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. Conclusion: These results indicate that any antidepressant‐associated downregulation of 5‐HT_1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness‐related binding levels.     

Pericranial injection of botulinum toxin type A (Dysport®) for tension-type headache – A multicentre, double-blind, randomized, placebo-controlled study

Increasingly, botulinum type A toxin is used to influence pathologically increased muscle activity in conditions such as dystonia and spasticity. Studies have also assessed its efficacy in tension-type headache, where muscle tenderness may be increased. We undertook a prospective, multicentre, randomized, double-blind, placebo-controlled trial. Patients received injections of Dysport^® (total dose of 420 or 210 units) or saline placebo in 18 sites on the head and neck. Of 125 patients treated, 118 were included in the intention-to-treat dataset. No significant differences between each verum group and placebo were seen for the primary efficacy parameter – change in the number of headache-free days at 4–8 weeks after injection compared with 4 weeks before injection. The groups receiving 420 or 210 units of Dysport experienced 2.60 and 2.87 more headache-free days respectively, compared with 1.93 more headache-free days for the placebo group ( P  = 0.66 versus 420 units; P  = 0.52 versus 210 units). Treatment with 420 units of Dysport was associated with significant improvements compared with placebo for two secondary efficacy parameters: mean change in headache duration from baseline to weeks 8–12 ( P  < 0.05) and improved global physician and patient assessment scores ( P  < 0.05). Further studies should address the possible value of multiple injections with extended observation periods, dose optimization, and whether duration of headache history and number of previous treatments are predictors of patient response.