Clinical failure of botulinum toxin A in movement disorders

ObjectiveBotulinum toxin (BTX) injections have been used extensively in medicine; however, little is known about the factors predicting the loss of effectiveness of botulin toxin.MethodsUsing a clinical database, we identified 401 subjects who had been treated for movement disorders from 1998 through 2010 with onabotulinumtoxin A (BTX A) or who switched from BTX A to rimabotulinumtoxin B (BTX B). We compared patients who switched from type A to type B with patients using type A only with regard to number of visits, total number of injections, number of initial and final sites, number of initial units used, and duration of treatments.ResultsWe observed that patients who switched from BTX A to B had a significantly higher number of initial injection sites than patients with BTX A only (BTX A to B median = 8.5; BTX A median = 6; p for difference = 0.006), had a higher number of final sites (BTX A to B median = 9 BTX A median = 7; p = 0.01), and were also more likely to have multiple reasons for injection (BTX A to B = 25.0%; botulin toxin A = 5.3%; p = 0.01). We did not find significant differences between groups based on the other variables.ConclusionsOur findings suggest that higher number of sites rather than higher number of units or years of treatment are associated with the loss of effectiveness to BTX A. It is possible that the loss of effectiveness to the BTX is more strongly elicited when the injections are widely diffuse.     

Long-term follow-up of cervical dystonia patients treated with botulinum toxin A.

We followed the course in 100 consecutive patients with cervical dystonia (CD) after they were initially treated with botulinum toxin (BTX) in the form of Dysport 10 to 12 years ago. A total of 4 patients had died, and 6 were lost to follow-up. Of the remaining 90 patients, 57 (63%) were still treated with BTX. In the patients treated at one centre over the whole period with Dysport, mean dose used during each treatment session was 833 (SD +/- 339) units Dysport with a cumulative dose of 20,943 (SD +/- 9462) units Dysport over a mean of 26.8 (SD +/- 8.6) treatment cycles. Secondary nonresponse was detected in 3 of the 90 patients. During follow-up, 12 patients developed blepharospasm, 13 oromandibular dystonia, and 17 patients writer's cramp. We conclude that BTX remains effective and safe for approximately 60% of CD patients for more than 10 years.     

Secondary non-response due to antibody formation in a child after three injections of botulinum toxin B into the salivary glands

Botulinum toxin (BTX) offers a new treatment option to reduce drooling in adults and children. Antibody formation against BTX is known to be one reason for clinical secondary non-response to this treatment. This is a case report on the development of secondary non-response to BTX type B (BTX-B) in a 15-year-old male, with bilateral dyskinetic cerebral palsy (Gross Motor Function Classification System Level IV) with additional learning disability* and microcephaly, treated for the indication of drooling. After three successful treatment sessions, the fourth and fifth injections showed no clinical response. This was associated with the presence of antibodies against BTX-B as determined using the mouse diaphragm assay. Thus, formation of neutralizing antibodies against BTX-B appears to be an important issue, not only in patients treated for cervical dystonia but also in children treated for drooling. Subsequent injections with an adequate dose of BTX type A (BTX-A) did not show any clinical response either, although no antibodies to BTX-A were detected. Besides the unanswered questions of dosing and distribution, a second possible explanation could be that BTX-B gave rise to non-neutralizing antibodies that cross-react with BTX-A. The resulting immune complexes could be taken up by phagocytes and, thereby, impede clinical response.     

Neutralizing botulinum toxin type a antibodies: clinical observations in patients with cervical dystonia

Neutralization of antibodies poses a problem for a substantial number of cervical dystonia (CD) patients treated with botulinum toxin type A (BoNT/A). Presence of these antibodies may lead to a secondary nonresponse to BoNT/A treatment. In this study, we compared 6 antibody-positive (Ab+) with 12 antibody- negative (Ab-) CD patients treated with BoNT/A (Dysport) and matched for du- ration of treatment, number of BoNT/A injections, and severity of clinical symptoms. The two groups differed in cumulative BoNT/A dose (Ab+, 5984 mouse units [MU ], SD = 3151 MU; Ab-, 3143 MU, SD =1294 MU; P <.05), in addition, ab+ patients were significantly younger (ab+ mean age = 41.3 y, sd =5.9 y; ab - mean age = 56.8 y, sd = 15.3 y; p <.05), in or- der to avoid formation of neutralizing antibodies, doses of bont/a should be kept as low as possible, the risk of antibody formation seems to be higher in younger patients.     

Antibody-induced failure of botulinum toxin type B therapy in de novo patients

Botulinum toxin type B (BT-B) therapy failure due to formation of botulinum toxin type B antibodies (BT-B-AB) has only been reported in patients with botulinum toxin type A antibodies (BT-A-AB). We are reporting BT-B-AB-induced therapy failure in 2 patients with no previous exposure to botulinum toxin. In patient 1 complete therapy failure occurred after a single exposure to 14,400 mouse units (MU) BT-B (NeuroBloc). The mouse diaphragm assay (MDA) revealed a BT-B-AB titre in excess of 10 mU/ml. Doubling the BT-B dose did not elicit any effects. Application of 360 MU BT-A (Botox) produced the original therapeutic effect, but the second BT-A application was followed by partial and the third by complete therapy failure. Doubling the BT-A dose did not elicit any effects. MDA testing showed a BT-A-AB titre in excess of 10 mU/ml. In patient 2 a single exposure to 7,200 MU BT-B lead to a complete therapy failure. MDA testing revealed a BT-B-AB titre in excess of 10 mU/ml. Doubling the BT-B dose did not elicit any effects. Application of 180 MU BT-A (Botox) produced the original response on 3 consecutive applications. Antibody formation can occur after a single exposure to botulinum toxin. However, this is highly unusual. Since therapy failure occurred after the first-ever botulinum toxin exposure, short intervals between injections and use of booster injections can be excluded as causes for BT-B-AB formation in both patients. A more likely cause may be the substantially higher amount of antigenic protein administered in BT-B therapy compared to BT-A therapy. Further studies are necessary to compare the incidence of antibody formation in BT-B and BT-A therapy.     

Botulinum toxin in the treatment of tics

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin A (BTX) injections in the treatment of tics in patients with Tourette syndrome (TS). BACKGROUND: BTX is an effective treatment for an increasing number of conditions characterized by abnormal muscle contractions. BTX may improve not only the motor component of tics, but also premonitory sensations that precede tics. METHODS: Thirty-five patients (30 male, 5 female) were treated with BTX in the sites of their most problematic tics. Response to BTX was based on a 0 to 4 clinical rating scale (0, no improvement, to 4, marked improvement in both severity and function). Questionnaires were administered to evaluate patients' impressions of overall efficacy and degree of benefit with premonitory sensations. RESULTS: Mean duration of tics prior to initial injection was 15.3 years (range, 1-62 years) and mean duration of follow-up was 21.2 months (range, 1. 5-84 months). The mean peak effect response in 35 patients treated in 115 sessions was 2.8 (range, 0-4); the mean duration of benefit was 14.4 weeks (maximum, 45 weeks); and the mean latency to onset of benefit was 3.8 days (maximum, 10 days). Twenty-one (84%) of 25 patients with premonitory sensations derived marked relief of these symptoms (mean benefit, 70.6%). Total mean dose was 502.1 U (range, 15-3550 U); mean number of visits, 3.3 (range, 1-16); and mean dose per visit, 119.9 U (range, 15-273 U). Sites of injections were as follows: cervical or upper thoracic area (17), upper face (14), lower face (7), vocal cords (4), upper back and/or shoulder (3), scalp (1), forearm (1), leg (1) and rectus abdominis (1). Complications included neck weakness (4), dysphagia (2), ptosis (2), nausea (1), hypophonia (1), fatigue (1), and generalized weakness (1), which were all mild and transient. CONCLUSIONS: Botulinum toxin A injections are an effective and well-tolerated treatment of tics. In addition to improving the motor component of tics, BTX also provides relief of premonitory sensations. Arch Neurol. 2000;57:1190-1193     

Botulinum toxin for treatment of craniofacial hyperhidrosis

The effect of botulinum toxin A (BTX) was studied on 12 patients with idiopathic craniofacial hyperhidrosis. After confirming the diagnosis by Minor's iodine starch test we first treated one-half of the forehead with an injection of 2.5–4 ng BTX (Dysport) equidistantly intracutaneously. After 4 weeks we assessed the efficacy by another Minor's iodine starch test and then treated the other half. Another 4 weeks later a standardized telephone interview was carried out. After 1–7 days the craniofacial sweating in the area injected had completely ceased in 11 patients and was mildly reduced in the remaining one. The efficacy was confirmed by repeated Minor's iodine starch tests. Mild weakness of frowning was the only side effect, lasting 1–12 weeks and completely resolving in all patients. Although sweating has not yet recurred in most patients at follow-up periods up to 27 months, one patient had a relapse 9 months after treatment. Following reports on palmar and axillary hyperhidrosis and gustatory sweating (Frey's syndrome) this is apparently the first report on the use of BTX in the treatment of idiopathic craniofacial hyperhidrosis. BTX seems a promising new treatment for localized hyperhidrosis. Received: 24 August 1999 / Received in revised form: 13 March 2000 / Accepted: 7 June 2000     

Immunological aspects of Botox®, Dysport® and MyoblocTM/NeuroBloc®

In some patients treated with botulinum toxin (BT), antibodies are produced in association with certain treatment parameters, patient characteristics and immunological properties of the BT preparation used. Therapeutic BT preparations are comprised of botulinum neurotoxin, non‐toxic proteins and excipients. Antibodies formed against botulinum neurotoxin can block BT's biological activity. The antigenicity of a BT preparation depends on the amount of botulinum neurotoxin presented to the immune system. This amount is determined by the specific biological activity, the relationship between the biological activity and the amount of botulinum neurotoxin contained in the preparation. For Botox^® the specific biological activity is 60 MU‐EV/ng neurotoxin, for Dysport^® 100 MU‐EV/ng neurotoxin and for Myobloc^TM/NeuroBloc^® 5 MU‐EV/ng neurotoxin. For Myobloc^TM/NeuroBloc^® this translates into an antibody‐induced therapy failure rate of 44% in patients treated for cervical dystonia, whereas for BT type A preparations this figure is approximately 5%. No obvious differences in antigenicity of BT type A preparations have been detected thus far. For the current formulation of Botox^®, the rate of antibody‐induced therapy failure is reportedly less than 1%. To determine the antigenicity of different BT preparations in more detail, prospective studies on large series of unbiased patients with sensitive and specific BT antibody tests are necessary.     

Botulinum toxin treatment of synkinesia and hyperlacrimation after facial palsy

OBJECTIVES—Toinvestigate the effects of injection of botulinum toxin type A (BTX A)into the orbicularis oculi muscle and lacrimal gland in patients withaberrant regeneration after facial palsy (facial synkinesias and hyperlacrimation).
METHODS—The effect ofthe toxin injection (on average 75 mouse units of BTX A) into theorbicularis oculi muscle on facial synkinesias was assessed on a fivepoint (0 to 4) scale in 10 patients with aberrant regeneration offacial nerve fibres after a peripheral facial nerve palsy. Six patientsunderwent a videographic control, which was assessed by a blindedindependent investigator. In two patients with hyperlacrimation anextra dose of botulinum toxin (on average 20 mouse units BTX A) wasinjected into the lacrimal gland and the effect was assessed using theSchirmer test and on a three point scale.
RESULTS—Botulinumtoxin type A had a good to excellent (grades 3 and 4) effect over anaverage of six months after 91% of injections. In 9% the injectionshad a moderate (grade 2) effect. Patients with hyperlacrimation showeda nearly complete recovery. There were no systemic side effects butfocal side effects due to a temporary weakness of the orbicularis oculimuscle were not uncommon.
CONCLUSIONS—Botulinumtoxin type A is the treatment of choice in motor and autonomic effectsof aberrant regeneration of facial nerve after a peripheral palsy. Therequired dose is similar to or slightly lower than the dose usuallyrecommended for hemifacial spasm.

     

Botulinum toxin and neuromotor rehabilitation: An integrated approach to idiopathic cervical dystonia.

Currently, the best treatment option for idiopathic cervical dystonia (ICD) is injection of botulinum toxin (BTX) into the affected muscles, whereas rehabilitative approaches have given disappointing results. We evaluated whether the association of an ad hoc rehabilitative program may improve the clinical efficacy of BTX treatment in a single-center, cross-over, controlled study. Forty patients with ICD were randomly assigned to two different treatment groups: (1) BTX type A (BTX-A) plus a specific program of physical therapy (BTX-PT) or (2) BTX-A alone (BTX-0). Patients in the BTX-PT group showed a longer duration of the clinical benefit (118.8 vs. 99.1 days) and needed a lower dose of BTX at reinjection (284.5 vs. 325.5 units). In addition, they showed more marked reductions in their disability in activities of daily living (-9.7 vs. -4.85 points) and subjective pain (-13.35 vs. 6.95 points) scores. Association of BTX-A therapy with a specific program of physical therapy may improve ICD treatment outcome.     

The clinical spectrum of laryngeal dystonia includes dystonic cough: Observations of a large series

Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincent's Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra‐laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra‐laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare. © 2014 International Parkinson and Movement Disorder Society     

Treatment with botulinum toxin improves the hyperexcitability of the facial motoneuron in patients with hemifacial spasm

Abstract

Botulinum toxin type A (BTX) injection into the orbicularis oculi muscle is an effective treatment for patients with hemifacial spasm (HFS). The objectives of this study were to investigate the effect of this treatment on HFS, in particular the associated hyperexcitability of the facial motor nucleus, and to discuss the potential mechanism of HFS. F waves in the mentalis muscle were examined before, 2 and 6 weeks after the BTX treatment of only the orbicularis oculi muscle in ten patients with HFS. F/M ratio, duration of F waves and frequency of F waves decreased significantly after the BTX treatment compared with those before the BTX treatment. These findings demonstrate that the excitability of the facial motonucleus decreases after BTX treatment of the orbicularis oculi muscle. From these results, we hypothesize that the trigeminal afferent input and the cortical control contribute to the hyperexcitability of the facial motor nucleus in patients with HFS. This warrants further investigation into the pathophysiology of HFS.     

Personality traits associated with blepharospasm: A comparison with healthy subjects,patients with facial hemispasm and patients with hyperhidrosis

The aim of this study is to explore the existence of specific personality traits related to patients with blepharospasm (BSP), treated with injections of botulinum neurotoxin (BTX). Sixteen patients with BSP, 22 with facial hemispasm (HFS), 20 with essential hyperhidrosis (EH) and 20 healthy controls (HCs) completed the Temperament and Character Inventory-Revised to explore personality traits based on Cloninger's Psychobiological Model. The results revealed that the four groups differed on the Harm Avoidance (HA) scale and fear of uncertainty subscale, as well as on Persistence (PS). On HA, BSP group did not differ from HCs, but had higher scores than HFS and EH groups. On PS scales, BSP and HFS patients did not differ between them but showed higher score than HCs and EH patients. Our findings suggested that a high level of Harm Avoidance and Persistence seem to be associated with BSP, when compared with any disorders treated with BTX. An evaluation of the personality traits might help the clinicians to early identify BSP patients at greater risk of developing psychopathological disturbances.     

Sudomotor testing discriminates between subjects with and without antibodies against botulinum toxin A--a preliminary observation.

With an increasing number of patients being treated with botulinum toxin A (BTX A), the incidence of neutralizing anti-BTX antibodies (ABA) is rising. Because BTX A is known to inhibit sweating, sudometry seems to be a promising tool to test the efficacy of BTX A. We injected BTX A subcutaneously in normal control subjects and four patients with spasmodic torticollis, two responders and two nonresponders with proven ABA. Sweating was visualized using iodine starch staining and quantified used capacitance hygrometry. BTX A inhibited sweating completely at the injection site in both control subjects and all responders without evidence for ABA. However, continued sweating was recorded when the nonresponders with proven ABA were tested. We conclude that sudomotor testing is able to discriminate between subjects with and without clinically important ABA.     

Functional and clinical changes in upper limb spastic patients treated with botulinum toxin (BTX)

Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks. In order to study the usefulness of botulinum toxin type A (BTX) as a therapy for spasticity, we studied 15 patients affected by spasticity secondary to stroke. Tests included: clinical evaluation of tone (Ashworth scale); active angles of extension and flexion at elbow and wrist; Hmax/Mmax ratio from flexor carpi radialis (FCR); Hreflex presynaptic inhibition from FCR during vibration; Task score; and video recording. Patients were injected with BTX into one or more muscles with total doses not exceeding 200 International Units (IU). The tests were performed immediately prior to injection and repeated 2 weeks afterwards. Furthermore, in eight patients, testing was also performed one month after BTX injection. Between two weeks and one month after BTX there were no statistically significant differences. A statistically significant difference in the Task and Ashworth scores before and after treatment emerged (p < 0.0014), but only 6 patients showed a clear improvement in motor performance. Overall, we observed an improvement in the angle of active extension and flexion at the wrist and elbow. There were no significant changes in the Hmax/Mmax ratio and the Hreflex presynaptic inhibition during vibration. All the patients reported a subjective improvement. The results suggest that subjective benefits can be gained from the use of BTX in patients affected by spasticity, and that the degree of motor improvement seems to depend on the motor recovery obtained before treatment.     

Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy.

A 71-year-old woman was treated by botulinum toxin (BTX) type A injections for cervical dystonia related to a multiple system atrophy (MSA). A few days later and persisting for the next 4 months, she developed a severe dysphagia, requiring nasogastric feeding. This implicates cautious use of BTX in a case of MSA.     

Patients' perception of stopping or continuing treatment of cervical dystonia with botulinum toxin type A.

Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystonia (ICD), no follow up has been performed to determine when and why some patients stop therapy. It has been suggested that some patients who stop BTX treatment may do so because of permanent improvement. We surveyed 155 patients with ICD who were treated over 6 years with BTX to determine when and why patients stopped treatment with BTX, and what adverse events and changes in dose and/or frequency of treatments occurred in those who continued treatment. Of the 133 (86.6%) individuals returning the surveys, 104 continued on BTX treatment and 29 had stopped therapy. Of the 29 subjects no longer receiving BTX, 11 individuals had only received one or two injections. Prior surgical treatment for ICD did not influence their decision to stop therapy. Of those 104 of 133 continuing on BTX treatments, two thirds of the subjects reported the injections always help, whereas one quarter estimated one set of injections did not help. One third of those continuing treatment reported the first injection was most helpful, whereas another one third felt all injections were similarly effective. After an initial adjustment, BTX dosages and frequency of treatment remained stable in this group.     

Oromandibular dystonia involving the lateral pterygoid muscles: four cases with different complexity.

The report describes oromandibular dystonia (OMD) in four women with involuntary activity of the lateral pterygoid muscles (LP), causing incapacitating protrusive and lateral jaw movements and displacements, and treatment with botulinum toxin type A (BTX). For initial survey and treatment control, OMD was analyzed with several, independent, and standardized methods. OMD severity and functional difficulties were evaluated subjectively and scored from videotapes. Jaw movements were assessed graphically with a magnetic tracking system, and electromyographical activity (EMG) of LP was recorded with needle electrodes using an intraoral approach, whereas activity of masseter muscles was recorded with surface electrodes. EMG-guided BTX injections (25-40 units Botox per muscle) into the muscles were performed with cannula electrodes. Compared with reference values for LP, OMD was associated with a markedly increased level of spontaneous activity, but almost normal level of maximum voluntary activity. The central pattern generator for mastication seemed to override the dystonic activity, as all patients were able to chew despite some distortion. BTX reduced both the spontaneous and the maximum activity for 3-9 months. Concomitantly, a marked reduction of the OMD severity, mandibular movements and functional disturbances were also present with the best effect in localized OMD with late onset.     

Long-term botulinum toxin treatment increases employment rate in patients with cervical dystonia.

We examined the impact of cervical dystonia (CD) and long-term botulinum toxin (BTX) treatment on employment status. Data on employment status at onset of CD, at initiation of BTX treatment, and at evaluation of long-term treatment were obtained from 62 CD patients aged 31-66 years (median, 53 years; 61% females) who had been treated for a median of 5 years (range, 1.5-10 years). The employment rate fell from 84% at the onset of CD to 47% before initiation of BTX treatment. With long-term BTX treatment, 72% of those who worked at the initiation of treatment stayed employed, and 67% of those on sick leave returned to work. A younger age and a higher level of education increased the probability of being employed and avoiding disability benefits. Among those who were younger than 55 years at evaluation of BTX treatment (n = 40), the employment rate increased from 47% to 65% with treatment, and among the male patients, it reached the level of the general population (86%). About half of the 34% who received disability benefits did so already before the BTX treatment was initiated.     

Amyloid-β 1-42 levels are modified by apolipoprotein E ε4 in Creutzfeldt-Jakob disease in a similar manner as in Alzheimer's disease

The presence of apolipoprotein E (ApoE) ε4 allele is a risk factor for Alzheimer's disease (AD) and associated with a more pronounced reduction of amyloid-β 1-42 (Aβ1-42) in the cerebrospinal fluid (CSF). Because a decrease of Aβ1-42 and increase of tau protein levels, both important biomarkers for AD, are also reported in Creutzfeldt-Jakob disease (CJD), we analyzed if a similar relationship can be observed in this rapid progressive dementia. Our study included 309 patients with sporadic CJD (147 neuropathologically confirmed and 162 probable cases). We analyzed the role of ApoE ε4 in sporadic CJD (sCJD), in particular the influence on the CSF-markers 14-3-3 protein, tau protein, neuron-specific enolase, S100 protein, Aβ1-42, and Aβ1-40. No differences in the ApoE ε4 allele frequency and ApoE genotype distribution between sCJD and published healthy controls were observed. The ApoE ε4 allele had no effect on disease duration or age at onset. We detected a dose-dependent ApoE ε4 effect on the decrease of Aβ1-42 in sCJD. ApoE ε4 carriers with one ApoE ε4 allele showed significantly reduced Aβ1-42 values (p < 0.0001) in comparison with non-carriers. ApoE ε4 allele is not a risk factor for sCJD but modifies the Aβ1-42 levels in CSF in a similar manner as in AD. Based on our results in sCJD patients, we hypothesize that the ApoE ε4 effect on Aβ1-42 values might not be disease-specific.