Visual system side effects caused by parasympathetic dysfunction after botulinum toxin type B injections.

Botulinum toxin type B (BTX-B) has been approved by the Food and Drug Administration for the treatment of cervical dystonia. However, as with botulinum toxin type A (BTX-A) it has off-label uses, such as for hyperhidrosis, focal dystonias, spasticity, and facial wrinkles. BTX-B has also been shown to be a safe and effective alternative for patients who are resistant to BTX-A. The most commonly reported side effects include dry mouth and dysphagia. To date, there have been few reports of visual disturbances associated with BTX-B use. In this study, we report on three individual patients who received BTX-B and who subsequently developed parasympathetic dysfunction of the visual system after injections of BTX-B at remote sites.     

Clinical value of botulinum toxin in neurological indications

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3–4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.     

Treatment of hip adductor spasticity with botulinum toxin type B

For the treatment of focal spasticity using botulinum toxin, only studies using type A have been published.Botulinum toxin type B (Neurobloc) is registered for cervical dystonia, but there is increasing interest in ist effectiveness for treating other diseases. Four patients, each with seriously disabling hip adductor spasticity of different origins, were treated with botulinum toxin type B following the failure of other therapeutic options.Total doses of 10,000 IU to 22,000 IU were injected bilaterally into the hip adductor muscles. A reduction in muscle tone or painful spasms was observed in all patients within 2 weeks, leading to an improvement in gait and increased ease of nursing care. Therefore, botulinum toxin type B may be a more cost-effective treatment for hip adductor spasticity than botulinum toxin type A.     

Secondary nonresponsiveness to botulinum toxin type A in patients with oromandibular dystonia.

Intramuscular injection of botulinum toxin type A is the treatment of choice for most cases of oromandibular dystonia. We report on five patients with oromandibular dystonia that developed secondary nonresponsiveness to botulinum toxin type A following multiple injections over a 6-year period.     

Other indications of botulinum toxin therapy

The therapeutic possibilities of botulinum toxin are manifold and certainly not yet fully exhausted. Apart from the classical indications – focal dystonia and focal spasticity – its use in the management of wrinkles has become well known. Moreover, the toxin is now being administered in many medical fields, including many other kinetic disorders like rare dystonias and tremor. The toxin is also used in a great number of autonomic disorders such as focal hyperhidrosis and even rhinitis. Substantial advances have been made in the field of urology after injections into the sphincter and detrusor muscle. Studies for approval are meanwhile under way concerning the treatment of detrusor hyperreflexia. Gastroenterology is another important field for application of botulinum toxin – be it to the esophagus (e.g. achalasia), stomach, gallbladder, or anorectum. Anal fissure is considered a particularly common indication. Controlled studies for many indications are frequently lacking because of the limited incidence of some of these disorders and symptoms.     

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 de novo therapy of cervical dystonia

Botulinum toxin induced therapy failure type B antibody (BT–B, BT–B–AB) has so far only been reported after previous formation of antibodies against botulinum toxin type A (BT–A, BTA– AB).We wanted to explore the risk of BT-B-AB-induced therapy failure in patients who were exposed to botulinum toxin for the first time. For this purpose we followed nine patients with cervical dystonia receiving BT-B (NeuroBloc^®/Myo- Bloc™, Elan Pharmaceuticals) in a dose of 11435 ± 2977MU during 4.9 ± 3.0 injection series. All patients showed a satisfactory initial therapeutic response as documented by a Toronto Western Spasmodic Torticollis Rating Scale score reduction from 17.7 ± 9.4 to 5.3 ± 4.8 and an overall subjective improvement of 56.1 ± 28.3%. Seven patients experienced systemic anticholinergic side effects. Five patients had stable therapeutic responses over subsequent injection series. Four patients experienced complete therapy failure with BT–B–AB titres in excess of 10mU/ml on the mouse diaphragm assay. Doubling the last effective BT–B dose produced neither therapeutic effects nor side effects. Subsequent applications of botulinum toxin type A produced a continued therapeutic response in one patient and complete therapy failure in the other.Despite the small sample size a frequency of 44 % indicates a high risk for BT–B–AB-induced complete therapy failure. The high amount of neurotoxin administered when NeuroBloc^®/MyoBloc™ is used might be a contributory factor. Further prospective comparative studies are necessary to monitor the frequency and time course of BT–B–AB formation.     

Elimination of dysphagia using ultrasound guidance for botulinum toxin injections in cervical dystonia

Introduction: Dysphagia is a common side effect after botulinum toxin injections for cervical dystonia, with an incidence of 10–40%, depending upon the study and dose used. Methods: Our study consisted of 5 preselected women who met criteria for cervical dystonia and subsequent dysphagia after electromyography (EMG)‐guided injections. Injections were performed with ultrasound (US) imaging, and the effects on swallowing were examined. Separately, sternocleidomastoid (SCM) thickness in healthy controls and treated patients was measured. Results: There were 34 episodes of dysphagia over 98 injection sessions using EMG guidance for a cumulative rate of 34.7%. Using US plus EMG guidance, there was 0% dysphagia across 27 injection sessions. SCM thickness was <1.1 cm. Conclusion: US combined with EMG guidance eliminated recurrent dysphagia after botulinum toxin treatment, possibly by keeping the injectate within the SCM. Muscle Nerve 46: 535–539, 2012     

Long-term efficacy of botulinum toxin A in treatment of various movement disorders over a 10-year period.

Although botulinum toxin A (BTX) has been licensed in Canada for treatment of various movement disorders since 1990, few clinical studies regarding its long-term efficacy and side effects have been reported. We conducted a retrospective analysis of 235 patients who received BTX from our movement disorders clinic over a 10-year period (January 1990 to December 1999). A total of 2,616 treatment cycles (multiple injections) were administered to 235 patients with cervical dystonia (CD), hemifacial spasm (HS), blepharospasm (BP), and other movement disorders. Substantial benefit at 5 years was seen in most patients (90% in BP, 88% in HS, 63% in CD, 100% in jaw closing and lower limb dystonia, and 56% in writer's cramp). Benefit was maintained for up to 10 years in CD, HS, and BP data, with a 75.8% benefit reported. Twenty-eight percent of patients discontinued treatment during the follow-up period due to a variety of reasons. Of these, 9.1% of patients developed primary resistance, and 7.5% of patients secondary resistance. Adverse effects, mostly minor, developed in 27% of patients at any one time, occurring over 4.5% of treatment cycles. These were most frequently reported in blepharospasm (22 of 36 patients in 40 cycles), followed by hemifacial spasm (21 of 70 patients in 46 cycles), and cervical dystonia (17 of 106 in 28 cycles). Only 1.3% of patients discontinued therapy due intolerable adverse effects. The results show that BTX is a safe and effective treatment of various types of movement disorders, and most side effects are well tolerated. Discontinuation for any reason was also low after 5 years. Efficacy was maintained after long periods of treatment with high degree of patient satisfaction.     

Five‐year experience with incobotulinumtoxinA (Xeomin®): the first botulinum toxin drug free of complexing proteins

In 2005, incobotulinumtoxinA (Xeomin^®), a new botulinum toxin (BT) type A drug without complexing proteins (CPs), became available. This paper reviews the specific features of Xeomin^® and the experience gathered with it during the last 5 years. Compared with conventional BT drugs, Xeomin^®’s extended shelf live and its simplified temperature restrictions indicate that CPs are not necessary for BT drug stability. Its reduced molecular size does not translate into diffusion differences, and its potency labelling is identical to that of onabotulinumtoxinA (Botox^®). With a reduced content of inactivated botulinum neurotoxin, Xeomin^® should have reduced antigenicity. Lack of CP’s may further reduce antigenicity. Xeomin^®’s therapeutic efficacy against cervical dystonia, blepharospasm and spasticity has been proven in large randomised, double‐blind and placebo‐controlled studies leading to registrations in many countries. Additional successful clinical use in axillary hyperhidrosis, hemifacial spasm, re‐innervation synkinesias and hypersalivation as well as in dystonia and spasticity in extended doses and throughout extended observation periods has been documented meanwhile. Lack of reported cases of antibody‐induced therapy failure (ABF), as to date, support the hypothesis of an improved antigenicity.     

Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test.

We studied 20 patients with cervical dystonia who had started to respond poorly to botulinum toxin A (BTXA) injections after an initial good response. All patients had extensor digitorum brevis (EDB) tests performed in addition to BTXA immunoprecipition assay (IPA) and mouse bioassay (MBA) antibody testing. The patients were reexamined and then treated with carefully placed electromyogram (EMG)-guided BTXA. Nine patients had a good clinical response to EMG-guided injections and all of these patients showed an obvious decrement on the EDB test. All were BTXA blocking antibodies (Abs)-negative via IPA and MBA (apart from one patient who had low BTXA antibodies titers using IPA but no antibodies by MBA). In the other 11 patients, there was a poor clinical response to EMG-guided BTXA injections. Seven of these 11 had small EDB decrement and BTXA antibodies using IPA, suggesting resistance to BTXA. Of the remaining four patients, two had obvious EDB decrement and low antibody titers via IPA (one of them had no antibodies via MBA), while the other two patients showed obvious decrement on the EDB test and no antibodies via IPA. This study shows that the EDB test correlates better with the clinical response than the antibody assays and that EDB decrement does not always correlate quantitatively with the BTXA antibody titers. In patients with secondary nonresponsiveness, it is recommended that an EDB test is the initial investigation of choice. In those patients where the EDB test does not demonstrate resistance to BTXA, a reexamination of the patients and carefully placed injections under EMG guidance may improve results.     

Treatment of hemifacial spasm with botulinum toxin.

The effectiveness of botulinum toxin injections in 11 patients with hemifacial spasm was investigated in a prospective placebo-controlled blinded study. The patients were treated with four sets of injections to various facial muscles, selected by clinical evaluation. Three injections were with graded doses of toxin and one was with placebo. The order of injections was random and unknown to the patients. Results were scored both subjectively by patient assessment of symptoms and objectively by blinded review of videotapes made one month after each injection. Subjective improvement occurred after 79% of injections with botulinum toxin, regardless of dose of toxin. Only 1 patient improved after placebo. Objective improvement was seen after 84% of injections with botulinum toxin. No patient showed objective improvement after placebo injection. The most frequent side effect was facial weakness, seen after 97% of injections of botulinum toxin. Facial bruising (20%), diplopia (13%), ptosis (7%), and various other mild side effects were seen less frequently. Botulinum toxin appears to be an effective and safe method of therapy for hemifacial spasm.     

Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases

Three patients are reported on who developed transient generalised weakness after receiving therapeutic doses of botulinum toxin for cervical dystonia (one case) and symptomatic hemidystonia (two cases) respectively. Clinical and electrophysiological findings were in keeping with mild botulism. All patients had received previous botulinum toxin injections without side effects and one patient continued injections without recurrence of generalised weakness. The cause is most likely presynaptic inhibition due to systemic spread of the toxin. Patients with symptomatic dystonia may be more likely to have this side effect and botulinum toxin injections in these patients should be carried out cautiously.     

A型肉毒毒素治疗口下颌肌张力障碍

目的观察A型肉毒毒素治疗口下颌肌张力障碍(OMD)患者的临床效果。方法对19例口下颌肌张力障碍患者进行临床分析,依据患者临床特点,将A型肉毒毒素注射到患者一侧或双侧咀嚼肌、颞肌及翼外肌,并根据肌肉收缩力量大小、肌肉体积及患者体重调整剂量。结果 68.4%的患者功能改善评分≥3分,疗效平均维持8～12周(有效范围2～28周)。4例患者注射后有轻度咀嚼无力,2～3周恢复。1例混合型患者注射后出现轻度鼻音,持续13天后症状消失。所有患者未出现其它严重副作用。结论 A型肉毒毒素对于口下颌肌张力障碍的治疗是有效、安全的。熟悉本病的临床特点及分型,选择正确的靶肌肉及注射适宜剂量的肉毒毒素是治疗本病的关键。     

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.     

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.     

Sustained attention in cranial dystonia patients treated with botulinum toxin

BACKGROUND: Primary cranial dystonia (PCD) is related to a functional disorder in basal ganglia usually accompanied by impaired executive function. AIM: To investigate symptom relief and neurocognitive change in response to treatment with botulinum toxin (BTX) in a group of patients with PCD. METHODS: We assessed nine patients with PCD and nine age- and educationally matched healthy individuals using tests of memory, sustained attention, span of auditory attention, and perceptual flexibility. RESULTS: Despite well-preserved intellectual skills relative to controls, we identified a sustained attention deficit in patients with PCD. After BTX treatment, there was an increase in the scores of the concentration endurance test (sustained attention) and the values did not differ significantly from control group patients' scores. CONCLUSION: The results support the view that executive dysfunction in PCD is secondary to the disrupting effects of the symptoms. Treatment with BTX alleviates the symptoms and, consequently, improves sustained attention.     

Lingual protrusion dystonia: Frequency,etiology and botulinum toxin therapy

The purpose of this study was to examine lingual protrusion dystonia (LPD); its frequency, etiology and response to botulinum toxin therapy. Previous literature suggests that LPD is more frequently the result of heredodegenerative disease and that the use of botulinum toxin therapy in LPD is associated with significant adverse effects. This is a retrospective database and record review from a movement disorder clinic. Of 421 dystonia patients, we identified 17 with LPD (4%). Of these cases, the diagnoses were: primary cranial dystonia (5), primary generalized dystonia (2), tardive dystonia (7), heredodegenerative disease (1), multifactorial (1) and post-infectious (1). All primary cases had concomitant oromandibular dystonia. In some secondary cases the LPD was the only cranial feature. Nine received botulinum toxin injections and 55.6% sustained moderate or marked improvement. Of 89 total botulinum toxin sessions, 66.3% had an excellent response, and 92.1% had some response. 97.8% of the sessions resulted in no significant adverse effects. On one occasion one patient developed severe dysphagia requiring placement of a percutaneous gastrostomy (PEG) tube. We conclude that LPD is rare, most commonly the result of tardive and primary dystonia. Botulinum toxin therapy may be very effective but needs to be utilized with care because of the possibility for the development of dysphagia.     

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.