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Hourglass Deformity After Botulinum Toxin Type A Injection
Abstract
Complications, such as eyelid ptosis, have been attributed to botulinum toxin type A. An "hourglass" deformity, which is the consequence of temporalis muscle atrophy, has not been reported previously.
To report a transient muscle deformity of the temporalis muscle caused by botulinum toxin type A.
Patients who underwent injection of 25 units of botulinum toxin type A into the temporal muscle, in a fan-shaped fashion, during an ongoing study for treatment of migraine were noted to develop temporary depression of the temples. Preinjection and postinjection photographs were taken. Patients were also sent questionnaires to verify the observed information.
Only 26 of 92 patients who underwent injection of botulinum toxin type A into the temporalis muscle subsequently reported depression of the muscle. When examined, all 92 patients exhibited this deformity ranging from minimal to significant. Patients who seemed to have less deformity were those who had excessive soft tissue overlying the muscle due to excess weight.
A newly recognized deformity is reported subsequent to the injection of botulinum toxin type A into the temporalis muscle. Informing patients of this transient deformity may minimize concern following treatment.
... The deformity was observed as early as one month post-injection, and resolved in all patients several months after recovery of muscle function. 13 In some instances, temporalis atrophy is the desired outcome. Ali et al described a patient with bilateral temporalis hypertrophy of unknown etiology that was successfully treated with botulinum toxin type A (80 units/side). ...
... Heavier patients experience a much lesser degree of visible atrophy. 13,15 In addition, clinical experience suggests that males require larger doses of botulinum toxin type A than females if similar responses are to be obtained. Furthermore, there is evidence that male subjects also exhibit a longer duration response (4-6 months) than females. ...
While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter.
... Fifth, demonstrating faith in a chosen analgesic in the presence of one's patient increases the chance of producing good pain control and may reduce the amount and duration of analgesic use [81]. Finally, over 25% of patients (26 of 92) can recognize the temporary depression of the temporalis muscle ("hour glass deformity") following BT-A injection [82]; this frequently visible expression of the injection procedure, as well as its other side effects [33], impairs masking between placebo and BT-A for both the patients and the investigators, as discussed previously. ...
... A specially challenging aspect of BT-A investigations involves the unblinding of some patients and their investigators by its side effects [33,82]. Although the RCT is at the pinnacle of the medical evidence pyramid, in order to make meaningful scientific progress, the limitations of the investigative tool that the RCT represents must be comprehended [84]. ...
Published on: 12 July 2004
Botulinum toxin for treatment of migraine: randomized controlled trials versus basic sciences
Vinod K Gupta, M.D., Physician
Dear Editor
Jankovic reviews the expanding list of approved and off-label indications for therapeutic use of botulinum toxin (BT). [1]. One of the prominent off-label indications for use of BT is migraine, the advent of which therapy was serendipitous.
Use of BT for migraine prevention is gaining momentum through the results of randomized controlled trials (RCT) – both completed and ongoing – and, in the effort to evolve a broad consensus, certain clinical reservations have been recently addressed [2].
In this period of elucidation of anti-migraine mechanisms of BT that would eventually lead towards formal approval of its use for clinical practice, it is important to maintain an open, cautious, and critical approach to the literature.
A direct skeletal muscle-spasmolysis independent prolonged analgesic action is believed to underlie efficacy of BT in preventing migraine attacks for three months or more [2-4]. The following facts do not sustain this theoretical premise: (i) Three RCTs in human volunteers do not support a direct or genuine analgesic action of BT [5-7]. (ii) Dose-dependent modification of analgesia-related behaviour in rats lasts only for two weeks with the higher (medium) dose tested [8]. (iii) In clinical trials in migraine patients, neither a predictable nor a dose-dependent response has been seen [9]. (iv) Peak responses to BT-A in migraine patients are seen at 8 -12 weeks [2,3,4], a pharmacotherapeutic delay that is inexplicable. (v) BT does not cross the blood-brain barrier [8]. and cannot influence either meningeal pain receptors or dural inflammation believed to underlie migraine headache [11]. or the aura [3].
While BT cannot influence central sensitization, blocking of peripheral sensitization through suppression of release of substance P does not contribute to analgesia in humans [6]. and is limited to 15 days in cultured embryonic rat dorsal root ganglia [12]. (vi) Donepezil – that exerts central and peripheral cholinergic activity opposite to that of BT -- remits migraine with aura or migraine without aura, an effect comparable to propranolol in controlled conditions [13]. (vii)
The clinical utility of BT in migraine has not been compared with other established prophylactic agents. (vii) Approximately 1% of patients receiving BT-A injections develop severe, debilitating headaches that may persist for 2-4 weeks [14].
The placebo effect cannot be reliably excluded in RCT, particularly with soft end points that hamper migraine research; RCT with BT in off- label indications such as migraine can misguide clinicians if undertaken without sufficient conceptual clarity [15]. Without a defensible core research vision to direct it, migraine remains a loosely-connected chain of assumptions and is in its infancy; great care should be taken before making further pathophysiological assumptions as well as therapeutic recommendations [16].
References
(1). Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004;75:951-7.
(2). Silberstein SD, Aoki KR. Botulinum toxin type A: myths, facts, and current research. Headache 2003;43(supplement 1): 1.
(3). Evans RW, Blumenfeld A. Botulinum toxin injections for headache. Headache 2003;43:682-5.
(4). Dodick DW. Botulinum neurotoxin for the treatment of migraine and other primary headache disorders: from bench to bedside. Headache 2003; 43: (supplement 1):25-33.
(5). Voller B, Sycha T, Gustorff B, Schmetterer L, Lehr S, Eichler HG, Auff E, Schnider P. A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A. Neurology 2003;61:940-4.
(6). Kramer HH, Angerer C, Erbguth F, Schmelz M, Birklein F. Botulinum Toxin A reduces neurogenic flare but has almost no effect on pain and hyperalgesia in human skin. J Neurol 2003;250:188-93.
(7). Blersch W, Schulte-Mattler WJ, Przywara S, May A, Bigalke H, Wohlfarth K. Botulinum toxin A and the cutaneous nociception in humans: a prospective, double-blind, placebo-controlled, randomized study. J Neurol Sci 2002;205:59-63.
(8). Cui M, Khanijou S, Rubino J, Kei Roger Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107:125-33.
(9). Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treatment. Headache 2000;40:445-50.
(10). de Paiva A, Meunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum toxin-A poisoning: bi-phasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci (USA). 1999;96:3200-5.
(11). Silberstein SD. Neurotoxins in the neurobiology of pain. Headache 2003;43(suppl 1):2-8.
(12). Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon 2000;38:245-58.
(13). Nicolodi M, Galeotti N, Ghelardini C, Bartolini A, Sicuteri F. Central cholinergic challenging of migraine by testing second-generation anticholinesterase drugs. Headache 2002;42:596-602.
(14). Alam M, Arndt KA, Dover JS. Severe, intractable headache after injection with botulinum A exotoxin: report of 5 cases. J Am Acad Dermatol 2002;46:62-5.
(15). Gupta VK. Randomized controlled trials: the hijacking of basic sciences by mathematical logic. BMJ Online (6 July 2004). Available at: http://bmj.bmjjournals.com/cgi/eletters/329/7456/2#65969
(16). Gupta VK. Bureaucratisation of migraine. Lancet Neurol 2004;3:396.
... Fifth, demonstrating faith in a chosen analgesic in the presence of one's patient increases the chance of producing good pain control and may reduce the amount and duration of analgesic use [81]. Finally, over 25% of patients (26 of 92) can recognize the temporary depression of the temporalis muscle ("hour glass deformity") following BT-A injection [82]; this frequently visible expression of the injection procedure, as well as its other side effects [33], impairs masking between placebo and BT-A for both the patients and the investigators, as discussed previously. ...
... A specially challenging aspect of BT-A investigations involves the unblinding of some patients and their investigators by its side effects [33,82]. Although the RCT is at the pinnacle of the medical evidence pyramid, in order to make meaningful scientific progress, the limitations of the investigative tool that the RCT represents must be comprehended [84]. ...
Scalp injection of botulinum toxin type A (BT-A) into the superficial musculature has evoked interest in the management of migraine headache. In clinical trials, prevention of migraine attacks for 3 months or more has been seen in some patients following BT-A scalp injections. In the majority of pain syndromes where BT-A is effective, inhibition of muscle spasms appears to be an important component of its activity. A direct or independent and prolonged analgesic action unrelated to skeletal muscle relaxation is believed to underlie the prophylactic efficacy of BT-A in migraine; peripheral and central modulation of pain impulses by BT-A has also been proposed. A direct peripheral antinociceptive effect was not seen in three controlled studies of BT-A in normal human volunteers. Experimental evidence for BT-A-induced analgesia in rats is suggestive but dose-dependent and lasts only 2 weeks. In migraine patients, a consistent or dose-dependent response to BT-A treatment has not been seen. Peak responses to BT-A in migraine patients are seen at 8–12 weeks, whereas BT-A-affected nerve endings in mice fully recover function between 63 and 91 days; the difference in species limits the interpretation of this dissonance. As BT-A does not normally cross the intact blood-brain barrier, meningeal nociceptors appear unlikely to be influenced by scalp injections of BT-A; the possibility of antidromic transfer of BT-A in the trigeminovascular system should be considered. The extended period for which migraine prophylaxis might be required, the antigenic and headache-provoking potential of BT-A, the inability of BT-A to affect central neuronal processes significantly, including the aura of migraine, the possible placebo effect of needling, and purely subjective outcome measures in headache studies are additional concerns in evaluating this treatment strategy. The clinical utility of BT-A has not been compared against established migraine prophylactic agents. The efficacy of BT-A in preventing migraine headache attacks remains controversial and the underlying scientific rationale is debatable.
... 29 A great deal of work has been done to study the role for BTX-A in migraine headaches, however, likely none more impactful than the 2010 Phase III Research Evaluating Migraine Prophylaxis Therapy 1 trial that provided the convincing and rigorous evidence for the efficacy of BTX-A as a prophylactic treatment of migraine headaches, which was largely responsible for the subsequent Food and Drug Administration (FDA) approval of the therapy in 2010. 30,31 Low doses of BTX-A ( Table 1) are injected directly into the muscle site that has been identified as a trigger point. Trigger points are identified during the initial work-up through history, physical examination, and often a headache diary, in which the patient keeps track of headaches for at least 1 month, carefully recording the characteristics of the migraines. ...
Migraine headaches affect more than 35 million Americans and are ranked the third-highest cause of disability worldwide, resulting in decreased quality of life and serious economic consequences. There are 4 types of migraine headaches: frontal, temporal, occipital, and rhinogenic. Each type has a well-described trigger site. Migraines headaches often are refractory to medical therapy and may respond well to botulinum toxin type A. Migraine surgery is another option to release trigger sites. A systematic review of the migraine surgery literature found an average success rate of 90%, with elimination or greater than 50% improvement of migraine headaches after migraine surgery.
... Guyuron et al noted a transient temporalis atrophy, or "hourglass deformity," in patients receiving BoNT-A in the temporalis muscle, which appeared to recover after cessation of BoNT-A injection. 44 However, in an animal study, Fortuna et al showed that repeated administration of BoNT-A in rabbits resulted in muscle atrophy, remodeling of contractile tissue with replacement of muscle with fat, and ultimately decreased muscle strength, which may not be completely reversible. 45 Currently, it remains unclear whether the induced muscle atrophy as an adverse effect of prolonged BoNT-A treatment is truly transient, and further study is warranted. ...
Botulinum toxin is integral to the practice of facial plastic surgery. Since it was approved by the U.S. Food and Drug Administration for the temporary improvement of glabellar rhytids in 2002, botulinum toxin has achieved a growing number of off-label clinical applications. These include the management of facial rhytids, brow ptosis, excessive gingival display, masseteric hypertrophy, platysmal banding, facial nerve paralysis, hypertrophic scars, and keloids. Many forms of botulinum toxin have been developed, and their safety and efficacy have been thoroughly established. This article will review the aesthetic and functional uses of botulinum toxin as it relates to the field of facial plastic and reconstructive surgery. In addition, the authors will discuss the suggested quantity of units per injection site based on onabotulinumtoxinA.
... Key Contribution: This manuscript highlights the probable mechanisms of botulinum toxin induced muscle atrophy and its impact on the clinical approach to botulinum toxin injections. series in humans are available describing muscle atrophy as either a wanted or untoward effect [13][14][15][16][17][18][19][20][21][22]. A recent review by Durand and colleagues [23] addressed the issue of BoNT-induced muscle atrophy in human subjects, but they were unable to formulate any conclusions about the mechanisms of BoNT-induced muscle atrophy. ...
Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have been well documented in the literature. However, the development of muscle atrophy following chronic exposure to BoNTs has not received sufficient attention. Muscle atrophy is not only cosmetically distressing, but also has an impact on future injections. An extensive literature search was conducted on atrophy and mechanisms of atrophy. Five hundred and four relevant articles in the English language were reviewed. This review revealed the surprising lack of documentation of atrophy within the literature. In addition, as demonstrated in this review, the mechanisms and the clinical factors that may lead to atrophy have also been poorly studied. However, even with this limited information it is possible to indicate factors that could modify the clinical approach to botulinum toxin injections. This review highlights the need for further study of atrophy following BoNT injections.
... 62 The "hourglass deformity" due to tempora- lis atrophy caused by repeated treatment of BoNT-A was described by Guyuron et al in patients treated for migraine and reported to resolve in all patients several months after recovery of muscle function. 63 ...
Botulinum toxin A is produced by anaerobic spore-forming bacteria and is used for various therapeutic and cosmetic purposes. Botulinum toxin A injections are the most popular nonsurgical procedure worldwide. Despite an increased demand for botulinum toxin A injections, the clinical pharmacology and differences in formulation of commonly available products are poorly understood. The various products available in the market are unique and vary in terms of units, chemical properties, biological activities, and weight, and are therefore not interchangeable. For safe clinical practice and to achieve optimal results, the practitioners need to understand the clinical issues of potency, conversion ratio, and safety issues (toxin spread and immunogenicity). In this paper, the basic clinical pharmacology of botulinum toxin A and differences between onabotulinum toxin A, abobotulinum toxin A, and incobotulinum toxin A are discussed.
... In addition, it is important to be aware that repeated injections may lead to temporalis muscle atrophy with the development of an hour-glass appearance of the head. 18 If this occurs, the injections are performed sufficiently behind the hairline. ...
Objective:
To provide clinically relevant insights on the identification of the muscles and techniques involved in the safe and effective use of onabotulinumtoxinA for chronic migraine prophylaxis.
Background:
Although guidance on the use of onabotulinumtoxinA for chronic migraine is available, based on the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program, clinical experience has shown that insufficient understanding of the anatomy and function of the head and neck muscles may lead to undesirable outcomes and suboptimal efficacy.
Design/methods:
Each muscle involved in the standardized PREEMPT injection paradigm is reviewed with a thorough description of each muscle's anatomy (ie, muscle description and location, innervation, vascular supply) and function. Key insights based on clinical experience are also provided to help improve outcomes.
Results:
The identification of the muscles in the PREEMPT injection paradigm should be based on each patient's unique anatomy and injections should be administered using the advised techniques. A thorough examination of the patient prior to treatment is also critical to determine if any preexisting conditions may increase the risk for unwanted outcomes and appropriate expectations should be communicated.
Conclusions:
Thorough knowledge of the functional anatomy of the muscles involved in the standardized PREEMPT injection paradigm is critical to achieve the efficacy and safety observed in clinical trials. In addition, it is important to assess a patient's baseline condition to anticipate the risk for unwanted outcomes that may result from treatment.
... Side effects may include blepharoptosis, diplopia, injection-site pain, and significant atrophy of the injected muscles, most notably seen in the temporalis muscles (temporal concavity known as hourglass deformity). 65,66 Therefore, botulinum toxin injection in this setting may best be used as a screening test for peripheral nerve irritation caused by muscle compression as a cause of migraine headache rather than a routine treatment modality. Those patients who are responders to botulinum toxin injection may then benefit from more definitive decompression of craniofacial peripheral nerves by surgical techniques. ...
Migraine headache can be a debilitating condition that confers a substantial burden to the affected individual and to society. Despite significant advancements in the medical management of this challenging disorder, clinical data have revealed a proportion of patients who do not adequately respond to pharmacologic intervention and remain symptomatic. Recent insights into the pathogenesis of migraine headache argue against a central vasogenic cause and substantiate a peripheral mechanism involving compressed craniofacial nerves that contribute to the generation of migraine headache. Botulinum toxin injection is a relatively new treatment approach with demonstrated efficacy and supports a peripheral mechanism. Patients who fail optimal medical management and experience amelioration of headache pain after injection at specific anatomical locations can be considered for subsequent surgery to decompress the entrapped peripheral nerves. Migraine surgery is an exciting prospect for appropriately selected patients suffering from migraine headache and will continue to be a burgeoning field that is replete with investigative opportunities.
... Physicians should review the known side effects of BotNT-A treatment, including possible headache, rash, bruising or eyebrow and eyelid ptosis with the patient and obtain informed consent. Out of 92 patients receiving BotNT-A into the temporalis muscle 26 patients have been reported to develop 'hourglass deformity' characterized by bilateral depression of the temporal region ranging from minimal to significant resembling an 'hourglass' (Guyuron 2004). ...
Botulinum toxin type A has been used clinically for the prophylaxis and treatment of various types of primary headache disorders for over 15 years. Several studies have been performed to demonstrate its mechanism of its effect. There is adequate data to support the idea that; beside its well-known effect on acetylcholine release, an additional antinociceptive effect related to a possible block in one or more pain transmitters exists. Earlier open-labeled studies investigating the clinical outcome of botulinum toxin in primary headache disorders have come out with positive results on the topic however recent evidence based evaluation of data do not seem to support the widespread clinical use of this agent. In this manuscript use of botulinum toxin is reviewed with special emphasize on its mechanism of effect, injection techniques and recent evidence-based data.
A mere serendipitous finding has culminated in a life-changing development for patients and a colossally fulfilling field for many surgeons. The surgical treatment of migraine headaches has been embraced by many plastic surgeons after numerous investigations ensuring that the risks are minimal and the rewards inestimable. Seldom has a plastic surgery procedure been the subject of such scrutiny. Through retrospective, prospective pilot, prospective randomized, prospective randomized with sham surgery, and 5-year follow-up studies, the safety, efficacy, and longevity of the given operation have been confirmed. Although the first decade of this journey was focused on investigating effectiveness and risk profile, the second decade was largely devoted to improving results, reducing invasiveness, and shortening recovery. Multiple publications in peer-reviewed journals over the past 20 years, several independent studies from reputable surgeons at recognized centers, and over 40 studies from the author's center have established the surgical treatment of headaches as a standard practice.
Purpose
The aim of this study was to assess any change between the preoperative and postoperative sizes of temporal and masseter muscles with magnetic resonance imaging (MRI) in patients undergoing unilateral temporomandibular joint surgery.
Materials and methods
This study was designed and implemented retrospectively. For clinical evaluation, a visual analog scale (VAS) and maximum mouth opening (MMO) were used. In order to make a preoperative diagnosis and perform a 6-month control, muscle size was measured in millimeters (mm) on T1 axial sections in MRI. Statistical analyses were performed using the SPSS 23.0 software package. Numeric variables were compared between two dependent groups using the Wilcoxon signed rank test. Statistical significance was set at p < 0.05.
Results
Twelve patients who underwent unilateral discectomy plus dermis-fat grafting, with classical preauricular inverse L incision, were included in the study, and data for eleven female patients were evaluated. The difference in size between the operated and non-operated sides was found to be statistically insignificant at the preoperative stage for both masseter muscle (operated side mM: 13.264 ± 1.822 mm; non-operated side mM: 13.264 ± 2.315 mm; pM = 0.929) and temporal muscle (operated side mT: 20.345 ± 2.609 mm; non-operated side mT: 20.582 ± 2.366 mm; pT = 0.594). There was a significant size reduction in the masseter muscle on the operated side in the postoperative period (preop mM: 13.264 ± 1.822 mm; postop mM: 12.036 ± 1.728 mm; pM = 0.018). Although there was also a size reduction in the operated side of the temporal muscle in the postoperative period, that difference did not reach statistical significance (preop mT: 20.345 ± 2.609 mm; postop mT: 19.445 ± 1.603 mm; pT = 0.182). On the non-operated side, there were no significant postoperative changes in the sizes of either the masseter muscle (preop mM: 13.264 ± 2.315 mm; postop mM: 12.682 ± 2.059 mm; pM = 0.248) or the temporal muscle (preop mT: 20.582 ± 2.366; postop mT: 19.891 ± 3.487 mm; pT = 0.625).
Conclusion
Considering the study findings as a whole, a size reduction was observed in the operated side of the masseter muscle after TMJ surgery. The etiology of this change may be surgical trauma to the temporal and masseter muscles, skeletal alteration resulting from condylar change secondary to discectomy, and patients restraining themselves from application of maximum bite force as a result of a self-protection mechanism due to postoperative pain.
It began with mere kismet and became a field with gratifying outcomes. Over 40 studies later published in respected peer-reviewed journals from our center alone and supported by many independent studies conducted by reputable surgeons from recognized centers over the last 20 years, there is now strong evidence that surgical treatment of headaches and migraines is safe and effective. The scientific course commenced with a retrospective study and continued with a prospective pilot study, a prospective randomized study, a 5-year follow-up study, and a prospective randomized study with sham surgery. During that time, we identified seven trigger sites from which migraine headaches could arise and developed ways of deactivating all of these sites. In the last 10 years, we have focused on improving results, extending care to adolescent patients with migraine headaches, researching the ultrastructural characteristics of peripheral nerves in headache patients, and investigating the socioeconomic benefits of migraine surgery as well as the specific factors contributing to the success and failure of these operations. The details of our progress are discussed in this chapter.
Sarcopenia, which refers to the muscle loss that accompanies aging, is a complex neuromuscular disorder with a clinically high prevalence and mortality. Despite many efforts to protect against muscle weakness and muscle atrophy, the incidence of sarcopenia and its related permanent disabilities continue to increase. In this study, we found that treatment with human placental hydrolysate (hPH) significantly increased the viability (approximately 15%) of H2O2‐stimulated C2C12 cells. Additionally, while H2O2‐stimulated cells showed irregular morphology, hPH treatment restored their morphology to that of cells cultured under normal conditions. We further showed that hPH treatment effectively inhibited H2O2‐induced cell death. Reactive oxygen species (ROS) generation and Mstn expression induced by oxidative stress are closely associated with muscular dysfunction followed by atrophy. Exposure of C2C12 cells to H2O2 induced abundant production of intracellular ROS, mitochondrial superoxide, and mitochondrial dysfunction as well as myostatin expression via nuclear factor‐κB (NF‐κB) signaling; these effects were attenuated by hPH. Additionally, hPH decreased mitochondria fission–related gene expression (Drp1 and BNIP3) and increased mitochondria biogenesis via the Sirt1/AMPK/PGC‐1α pathway and autophagy regulation. In vivo studies revealed that hPH‐mediated prevention of atrophy was achieved predominantly through regulation of myostatin and PGC‐1α expression and autophagy. Taken together, our findings indicate that hPH is potentially protective against muscle atrophy and oxidative cell death.
Although the use of botulinum toxin has been recommended for the management of myofascial pain and dysfunction, the precise mechanism of its action remains undetermined and studies on its effectiveness are equivocal. Moreover, even if such treatment may temporarily relieve the symptoms, it does not address the cause of the problem. Also, its use is not free of potential complications. On this basis, botulinum toxin does not seem to be a logical treatment of myofascial pain and dysfunction.
The use of botulinum toxin as a treatment for migraine has an inconsistent and lingering history. Following years of rejection, the PREEMPT trials eventually found that it is useful as a prophylactic for chronic migraines. The surgical and neurological approaches employing botulinum, however, are fundamentally different. Furthermore, the surgical use is based on its peripheral mechanism, a localized muscle paralysis, whereas the neurological use is based on alleged central mechanisms and directly antinociceptive properties. The botulinum-induced deactivation of trigger sites can simulate the surgical procedure and should be used as a preoperative test. There is no standardized method to determine the individual selection of trigger sites; the approach presented herewith is a recommendation. Botulinum toxin is a safe and effective agent with rare, mild, and transient side effects.
Aim
To examine the effectiveness of Botulinum Toxin Type A (Dysport®) in treating TMD and a small number of other maxillofacial conditions in our department. The secondary aim was to identify any predictors of outcome.
Methods
A retrospective open cohort study1; data abstraction from 38 case files.
Results
The effectiveness of Dysport® in treating TMD lies between 60% and 79%. Sixty‐nine per cent of patients who obtained benefit received repeat treatment.
Conclusions
Our findings suggest Dysport® is a safe, well‐tolerated and effective treatment for TMD and Masseteric hypertrophy.
The use of neuromodulators for therapeutic and cosmetic indications has proven to be remarkably safe. While aesthetic and functional adverse events are uncommon, each anatomic region has its own set of risks of which the physician and patient must be aware before treatment. The therapeutic usages of botulinum toxins now include multiple specialties and multiple indications. New aesthetic indications have also developed, and there has been an increased utilization of combination therapies to combat the effects of global aging. In the second article in this continuing medical education series, we review the prevention and treatment of adverse events, therapeutic and novel aesthetic indications, controversies, and a brief overview of combination therapies.
As a biopharmaceutical, botulinum toxin has increasingly been administered for therapeutic indications both approved and not approved by the US Food and Drug Administration. Local adverse effects from its administration have been recognized since its original introduction, but recently generalized and remote adverse effects have been witnessed, some life threatening or fatal. While uncommon, these effects are currently unexplained and necessitate practitioner familiarity with their potential occurrence as well as requiring clear and consistent education of patients as to the risk, benefits and early signs of adverse reactions after botulinum toxin administration.
Headaches affect millions of people a year and are associated with a great deal of morbidity. Though the causes of headaches
are many, a subset of headaches refractory to traditional pharmacologic treatment — namely migraine and cluster headaches
— can be treated surgically. All patients should undergo a thorough history and physical examination and evaluation by a headache
specialist. Patients who are diagnosed with migraine headaches have potential trigger sites identi-fied by consideration of
the constellation of symptoms, intranasal examination, CT scan, and by injection with 12.5 U of botulinum toxin A for each
muscle involved. The use of botulinum toxin A as definitive treatment for headaches remains controversial; we use it as a
diagnostic aid. Glabellar trigger sites are treated with corrugator supercilii resection, temporal trigger sites are treated
with resection of the zygomaticotemporal branch of the trigeminal nerve (ZMTBTN), occipital trigger sites are treated with
surgical release of the greater occipital nerve, and patients with intranasal triggers are treated with septo-plasty and inferior
turbinate resection. Patients with cluster headaches are treated with resection of the ZMTBTN. Surgery does have a role in
the treatment of refractory migraine and cluster headaches.
Onabotulinum toxin has been used to treat a variety of headaches. We report a case of a 29-year-old woman who developed temporary and reversible atrophy of corrugator supercilii muscle after onabotulinum toxin (Botox, Allergan, Irvine, CA, USA) injection. To our best knowledge this has not been described in the literature before.
To evaluate the effect of botulinum toxin type A on nocturnal bruxism.
Twelve subjects reporting nocturnal bruxism were recruited for a double-blind, randomized clinical trial. Six bruxers were injected with botulinum toxin in both masseters, and six with saline. Nocturnal electromyographic activity was recorded in the subject's natural sleeping environment from masseter and temporalis muscles before injection, and 4, 8, and 12 wks after injection and then used to calculate bruxism events. Bruxism symptoms were investigated using questionnaires.
Bruxism events in the masseter muscle decreased significantly in the botulinum toxin injection group (P = 0.027). In the temporalis muscle, bruxism events did not differ between groups or among times. Subjective bruxism symptoms decreased in both groups after injection (P < 0.001).
Our results suggest that botulinum toxin injection reduced the number of bruxism events, most likely mediated its effect through a decrease in muscle activity rather than the central nervous system. We controlled for placebo effects by randomizing the interventions between groups, obtaining subjective and objective outcome measures, using the temporalis muscle as a control, and collecting data at three postinjection times. Our controlled study supports the use of botulinum toxin injection as an effective treatment for nocturnal bruxism.
Children and adolescents experience headaches as do adults and usually present with migraine and chronic daily or tension-type headaches. As some adolescents are unable to achieve headache relief after various treatment strategies, we currently provide botulinum toxin type A (Botox) injections as a clinical treatment (off-label use) in selected cases. Botulinum toxin type A by injection has been found to be effective in the treatment of headache disorders in adults. We treated 12 adolescents (aged 14 to 18 years) with Botox injections for migraine and chronic daily headache. Six patients (all female adolescents) were in long-term treatment and received Botox in the standard "migraine" and "follow-the-pain" patterns every 3 months. Effectiveness was evaluated using pain scales and a standardized quality-of-life survey at baseline and prior to each treatment session. Duration of treatment was 3-29 months. Each patient had 9-63 (average = 42) injections per treatment. All 6 long-term patients reported improvement in headache symptoms, with decreases on pain scales and an average of 33%-75% improvement in quality of life. Two long-term patients had complete relief of headaches between injection series. Four patients had only one series of injections with good results. Two patients had no improvement and refused additional injections. Side effects were mild ptosis (n = 1), blurred vision (n = 1), hematoma at neck injection site with tingling in one arm lasting 24 hours (n = 1), and burning sensations at all injection sites which lasted 1 week (n = 1). Our group findings warrant a controlled trial evaluation of Botox because it may be an effective treatment option for certain adolescents with intractable migraine and chronic daily headaches.
The purpose of this study was to investigate the efficacy of surgical deactivation of migraine headache trigger sites. Of 125 patients diagnosed with migraine headaches, 100 were randomly assigned to the treatment group and 25 served as controls, with 4:1 allocation. Patients in the treatment group were injected with botulinum toxin A for identification of trigger sites. Eighty-nine patients who noted improvement in their migraine headaches for 4 weeks underwent surgery. Eighty-two of the 89 patients (92 percent) in the treatment group who completed the study demonstrated at least 50 percent reduction in migraine headache frequency, duration, or intensity compared with the baseline data; 31 (35 percent) reported elimination and 51 (57 percent) experienced improvement over a mean follow-up period of 396 days. In comparison, three of 19 control patients (15.8 percent) recorded reduction in migraine headaches during the 1-year follow-up (p < 0.001), and no patients observed elimination. All variables for the treatment group improved significantly when compared with the baseline data and the control group, including the Migraine-Specific Questionnaire, the Migraine Disability Assessment score, and the Short Form-36 Health Survey. The mean annualized cost of migraine care for the treatment group (925 dollars) was reduced significantly compared with the baseline expense (7612 dollars) and the control group (5530 dollars) (p < 0.001). The mean monthly number of days lost from work for the treatment group (1.2) was reduced significantly compared with the baseline data (4.41) and the control group (4.4) (p = 0.003). The common adverse effects related to injection of botulinum toxin A included discomfort at the injection site in 27 patients after 227 injections (12 percent), temple hollowing in 19 of 82 patients (23 percent), neck weakness in 15 of 55 patients (27 percent), and eyelid ptosis in nine patients (10 percent). The common complications of surgical treatment were temporary dryness of the nose in 12 of 62 patients who underwent septum and turbinate surgery (19.4 percent), rhinorrhea in 11 (17.7 percent), intense scalp itching in seven of 80 patients who underwent forehead surgery (8.8 percent), and minor hair loss in five (6.3 percent). Surgical deactivation of migraine trigger sites can eliminate or significantly reduce migraine symptoms. Additional studies are necessary to clarify the mechanism of action and to determine the long-term results.
Injuries to neurovascular structures are not among the most common injuries seen in athletes and for this reason may often be overlooked. Additionally, diagnosis and management may be more difficult because of inexperience with these injuries. The majority of acute sports-related neurovascular injuries are associated with contact sports such as rugby, wrestling, ice hockey, and, especially, football. These injuries most commonly occur about the shoulder girdle and brachial plexus, with burners syndrome being the most common. Less common injuries include thoracic outlet syndrome, effort-induced thrombosis, axillary artery occlusion, and peripheral nerve injuries and compression syndromes involving the axillary, suprascapular, and long thoracic nerves.
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Plast Reconstr Surg. 2002 Jun;109(7):2183-2189
This prospective study was conducted to investigate the role of removal of corrugator supercilii muscles, transection of the zygomaticotemporal branch of the trigeminal nerve, and temple soft-tissue repositioning in the treatment of migraine headaches. Using the criteria set forth by the International Headache Society, the research team's neurologist evaluated patients with moderate to severe migraine headaches, to confirm the diagnosis. Subsequently, the patients completed a comprehensive migraine headaches questionnaire and the team's plastic surgeon injected 25 units of botulinum toxin type A (Botox) into each corrugator supercilii muscle. The patients were asked to maintain an accurate diary of their migraine headaches and to complete a monthly questionnaire documenting pertinent information related to their headaches. Patients in whom the injection of Botox resulted in complete elimination of the migraine headaches then underwent resection of the corrugator supercilii muscles. Those who experienced only significant improvement underwent transection of the zygomaticotemporal branch of the trigeminal nerve with repositioning of the temple soft tissues, in addition to removal of the corrugator supercilii muscles. Once again, patients kept a detailed postoperative record of their headaches. Of the 29 patients included in the study, 24 were women and five were men, with an average age of 44.9 years (range, 24 to 63 years). Twenty-four of 29 patients (82.8 percent, p < 0.001) reported a positive response to the injection of Botox, 16 (55.2 percent, p < 0.001) observed complete elimination, eight (27.6 percent, p < 0.04) experienced significant improvement (at least 50 percent reduction in intensity or severity), and five (17.2 percent, not significant) did not notice a change in their migraine headaches. Twenty-two of the 24 patients who had a favorable response to the injection of Botox underwent surgery, and 21 (95.5 percent, p < 0.001) observed a postoperative improvement. Ten patients (45.5 percent, p < 0.01) reported elimination of migraine headaches and 11 patients (50.0 percent, p < 0.004) noted a considerable improvement. For the entire surgical group, the average intensity of the migraine headaches reduced from 8.9 to 4.1 on an analogue scale of 1 to 10, and the frequency of migraine headaches changed from an average of 5.2 per month to an average of 0.8 per month. For the group who only experienced an improvement, the intensity fell from 9.0 to 7.5 and the frequency was reduced from 5.6 to 1.0 per month. Only one patient (4.5 percent, not significant) did not notice any change. The follow-up ranged from 222 to 494 days, the average being 347 days. In conclusion, this study confirms the value of surgical treatment of migraine headaches, inasmuch as 21 of 22 patients benefited significantly from the surgery. It is also evident that injection of Botox is an extremely reliable predictor of surgical outcome.
Comment: Many small placebo-controlled studies and much anecdotal literature suggests that botulinum toxin may be effective in prevention of migraine, perhaps to the same extent as conventional prophylactic treatment. Larger, randomized clinical trials are underway to resolve this issue. In the meantime, those who believe in the effectiveness of botulinum toxin prophylaxis argue about how it works, that is whether its antinociceptive properties are due to peripheral effects, central or presynaptic effects, or both. Dr. Guyuron's group favors the idea that botulinum toxin interrupts a reflex arc between the central nervous system (CNS) and peripheral musculature, and that after establishing efficacy by low dose botulinum injection in the corrugator supercilii muscles, surgical resection of these muscles results in prolonged and effective prophylaxis. The idea is radical but intriguing and should not be dismissed out of hand. However, a trial is necessary in which both the botulinum toxin injections are blinded with vehicle, and the study of the surgery involves a sham surgery control group with extended long-term follow-up, before these forms of prophylaxis can be recommended to patients. SJT
The "Hourglass Facial Deformity" is the result of bilateral irradiation of the orbits and anterior cranial base during infancy. The deformity is uniformly characterized by a distinctly misshapen upper face at the level of the orbits, with depression of the temporal region, hypotelorism, and flattened nasal root. These patients exhibited varying degrees of frontal bossing. Since they had previous enucleation, the orbital soft-tissue can be dissected off the eye socket, lateral orbital walls, and if necessary, the orbital cone, through a bicoronal incision. The deformity is then easily corrected with implantation of acrylic alloplastic material. Four cases are presented which had varying degrees of the same deformity and were successfully corrected using the operative procedure described. No complications have been encountered. Two patients required eye socket revisions.
This retrospective study is a review of 18 patients who received radiotherapy to the orbit between the ages of 1 month and 10 years. Patients were followed for 7-21 years in an attempt to define the effects of orbital irradiation on a growing child. None of the patients in the study was spared injurious effects on soft tissue or bone, but soft tissue appeared to be more vulnerable to radiation than bone. Orbital irradiation caused soft tissue deficits of the upper face in 100% of the patients. Sixty-seven percent of patients had soft tissue deformities of the midface, and 13% had soft tissue deformities of the lower face. Bony deficits were found in the upper face in 67% of the patients, the midface in 50%, and the lower face in 6%. This study found no correlation between age and time of radiotherapy on the effects of facial growth.
This retrospective study is a review of 41 patients who had received irradiation to the head and face during the growth period. Not only is growth of soft tissue and bone of the irradiated area noticeably affected, but other parts of the face can also be involved, especially if the dose is to the upper face and the cranial base. We were able to define a definite cutoff point for a harmful dose for growing facial bones, but the harmful dose for soft tissue could not be determined and may be as low as 400 rads.
A clinical trial was undertaken to evaluate the effects of commercially available botulinum toxin on 14 hyperactive corrugator muscles, 14 procerus muscles, one case of congenital aplasia of the depressor labii inferioris muscle, and one case of iatrogenic injury to the ramus mandibularis branch of the facial nerve with paralysis of the depressor labii and mentalis muscles. Of the 31 muscles injected, 28 were appropriately paralyzed with the initial injection. The desired results were obtained in the 3 remaining muscles following a second injection. The ability to frown was nullified in all subjects, resulting in the elimination of glabellar lines. Facial symmetry was achieved in both patients with muscle imbalance. The average duration of the paralysis was 8 weeks, with a range of 2 to 16 weeks. However, this period was prolonged in the latter part of the study with an adjustment of the toxin dose. Our results demonstrate that botulinum toxin injected into overactive facial muscles does produce a predictable and reversible paralysis and eliminates or ameliorates deep frown lines. We also illustrate its use in achieving facial symmetry in one patient with congenitally absent depressor labii inferioris and platysma muscles and in another with postrhytidectomy facial nerve paralysis.
The purpose of this clinical investigation is to confirm the efficacy of eliminating facial wrinkles by injecting botulinum toxin A into mimetic muscles. Fifty-four patients were injected with BOTOX A-14 in the corrugator superciliaris, 19 in the frontalis muscles, and 13 in the orbicularis oculis. Dilution was obtained by adding 4 ml preservative-free saline to 100 IU of BOTOX A. The dose used varied according to the patient. The severity of wrinkles and the intensity of muscle contraction (facial expression) were taken into account. The paralysis obtained in the mimetic muscles was effective for 6 months in 39 patients, 8 months in 10 patients, and 9 months in 1 patient. The results were documented by photographs, videotape, and electromyographies pre- and postinjection. To preserve the results, 21 patients (39%) demanded a second infiltration to achieve satisfactory results. Neither local nor general adverse effects were noted, except transitory eyebrow palsy in 2 patients, and edema and ecchymosis in 4 patients. The improvement obtained in facial mimetic wrinkles was satisfactory to the patient and to us.
This prospective study was conducted to investigate the role of removal of corrugator supercilii muscles, transection of the zygomaticotemporal branch of the trigeminal nerve, and temple soft-tissue repositioning in the treatment of migraine headaches. Using the criteria set forth by the International Headache Society, the research team's neurologist evaluated patients with moderate to severe migraine headaches, to confirm the diagnosis. Subsequently, the patients completed a comprehensive migraine headaches questionnaire and the team's plastic surgeon injected 25 units of botulinum toxin type A (Botox) into each corrugator supercilii muscle. The patients were asked to maintain an accurate diary of their migraine headaches and to complete a monthly questionnaire documenting pertinent information related to their headaches. Patients in whom the injection of Botox resulted in complete elimination of the migraine headaches then underwent resection of the corrugator supercilii muscles. Those who experienced only significant improvement underwent transection of the zygomaticotemporal branch of the trigeminal nerve with repositioning of the temple soft tissues, in addition to removal of the corrugator supercilii muscles. Once again, patients kept a detailed postoperative record of their headaches. Of the 29 patients included in the study, 24 were women and five were men, with an average age of 44.9 years (range, 24 to 63 years). Twenty-four of 29 patients (82.8 percent, p < 0.001) reported a positive response to the injection of Botox, 16 (55.2 percent, p < 0.001) observed complete elimination, eight (27.6 percent, p < 0.04) experienced significant improvement (at least 50 percent reduction in intensity or severity), and five (17.2 percent, not significant) did not notice a change in their migraine headaches. Twenty-two of the 24 patients who had a favorable response to the injection of Botox underwent surgery, and 21 (95.5 percent, p < 0.001) observed a postoperative improvement. Ten patients (45.5 percent, p < 0.01) reported elimination of migraine headaches and 11 patients (50.0 percent, p < 0.004) noted a considerable improvement. For the entire surgical group, the average intensity of the migraine headaches reduced from 8.9 to 4.1 on an analogue scale of 1 to 10, and the frequency of migraine headaches changed from an average of 5.2 per month to an average of 0.8 per month. For the group who only experienced an improvement, the intensity fell from 9.0 to 7.5 and the frequency was reduced from 5.6 to 1.0 per month. Only one patient (4.5 percent, not significant) did not notice any change. The follow-up ranged from 222 to 494 days, the average being 347 days. In conclusion, this study confirms the value of surgical treatment of migraine headaches, inasmuch as 21 of 22 patients benefited significantly from the surgery. It is also evident that injection of Botox is an extremely reliable predictor of surgical outcome.
Injuries to neurovascular structures are not the most common injuries seen in athletes and for this reason may often be overlooked. Additionally, diagnosis and management may be more difficult because of inexperience with these injuries. The majority of acute sports-related neurovascular injuries are associated with contact sports such as rugby, wrestling, ice hockey, and especially football. These injuries most commonly occur about the shoulder girdle and brachial plexus, with "burners" syndrome being the most common. Less common injuries include thoracic outlet syndrome, effort-induced thrombosis, axillary artery occlusion, and peripheral nerve injuries, as well as compression syndromes involving the axillary, suprascapular, and long thoracic nerves.
Rob-bins Pathologic Basic of Disease
- Cotran Rs V Kumar
- Collins T Sl
Cotran RS, Kumar V, Collins T, Robbins SL. Rob-bins Pathologic Basic of Disease, 6th edition. W.B. Saunders Company, 1999;1273-1275.
Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders
Therapeutics and Technology Assessment Subcommittee to the American Academy of Neurology:
Assessment: the clinical usefulness of botulinum
toxin-A in treating neurologic disorders. Neurology.
1990;40:1332-1336.
Therapeutics and Technology Assessment Subcommittee to the American Academy of Neurology: Assessment: the clinical usefulness of botulinum toxin-A in treating neurologic disorders
Temporal brow lift using botulinum toxin type A [discussion]
- Guyuron