Toxicon xxx (2017) 1e4
Contents lists available at ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections Francisco Cardoso* Movement Disorders Unit, Neurology Service, Internal Medicine Department, The Federal University of Minas Gerais, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 July 2017 Received in revised form 15 August 2017 Accepted 20 August 2017 Available online xxx
The aim of this article is to provide a review of the use of injections of botulinum toxin in the management of selected symptoms and signs of Parkinson's disease and other forms of parkinsonism. Sialorrhea is defined as inability to control oral secretions, resulting in excessive saliva in the oropharynx. There is a high level of evidence for the treatment of sialorrhea in parkinsonism with injections of different forms of botulinum toxin type A as well as botulinum toxin type B. Tremor can be improved by the use of botulinum toxin injections but improved tremor control often leads to concomitant motor weakness, limiting its use. Levodopa induced dyskinesias are difficult to treat with botulinum toxin injections because of their variable frequency and direction. Apraxia of eyelid opening, a sign more commonly seen in progressive supranuclear palsy and other tauopathies, often improves after botulinum toxin injections. Recent data suggest that regardless of the underlying mechanism, pain in parkinsonism can be alleviated by botulinum toxin injections. Finally, freezing of gait, camptocormia and Pisa syndrome in parkinsonism almost invariably fail to respond to botulinum toxin injections. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Botulinum toxin Parkinsonism Parkinson's disease Atypical parkinsonism Sialorrhea Dyskinesias Pain Freezing of gait Camptocormia
1. Introduction The mainstay of the treatment of Parkinson's disease (PD) and other parkinsonian syndromes is pharmacological management of dopamine and other neurotransmitters. Surgical procedures such as deep brain stimulation may provide help to a relatively small proportion of patients with PD who fail to improve with best medical treatment. There are patients who remain with symptoms and signs non-responsive to these therapeutic options. In a few of these instances injections of botulinum toxin (BoNT) may be beneficial. The list of symptoms and signs in different parkinsonian disorders reported to be amenable to treatment with BoNT is long and includes sialorrhea, freezing of gait, overactive bladder, dystonia, apraxia of eyelid opening, levodopa-induced dyskinesias, limb and jaw tremor, camptocormia, intestinal constipation, and pain. One recently published retrospective chart review of a busy Canadian movement disorders clinic identified no more than 160 patients with parkinsonism with clinical features treated with injections of BoNT in the period from 1995 to 2014. Out of these
individuals, 117 had PD, 36 received the diagnosis of atypical parkinsonism and the etiology was not identified in seven patients (Bruno et al., 2016). According to the criteria of evidence based medicine there are Class I studies only for sialorrhea and freezing of gait and open-label studies for overactive bladder. Unfortunately for the other parkinsonian symptoms and signs previously listed, there are just case reports that render it difficult to understand the actual role of injections of BoNT injections in their management. The aim of this article is to provide a critical personal review of the use of BoNT to treat selected symptoms and signs in PD and other parkinsonian syndromes. The article is based on personal experience of the author as well as a review of the published literature in English using the following search words: botulinum toxin, parkinsonism, sialorrhea, drooling, dyskinesia, tremor, dystonia, levodopa-induced dyskinesia, apraxia of the eyelid opening, overactive bladder, pain, camptocormia, other postural deformities, freezing of gait, and pain. The subject was reviewed in Toxicon in the past (Jankovic, 2009). 2. Sialorrhea
* Av Pasteur 89/1107, 30150-290, Belo Horizonte, MG, Brazil. E-mail address: [email protected].
Sialorrhea is defined as the inability to control oral secretions, resulting in excessive saliva in the oropharynx. Unlike what
http://dx.doi.org/10.1016/j.toxicon.2017.08.018 0041-0101/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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F. Cardoso / Toxicon xxx (2017) 1e4
common sense indicates, the pathogenesis of drooling in PD does not involve excessive production of saliva but rather impairment of swallowing. The flexion of head adds further difficulty in the clearance of saliva. The frequency of sialorrhea is reported to range from 31% to 86% of patients with PD (Barone et al., 2009; Chou et al., 2007). The discrepancy of the numbers depends on the method used to assess the accumulation of saliva as well as the characteristics of the studied population. Regarding the latter, as expected the prevalence is greater in patients with dysphagia (86%) in comparison with those without swallowing impairment (44%) (Chou et al., 2007). Interestingly, drooling is seen in very early stage of the disease when patients list it as one of the most disabling nonmotor findings of PD (Khoo et al., 2013). Despite its frequency and related disability, there are few proven efficacious treatments for sialorrhea in parkinsonism. Potential treatments for this condition include anticholinergics (sublingual atropine, ipratoprium bromide spray, and glycopyrrolate), adrenergic receptor agonists (clonidine and modafinil) and non-pharmacological approaches such as chewing gum, behavioral modification, speech therapy, surgery and even radiotherapy of the salivary glands (Chou et al., 2007). Unfortunately, only ipratoprium bromide spray and glycopyrrolate underwent clinical trials of good quality that led to the conclusion that the former is investigational and the latter possibly useful for the management of sialorrhea (Seppi et al., 2011). There is, therefore, the need for alternative and more efficacious treatments for this condition. The rationale for the use of BoNT injections of the salivary glands to treat drooling is based on the blocking of cholinergic transmission that underlies the secretion of saliva. An important issue that needs to be taken into account when designing the strategy to use BoNT injections to manage sialorrhea is to understand that the majority of saliva is secreted by the parotid and submandibular glands. There have been several well-designed trials assessing the role of BoNT injections into the parotid and submandibular glands to treat sialorrhea in PD. Seven studies, of which two were placebo controlled, assessed the use of Onabotulinumtoxin A in drooling in PD. The dosage for the parotid and submandibular glands were, respectively, 5e50U and 5U. The data show that the active drug is significantly more efficacious than placebo and the effect lasted from one to four months. Moreover, the treatment was well tolerated with few and mild side effects (dryness of mouth and dysphagia). Three trials, two of which were placebo controlled, replicated these findings with Abobotulinumtoxin A. The dosage for each parotid gland ranged from 75 to 146U and each submandibular gland was injected with 78U (Srivanitchapoom et al., 2014). Because of its greater affinity for autonomic terminals, it was expected that Rimabotulinumtoxin B could be more efficacious than the type A toxins. In fact, in studies of treatment of cervical dystonia with toxin type A and type B, dry mouth was more commonly seen in the latter group (Pappert et al., 2008). However, five studies of this BoNT (three of them were placebo controlled) found results similar to those reported for BoNT A: better response than placebo, resulting in improvement of drooling for up to four months, with a few patients also developing dysphagia and dryness of mouth. In these trials the dosage per parotid gland was 500e2000U and each submandibular gland received 250U (Srivanitchapoom et al., 2014). One more recent report describes the open label long term experience of BoNT injections in the management of drooling in 33 PD patients and 32 individuals with amyotrophic lateral sclerosis. The authors performed ultrasound guided injections either of Abobotulinumtoxin A (250U) in 136 sessions or Rimabotulinumtoxin B (2500U) in 181 sessions. There was ‘clearcut’ benefit in 89% of sessions without any difference between the two types of BoNT. The average benefit lasted 87 days and side effects were reported solely in 8.9% of sessions (Petracca et al., 2015). Based on these
results, the MDS Evidence Based group concluded that injections of both BoNT A and B are an efficacious and clinically useful treatment for sialorrhea in PD carrying an acceptable risk with specialized monitoring (Seppi et al., 2011). There are, however, unsettled issues that require further studies to be solved: number of injection sites; parotid versus submandibular gland injections; blind versus ultrasound guided injections; and type A or type B toxin (Dogu et al., 2004). 3. Hyperkinesias Bradykinesia is the hallmark of all parkinsonian syndromes. Nevertheless, a proportion of patients with parkinsonism may develop hyperkinesias either spontaneously as part of the underlying disease or because of use of pharmacological agents, particularly dopaminergic drugs. 3.1. Tremor Tremor is the most common spontaneous hyperkinesia associated with parkinsonism, in particular PD. Because it is often a tremor at rest that improves or even disappears with action, it does not cause marked disability in the majority of individuals. It is true though that a few patients with PD have re-emergent tremor, tremor at rest that re-emerges after a variable delay while maintaining a posture tremor. This particular tremor may lead to functional disability (Jankovic et al., 1999). There have been a few open label studies of the use of BoNT injections to treat parkinsonian tremor refractory to conventional treatments. For hand tremor, there are reports showing that OnabotulinumtoxinA, 15U into the extensor compartment and 50e100U for the flexor compartment, improves parkinsonian tremor but at the expense of disabling weakness (Sheffield and Jankovic, 2007). This result mimics the experience of most experts in the field leading to the conclusion that the role of BoNT injections in the management of parkinsonian hand tremor is very limited. Although there are no published data supporting this, clinicians treating tremor with BoNT injections currently avoid injecting the forearm extensor muscles to prevent development of finger weakness. There is one description of a series of PD patients with jaw tremor treated with injections of 30e100U of AbobotulinumtoxinA per masseter. The authors reported that the injections were efficacious and without side effects (Schneider et al., 2006). 3.2. Levodopa-induced dyskinesias It is estimated that for every year of exposure to levodopa, 10% of PD patients develop dyskinesias. In fact, a recent study showed that they are the clinical feature best correlated with the pathological findings of PD at autopsy (Adler et al., 2014). The most common dyskinesias occur during the on period, ie, when the patients are under the effect of levodopa. Typically, these dyskinesias are mobile and have a choreo-dystonic nature. A few patients with on dyskinesias and the majority of subjects with off dyskinesias have dystonia or stereotypies that have a predictable phenomenology. Their management involves changes of levodopa administration, use of other drugs such as amantadine, and, in selected patients, surgery. Exceptionally, when they fail to respond to these options, they can be treated with BoNT injections. This applies in particular when the phenomenology involves blepharospasm, jaw closing dystonia, and other predictable phenomena (Gupta and Visvanathan, 2016; Pacchetti et al., 1995). Because of the fluctuating and unpredictable phenomenology, treatment of levodopa-induced cervical dystonia with BoNT injections has been reported to have an unfavorable risk-benefit ratio (Espay et al., 2011). This is the opposite of
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
F. Cardoso / Toxicon xxx (2017) 1e4
off period foot dyskinesia in PD, which is a fixed painful dystonia. An open label study of 30 patients with this condition reported that 40U of OnabotulinumtoxinA per affected muscle resulted in improvement of the pain and mobility in, respectively, 70% and 30% of individuals without significant adverse events (Pacchetti et al., 1995). The identification of the muscles involved can be done by inspection, palpation and, in a few selected subjects, electromyography. In summary, BoNT injections are not a promising therapy for levodopa on dyskinesias but are helpful in selected patients with painful off period foot dystonia or other types of predictable phenomena. 3.3. Spontaneous dystonia As a rule, spontaneous cranial dystonia in association with parkinsonian syndrome argues against the diagnosis of PD and suggests the patient may have atypical parkinsonism, particularly progressive supranuclear palsy (PSP) or other tauopathies. Arguably the so-called apraxia of eyelid opening, inability to voluntarily open the eyes, is the most common form of dystonia in PSP. Despite the lack of obvious muscle contraction of the eyelids, this phenomenon is now known to result from dystonic contraction of the pretarsal portion of the orbicularis oculi muscle (Krack and Marion, 1994). Although there are no controlled studies, most authorities agree that injections of small dosages of BoNT in this particular area of the eyelids are the treatment of choice for apraxia of the eyelid opening. Clinical experience also suggests that other forms of spontaneous dystonia (e.g., oro-mandibular, cervical, and limb dystonia) associated with atypical parkinsonism, such as PSP and Multiple System Atrophy, are also amenable to treatment with BoNT injections similarly to what happens in idiopathic dystonias (Sheffield and Jankovic, 2007).
3
underrecognized and undertreated in PD and other forms of parkinsonism. Despite the high frequency of pain, its underlying mechanism in parkinsonism remains to be determined. There is evidence suggesting that multiple factors may contribute to its occurrence: osteo-muscular deformity, radiculopathy, muscle rigidity, dystonia, levodopa-induced dyskinesias and changes in central processing of sensory stimuli. Recent studies suggest that BoNT inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. It is more controversial whether BoNT could have a central analgesic effect after undergoing retrograde axonal transport (Oh and Chung, 2015). A recent chart review of a Canadian center found that 81/160 of patients with parkinsonism had pain. The authors considered that it was dystonic pain, related to muscle contractions, in 77.6% of these individuals. In the remaining group the authors concluded that the pain was caused by musculoskeletal conditions. Treatment with BoNT injections resulted in improvement of pain in 81% of individuals regardless of type of pain, etiology of parkinsonism and even dosage of toxin (Bruno et al., 2016). Despite the obvious limitations of this study (retrospective chart review, uncontrolled injections), it suggests that further studies need to explore the role of BoNT in the management of pain in parkinsonism. This is of relevance since this symptom is often refractory to other forms of treatment (Trenkwalder et al., 2015). 6. Conditions usually non-responsive to botulinum toxin injections
Urinary dysfunction, characterized by urgency or even incontinence, and resulting from detrusor muscle hyperactivity occurs in at least 35% of patients with PD (Barone et al., 2009). It causes significant disability and social embarrassment, and is often nonresponsive to pharmacological measures such as peripheral anticholinergic agents and alpha-adrenergic drugs (Seppi et al., 2011). In contrast, well designed controlled studies have established BoNT injections in the detrusor muscle as an efficacious and safe treatment for urinary incontinence in neurological conditions such as multiple sclerosis and other causes of spinal cord lesions. In PD, for open label studies, three of them with OnabotulinumtoxinA (100e200U) and one with AbobotulinumtoxinA (500U), demonstrated that BoNT injections are efficacious for five to nine months with a small proportion of patients developing transient urinary retention (Anderson et al., 2014; Giannantoni et al., 2009, 2011; Kulaksizoglu and Parman, 2010). The evidence based medicine review of the treatment of non-motor findings in PD of the International Parkinson Disease and Movement Disorders Society concluded that BoNT injections are potentially clinically useful for the treatment of urinary dysfunction in these patients (Seppi et al., 2011).
Patients with PD and other forms of parkinsonism have several symptoms and signs that are non-responsive to dopaminergic treatments. There have been attempts to explore the use of BoNT injections to treat some of these findings. One of them is abnormal posture of the trunk that can be either camptocormia (anterior flexion of the trunk greater than 30 ) or Pisa syndrome, when there is lateral abnormal posture. The pathogenesis of these abnormalities is poorly understood although they seem to be multifactorial as result of musculoskeletal abnormalities, myopathy of axial muscles and, in a small proportion of patients, dystonic contractions (Doherty et al., 2011). Unfortunately attempts to correct these abnormal postures with BoNT injections have largely failed with the patients remaining quite disabled (Dupeyron et al., 2015; von Coelln et al., 2008). There seem to be, though, a few rare patients where dystonia of axial muscles causing camptocormia can be alleviated by BoNT (Doherty et al., 2011). Freezing of gait is characterized by difficulty or inability to move the feet during the gait. It can happen at the initiation of the gait or when going through narrow passages or nearing objects. Most patients with this phenomenon fail to respond to any pharmacological treatment (Nonnekes et al., 2015). Because of the hypothesis that freezing of gait results from dystonic contractions of leg muscles, it was proposed to treat this condition with BoNT injections in the gastrocnemius muscles. Unfortunately, the results of two studies, one of them a placebo controlled trial of a small group of patients, failed to demonstrate any benefit (Gurevich et al., 2007; Wieler et al., 2005). The conclusion is that there is no role for BoNT injections in the management of freezing of gait in parkinsonism.
5. Pain
7. Conclusions
There is still a common view of PD as a predominantly motor disorder. This has changed lately with a myriad of studies. They show not only that non-motor findings are common in PD, present in more than 90% of subjects, but also are highly correlated with impairment of quality of life (Barone et al., 2009; Khoo et al., 2013). In this context, pain, reported by at least 40% of patients, is often
Considering the available evidence, it can be concluded that 1) BoNT A and B injections are efficacious and safe treatments for sialorrhea in PD; 2) BoNT injections are an investigational and unsatisfactory treatment for tremor in PD; 3) BoNT injections are an investigational and promising treatment for selected dyskinesias in PD; 4) BoNT injections are an investigational and promising
4. Urinary dysfunction
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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treatment for urinary dysfunction in PD; 5) BoNT injections are an investigational and promising treatment for pain in parkinsonism; 6) BoNT injections are not effective for camptocormia and freezing of gait in parkinsonism. References Adler, C.H., Beach, T.G., Hentz, J.G., et al., 2014. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 83, 406e412. Anderson, R.U., Orenberg, E.K., Glowe, P., 2014. OnabotulinumtoxinA office treatment for neurogenic bladder incontinence in Parkinson's disease. Urology 83, 22e27. Barone, P., Antonini, A., Colosimo, C., et al., 2009. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov. Disord. 24, 1641e1649. Bruno, V.A., Fox, S.H., Mancini, D., Miyasaki, J.M., 2016. Botulinum toxin use in refractory pain and other symptoms in parkinsonism. Can. J. Neurol. Sci. 43, 697e702. Chou, K.L., Evatt, M., Hinson, V., Kompoliti, K., 2007. Sialorrhea in Parkinson's disease: a review. Mov. Disord. 16, 2306e2313. Dogu, O., Apaydin, D., Sevim, S., et al., 2004. Ultrasound-guided versus 'blind' intraparotid injections of botulinum toxin-A for the treatment of sialorrhoea in patients with Parkinson's disease. Clin. Neurol. Neurosurg. 106, 93e96. Doherty, K.M., van de Warrenburg, B.P., Peralta, M.C., et al., 2011. Postural deformities in Parkinson's disease. Lancet Neurol. 10, 538e549. Dupeyron, A., Viollet, E., Coroian, F., et al., 2015. Botulinum Toxin-A for treatment of Pisa syndrome: a new target muscle. Park. Relat. Disord. 21, 669e670. Espay, A.J., Vaughan, J.E., Shukla, R., et al., 2011. Botulinum toxin type A for Levodopa-induced cervical dyskinesias in Parkinson's disease: unfavorable riskbenefit ratio. Mov. Disord. 26, 913e914. Giannantoni, A., Rossi, A., Mearini, E., et al., 2009. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson's disease and multiple system atrophy. J. Urol. 182, 1453e1457. Giannantoni, A., Conte, A., Proietti, S., et al., 2011. Botulinum toxin type A in patients with Parkinson's disease and refractory overactive bladder. J. Urol. 186, 960e964. Gupta, A.D., Visvanathan, R., 2016. Botulinum toxin for foot dystonia in patients with Parkinson's disease having deep brain stimulation: a case series and a pilot study. J. Rehabil. Med. 48, 559e562. Gurevich, T., Peretz, C., Moore, O., et al., 2007. The effect of injecting botulinum toxin type A into the calf muscles on freezing of gait in Parkinson's disease: a double blind placebo-controlled pilot study. Mov. Disord. 22, 880e883.
Jankovic, J., 2009. Disease-oriented approach to botulinum toxin use. Toxicon 54, 614e623. Jankovic, J., Schwartz, K.S., Ondo, W., 1999. Re-emergent tremor of Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 67, 646e650. Khoo, T.K., Yarnall, A.J., Duncan, G.W., et al., 2013. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 80, 276e281. Krack, P., Marion, M.F., 1994. “Apraxia of lid opening,” a focal eyelid dystonia: clinical study of 32 patients. Mov. Disord. 9, 610e615. Kulaksizoglu, H., Parman, Y., 2010. Use of botulinum toxin-A for the treatment of overactive bladder symptoms in patients with Parkinson's disease. Park. Relat. Disord. 16, 531e534. Nonnekes, J., Snijders, A.H., Nutt, J.G., et al., 2015. Freezing of gait: a practical approach to management. Lancet Neurol. 14, 768e778. Oh, H.M., Chung, M.E., 2015. Botulinum toxin for neuropathic pain: a review of the literature. Toxins (Basel) 7, 3127e3154. Pacchetti, C., Albani, G., Martignoni, E., et al., 1995. “Off” painful dystonia in Parkinson's disease treated with botulinum toxin. Mov. Disord. 10, 333e336. Pappert, E.J., Germanson, T., Myobloc/Neurobloc European Cervical Dystonia Study Group, 2008. Botulinum toxin type B vs. type A in toxin-naïve patients with cervical dystonia: randomized, double-blind, noninferiority trial. Mov. Disord. 23, 510e517. Petracca, M., Guidubaldi, A., Ricciardi, L., et al., 2015. Botulinum Toxin A and B in sialorrhea: long-term data and literature overview. Toxicon 107 (Pt A), 129e140. Schneider, S.A., Edwards, M.J., Cordivari, C., 2006. Botulinum toxin A may be efficacious as treatment for jaw tremor in Parkinson's disease. Mov. Disord. 21, 1722e1724. Seppi, K., Weintraub, D., Coelho, M., et al., 2011. The movement disorder society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson's disease. Mov. Disord. 66 (3), S42eS80. Sheffield, J.K., Jankovic, J., 2007. Botulinum toxin in the treatment of tremors, dystonias, sialorrhea and other symptoms associated with Parkinson's disease. Expert. Rev. Neurother. 7, 637e647. Srivanitchapoom, P., Pandey, S., Hallett, M., 2014. Drooling in Parkinson's disease: a review. Park. Relat. Disord. 20, 1109e1118. Trenkwalder, C., Chaudhuri, K.R., Martinez-Martin, P., et al., 2015. Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 14, 1161e1170. von Coelln, R., Raible, A., Gasser, T., Asmus, F., 2008. Ultrasound-guided injection of the iliopsoas muscle with botulinum toxin in camptocormia. Mov. Disord. 23, 889e892. Wieler, M., Camicioli, R., Jones, C.A., Martin, W.R., 2005. Botulinum toxin injections do not improve freezing of gait in Parkinson disease. Neurology 65, 626e628.
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
Contents lists available at ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections Francisco Cardoso* Movement Disorders Unit, Neurology Service, Internal Medicine Department, The Federal University of Minas Gerais, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 July 2017 Received in revised form 15 August 2017 Accepted 20 August 2017 Available online xxx
The aim of this article is to provide a review of the use of injections of botulinum toxin in the management of selected symptoms and signs of Parkinson's disease and other forms of parkinsonism. Sialorrhea is defined as inability to control oral secretions, resulting in excessive saliva in the oropharynx. There is a high level of evidence for the treatment of sialorrhea in parkinsonism with injections of different forms of botulinum toxin type A as well as botulinum toxin type B. Tremor can be improved by the use of botulinum toxin injections but improved tremor control often leads to concomitant motor weakness, limiting its use. Levodopa induced dyskinesias are difficult to treat with botulinum toxin injections because of their variable frequency and direction. Apraxia of eyelid opening, a sign more commonly seen in progressive supranuclear palsy and other tauopathies, often improves after botulinum toxin injections. Recent data suggest that regardless of the underlying mechanism, pain in parkinsonism can be alleviated by botulinum toxin injections. Finally, freezing of gait, camptocormia and Pisa syndrome in parkinsonism almost invariably fail to respond to botulinum toxin injections. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Botulinum toxin Parkinsonism Parkinson's disease Atypical parkinsonism Sialorrhea Dyskinesias Pain Freezing of gait Camptocormia
1. Introduction The mainstay of the treatment of Parkinson's disease (PD) and other parkinsonian syndromes is pharmacological management of dopamine and other neurotransmitters. Surgical procedures such as deep brain stimulation may provide help to a relatively small proportion of patients with PD who fail to improve with best medical treatment. There are patients who remain with symptoms and signs non-responsive to these therapeutic options. In a few of these instances injections of botulinum toxin (BoNT) may be beneficial. The list of symptoms and signs in different parkinsonian disorders reported to be amenable to treatment with BoNT is long and includes sialorrhea, freezing of gait, overactive bladder, dystonia, apraxia of eyelid opening, levodopa-induced dyskinesias, limb and jaw tremor, camptocormia, intestinal constipation, and pain. One recently published retrospective chart review of a busy Canadian movement disorders clinic identified no more than 160 patients with parkinsonism with clinical features treated with injections of BoNT in the period from 1995 to 2014. Out of these
individuals, 117 had PD, 36 received the diagnosis of atypical parkinsonism and the etiology was not identified in seven patients (Bruno et al., 2016). According to the criteria of evidence based medicine there are Class I studies only for sialorrhea and freezing of gait and open-label studies for overactive bladder. Unfortunately for the other parkinsonian symptoms and signs previously listed, there are just case reports that render it difficult to understand the actual role of injections of BoNT injections in their management. The aim of this article is to provide a critical personal review of the use of BoNT to treat selected symptoms and signs in PD and other parkinsonian syndromes. The article is based on personal experience of the author as well as a review of the published literature in English using the following search words: botulinum toxin, parkinsonism, sialorrhea, drooling, dyskinesia, tremor, dystonia, levodopa-induced dyskinesia, apraxia of the eyelid opening, overactive bladder, pain, camptocormia, other postural deformities, freezing of gait, and pain. The subject was reviewed in Toxicon in the past (Jankovic, 2009). 2. Sialorrhea
* Av Pasteur 89/1107, 30150-290, Belo Horizonte, MG, Brazil. E-mail address: [email protected].
Sialorrhea is defined as the inability to control oral secretions, resulting in excessive saliva in the oropharynx. Unlike what
http://dx.doi.org/10.1016/j.toxicon.2017.08.018 0041-0101/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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common sense indicates, the pathogenesis of drooling in PD does not involve excessive production of saliva but rather impairment of swallowing. The flexion of head adds further difficulty in the clearance of saliva. The frequency of sialorrhea is reported to range from 31% to 86% of patients with PD (Barone et al., 2009; Chou et al., 2007). The discrepancy of the numbers depends on the method used to assess the accumulation of saliva as well as the characteristics of the studied population. Regarding the latter, as expected the prevalence is greater in patients with dysphagia (86%) in comparison with those without swallowing impairment (44%) (Chou et al., 2007). Interestingly, drooling is seen in very early stage of the disease when patients list it as one of the most disabling nonmotor findings of PD (Khoo et al., 2013). Despite its frequency and related disability, there are few proven efficacious treatments for sialorrhea in parkinsonism. Potential treatments for this condition include anticholinergics (sublingual atropine, ipratoprium bromide spray, and glycopyrrolate), adrenergic receptor agonists (clonidine and modafinil) and non-pharmacological approaches such as chewing gum, behavioral modification, speech therapy, surgery and even radiotherapy of the salivary glands (Chou et al., 2007). Unfortunately, only ipratoprium bromide spray and glycopyrrolate underwent clinical trials of good quality that led to the conclusion that the former is investigational and the latter possibly useful for the management of sialorrhea (Seppi et al., 2011). There is, therefore, the need for alternative and more efficacious treatments for this condition. The rationale for the use of BoNT injections of the salivary glands to treat drooling is based on the blocking of cholinergic transmission that underlies the secretion of saliva. An important issue that needs to be taken into account when designing the strategy to use BoNT injections to manage sialorrhea is to understand that the majority of saliva is secreted by the parotid and submandibular glands. There have been several well-designed trials assessing the role of BoNT injections into the parotid and submandibular glands to treat sialorrhea in PD. Seven studies, of which two were placebo controlled, assessed the use of Onabotulinumtoxin A in drooling in PD. The dosage for the parotid and submandibular glands were, respectively, 5e50U and 5U. The data show that the active drug is significantly more efficacious than placebo and the effect lasted from one to four months. Moreover, the treatment was well tolerated with few and mild side effects (dryness of mouth and dysphagia). Three trials, two of which were placebo controlled, replicated these findings with Abobotulinumtoxin A. The dosage for each parotid gland ranged from 75 to 146U and each submandibular gland was injected with 78U (Srivanitchapoom et al., 2014). Because of its greater affinity for autonomic terminals, it was expected that Rimabotulinumtoxin B could be more efficacious than the type A toxins. In fact, in studies of treatment of cervical dystonia with toxin type A and type B, dry mouth was more commonly seen in the latter group (Pappert et al., 2008). However, five studies of this BoNT (three of them were placebo controlled) found results similar to those reported for BoNT A: better response than placebo, resulting in improvement of drooling for up to four months, with a few patients also developing dysphagia and dryness of mouth. In these trials the dosage per parotid gland was 500e2000U and each submandibular gland received 250U (Srivanitchapoom et al., 2014). One more recent report describes the open label long term experience of BoNT injections in the management of drooling in 33 PD patients and 32 individuals with amyotrophic lateral sclerosis. The authors performed ultrasound guided injections either of Abobotulinumtoxin A (250U) in 136 sessions or Rimabotulinumtoxin B (2500U) in 181 sessions. There was ‘clearcut’ benefit in 89% of sessions without any difference between the two types of BoNT. The average benefit lasted 87 days and side effects were reported solely in 8.9% of sessions (Petracca et al., 2015). Based on these
results, the MDS Evidence Based group concluded that injections of both BoNT A and B are an efficacious and clinically useful treatment for sialorrhea in PD carrying an acceptable risk with specialized monitoring (Seppi et al., 2011). There are, however, unsettled issues that require further studies to be solved: number of injection sites; parotid versus submandibular gland injections; blind versus ultrasound guided injections; and type A or type B toxin (Dogu et al., 2004). 3. Hyperkinesias Bradykinesia is the hallmark of all parkinsonian syndromes. Nevertheless, a proportion of patients with parkinsonism may develop hyperkinesias either spontaneously as part of the underlying disease or because of use of pharmacological agents, particularly dopaminergic drugs. 3.1. Tremor Tremor is the most common spontaneous hyperkinesia associated with parkinsonism, in particular PD. Because it is often a tremor at rest that improves or even disappears with action, it does not cause marked disability in the majority of individuals. It is true though that a few patients with PD have re-emergent tremor, tremor at rest that re-emerges after a variable delay while maintaining a posture tremor. This particular tremor may lead to functional disability (Jankovic et al., 1999). There have been a few open label studies of the use of BoNT injections to treat parkinsonian tremor refractory to conventional treatments. For hand tremor, there are reports showing that OnabotulinumtoxinA, 15U into the extensor compartment and 50e100U for the flexor compartment, improves parkinsonian tremor but at the expense of disabling weakness (Sheffield and Jankovic, 2007). This result mimics the experience of most experts in the field leading to the conclusion that the role of BoNT injections in the management of parkinsonian hand tremor is very limited. Although there are no published data supporting this, clinicians treating tremor with BoNT injections currently avoid injecting the forearm extensor muscles to prevent development of finger weakness. There is one description of a series of PD patients with jaw tremor treated with injections of 30e100U of AbobotulinumtoxinA per masseter. The authors reported that the injections were efficacious and without side effects (Schneider et al., 2006). 3.2. Levodopa-induced dyskinesias It is estimated that for every year of exposure to levodopa, 10% of PD patients develop dyskinesias. In fact, a recent study showed that they are the clinical feature best correlated with the pathological findings of PD at autopsy (Adler et al., 2014). The most common dyskinesias occur during the on period, ie, when the patients are under the effect of levodopa. Typically, these dyskinesias are mobile and have a choreo-dystonic nature. A few patients with on dyskinesias and the majority of subjects with off dyskinesias have dystonia or stereotypies that have a predictable phenomenology. Their management involves changes of levodopa administration, use of other drugs such as amantadine, and, in selected patients, surgery. Exceptionally, when they fail to respond to these options, they can be treated with BoNT injections. This applies in particular when the phenomenology involves blepharospasm, jaw closing dystonia, and other predictable phenomena (Gupta and Visvanathan, 2016; Pacchetti et al., 1995). Because of the fluctuating and unpredictable phenomenology, treatment of levodopa-induced cervical dystonia with BoNT injections has been reported to have an unfavorable risk-benefit ratio (Espay et al., 2011). This is the opposite of
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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off period foot dyskinesia in PD, which is a fixed painful dystonia. An open label study of 30 patients with this condition reported that 40U of OnabotulinumtoxinA per affected muscle resulted in improvement of the pain and mobility in, respectively, 70% and 30% of individuals without significant adverse events (Pacchetti et al., 1995). The identification of the muscles involved can be done by inspection, palpation and, in a few selected subjects, electromyography. In summary, BoNT injections are not a promising therapy for levodopa on dyskinesias but are helpful in selected patients with painful off period foot dystonia or other types of predictable phenomena. 3.3. Spontaneous dystonia As a rule, spontaneous cranial dystonia in association with parkinsonian syndrome argues against the diagnosis of PD and suggests the patient may have atypical parkinsonism, particularly progressive supranuclear palsy (PSP) or other tauopathies. Arguably the so-called apraxia of eyelid opening, inability to voluntarily open the eyes, is the most common form of dystonia in PSP. Despite the lack of obvious muscle contraction of the eyelids, this phenomenon is now known to result from dystonic contraction of the pretarsal portion of the orbicularis oculi muscle (Krack and Marion, 1994). Although there are no controlled studies, most authorities agree that injections of small dosages of BoNT in this particular area of the eyelids are the treatment of choice for apraxia of the eyelid opening. Clinical experience also suggests that other forms of spontaneous dystonia (e.g., oro-mandibular, cervical, and limb dystonia) associated with atypical parkinsonism, such as PSP and Multiple System Atrophy, are also amenable to treatment with BoNT injections similarly to what happens in idiopathic dystonias (Sheffield and Jankovic, 2007).
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underrecognized and undertreated in PD and other forms of parkinsonism. Despite the high frequency of pain, its underlying mechanism in parkinsonism remains to be determined. There is evidence suggesting that multiple factors may contribute to its occurrence: osteo-muscular deformity, radiculopathy, muscle rigidity, dystonia, levodopa-induced dyskinesias and changes in central processing of sensory stimuli. Recent studies suggest that BoNT inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. It is more controversial whether BoNT could have a central analgesic effect after undergoing retrograde axonal transport (Oh and Chung, 2015). A recent chart review of a Canadian center found that 81/160 of patients with parkinsonism had pain. The authors considered that it was dystonic pain, related to muscle contractions, in 77.6% of these individuals. In the remaining group the authors concluded that the pain was caused by musculoskeletal conditions. Treatment with BoNT injections resulted in improvement of pain in 81% of individuals regardless of type of pain, etiology of parkinsonism and even dosage of toxin (Bruno et al., 2016). Despite the obvious limitations of this study (retrospective chart review, uncontrolled injections), it suggests that further studies need to explore the role of BoNT in the management of pain in parkinsonism. This is of relevance since this symptom is often refractory to other forms of treatment (Trenkwalder et al., 2015). 6. Conditions usually non-responsive to botulinum toxin injections
Urinary dysfunction, characterized by urgency or even incontinence, and resulting from detrusor muscle hyperactivity occurs in at least 35% of patients with PD (Barone et al., 2009). It causes significant disability and social embarrassment, and is often nonresponsive to pharmacological measures such as peripheral anticholinergic agents and alpha-adrenergic drugs (Seppi et al., 2011). In contrast, well designed controlled studies have established BoNT injections in the detrusor muscle as an efficacious and safe treatment for urinary incontinence in neurological conditions such as multiple sclerosis and other causes of spinal cord lesions. In PD, for open label studies, three of them with OnabotulinumtoxinA (100e200U) and one with AbobotulinumtoxinA (500U), demonstrated that BoNT injections are efficacious for five to nine months with a small proportion of patients developing transient urinary retention (Anderson et al., 2014; Giannantoni et al., 2009, 2011; Kulaksizoglu and Parman, 2010). The evidence based medicine review of the treatment of non-motor findings in PD of the International Parkinson Disease and Movement Disorders Society concluded that BoNT injections are potentially clinically useful for the treatment of urinary dysfunction in these patients (Seppi et al., 2011).
Patients with PD and other forms of parkinsonism have several symptoms and signs that are non-responsive to dopaminergic treatments. There have been attempts to explore the use of BoNT injections to treat some of these findings. One of them is abnormal posture of the trunk that can be either camptocormia (anterior flexion of the trunk greater than 30 ) or Pisa syndrome, when there is lateral abnormal posture. The pathogenesis of these abnormalities is poorly understood although they seem to be multifactorial as result of musculoskeletal abnormalities, myopathy of axial muscles and, in a small proportion of patients, dystonic contractions (Doherty et al., 2011). Unfortunately attempts to correct these abnormal postures with BoNT injections have largely failed with the patients remaining quite disabled (Dupeyron et al., 2015; von Coelln et al., 2008). There seem to be, though, a few rare patients where dystonia of axial muscles causing camptocormia can be alleviated by BoNT (Doherty et al., 2011). Freezing of gait is characterized by difficulty or inability to move the feet during the gait. It can happen at the initiation of the gait or when going through narrow passages or nearing objects. Most patients with this phenomenon fail to respond to any pharmacological treatment (Nonnekes et al., 2015). Because of the hypothesis that freezing of gait results from dystonic contractions of leg muscles, it was proposed to treat this condition with BoNT injections in the gastrocnemius muscles. Unfortunately, the results of two studies, one of them a placebo controlled trial of a small group of patients, failed to demonstrate any benefit (Gurevich et al., 2007; Wieler et al., 2005). The conclusion is that there is no role for BoNT injections in the management of freezing of gait in parkinsonism.
5. Pain
7. Conclusions
There is still a common view of PD as a predominantly motor disorder. This has changed lately with a myriad of studies. They show not only that non-motor findings are common in PD, present in more than 90% of subjects, but also are highly correlated with impairment of quality of life (Barone et al., 2009; Khoo et al., 2013). In this context, pain, reported by at least 40% of patients, is often
Considering the available evidence, it can be concluded that 1) BoNT A and B injections are efficacious and safe treatments for sialorrhea in PD; 2) BoNT injections are an investigational and unsatisfactory treatment for tremor in PD; 3) BoNT injections are an investigational and promising treatment for selected dyskinesias in PD; 4) BoNT injections are an investigational and promising
4. Urinary dysfunction
Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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treatment for urinary dysfunction in PD; 5) BoNT injections are an investigational and promising treatment for pain in parkinsonism; 6) BoNT injections are not effective for camptocormia and freezing of gait in parkinsonism. References Adler, C.H., Beach, T.G., Hentz, J.G., et al., 2014. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology 83, 406e412. Anderson, R.U., Orenberg, E.K., Glowe, P., 2014. OnabotulinumtoxinA office treatment for neurogenic bladder incontinence in Parkinson's disease. Urology 83, 22e27. Barone, P., Antonini, A., Colosimo, C., et al., 2009. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov. Disord. 24, 1641e1649. Bruno, V.A., Fox, S.H., Mancini, D., Miyasaki, J.M., 2016. Botulinum toxin use in refractory pain and other symptoms in parkinsonism. Can. J. Neurol. Sci. 43, 697e702. Chou, K.L., Evatt, M., Hinson, V., Kompoliti, K., 2007. Sialorrhea in Parkinson's disease: a review. Mov. Disord. 16, 2306e2313. Dogu, O., Apaydin, D., Sevim, S., et al., 2004. Ultrasound-guided versus 'blind' intraparotid injections of botulinum toxin-A for the treatment of sialorrhoea in patients with Parkinson's disease. Clin. Neurol. Neurosurg. 106, 93e96. Doherty, K.M., van de Warrenburg, B.P., Peralta, M.C., et al., 2011. Postural deformities in Parkinson's disease. Lancet Neurol. 10, 538e549. Dupeyron, A., Viollet, E., Coroian, F., et al., 2015. Botulinum Toxin-A for treatment of Pisa syndrome: a new target muscle. Park. Relat. Disord. 21, 669e670. Espay, A.J., Vaughan, J.E., Shukla, R., et al., 2011. Botulinum toxin type A for Levodopa-induced cervical dyskinesias in Parkinson's disease: unfavorable riskbenefit ratio. Mov. Disord. 26, 913e914. Giannantoni, A., Rossi, A., Mearini, E., et al., 2009. Botulinum toxin A for overactive bladder and detrusor muscle overactivity in patients with Parkinson's disease and multiple system atrophy. J. Urol. 182, 1453e1457. Giannantoni, A., Conte, A., Proietti, S., et al., 2011. Botulinum toxin type A in patients with Parkinson's disease and refractory overactive bladder. J. Urol. 186, 960e964. Gupta, A.D., Visvanathan, R., 2016. Botulinum toxin for foot dystonia in patients with Parkinson's disease having deep brain stimulation: a case series and a pilot study. J. Rehabil. Med. 48, 559e562. Gurevich, T., Peretz, C., Moore, O., et al., 2007. The effect of injecting botulinum toxin type A into the calf muscles on freezing of gait in Parkinson's disease: a double blind placebo-controlled pilot study. Mov. Disord. 22, 880e883.
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Please cite this article in press as: Cardoso, F., Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections, Toxicon (2017), http://dx.doi.org/10.1016/j.toxicon.2017.08.018
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