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REVIEW ARTICLE
Year : 2018  |  Volume : 66  |  Issue : 7  |  Page : 79-89

Botulinum toxin in movement disorders


Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India

Date of Web Publication1-Mar-2018

Correspondence Address:
Dr. Sanjay Pandey
Department of Neurology, Academic Block, Room No 507, Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi - 110 002
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.226441

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 » Abstract 

Botulinum toxin has gained immense popularity since its introduction for therapeutic use. It is used in a variety of movement disorders like hemi-facial spasm, focal dystonias like blepharospasm, cervical dystonia, oromandibular dystonia, limb dystonias. It is also being used in patients with tremors, tics and for a variety of indications in Parkinson's disease as well. There are eight subtypes of toxins available, but type A and B are the ones used in movement disorder clinics. The toxin mainly acts by inhibiting the release of acetylcholine at the neuromuscular junction and causing weakness. Type B toxin has more effect over the autonomic nervous system and hence is preferred for hyper-secretory disorders. The use of electromyography and ultrasound further improve the accuracy of the procedure. It is a relatively safe therapeutic option with its effect lasting for around three months. It has very few side effects. The key is to start with the lowest possible dose and then gradually increase the dose depending upon the patient's response. Selecting the right muscles for injection is of utmost importance and is guided by the knowledge of anatomy of the muscles.


Keywords: Dystonia, muscle, Parkinson's disease, tremor
Key Message: The role of botulinum toxin in the amelioration of a variety of symptoms associated with movement disorders like hemifacial spasm, focal dystonias like blepharospasm, cervical dystonia, oromandibular dystonia, limb dystonias, tremors, tics and Parkinson′s disease is discussed. The method of administering the injection at various sites and the side effects produced have also been presented.


How to cite this article:
Tater P, Pandey S. Botulinum toxin in movement disorders. Neurol India 2018;66, Suppl S1:79-89

How to cite this URL:
Tater P, Pandey S. Botulinum toxin in movement disorders. Neurol India [serial online] 2018 [cited 2018 Dec 16];66, Suppl S1:79-89. Available from: http://www.neurologyindia.com/text.asp?2018/66/7/79/226441


Botulinum toxin has come a long way from being a food poison to being readily used for various clinical conditions including movement disorders. The word 'botulinum' is derived from the Latin word “botulus” meaning 'sausage', as it was found as a contaminant in an improperly preserved sausage.[1] It has shown a tremendous therapeutic potential as a neurotoxin since its discovery in the 18th century [Figure 1].[2],[3],[4],[5] In the 1980s, it was found that this toxin produced acute neuromuscular weakness and anticholinergic effects, findings that opened up the horizon for its medical usage.[6],[7]
Figure 1: History of botulinum toxin

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Types of toxin and mechanism of action

Botulinum toxin is produced by an anaerobic bacterium named “Clostridium bacillus”. It is an exotoxin having eight serotypes named A to H. The types A and B were first designated by Georgenia Burke in 1919 and are the only ones approved by the United States Food and Drug Administration (FDA) currently for therapeutic use. Bengston and Seddon first described the type C toxin in 1922; and later in 1928, Meyer and Gunnison described the type D and E varieties.[8],[9] The type F and G botulinum toxin were introduced by Moller and Scheibein in 1960 and Gimenex and Ciccarelli in 1970.[9] The type H is the deadliest toxin available, that was discovered by Stephen Arnon in 2009.[9] The type A was initially called Oculinum and later renamed by Allergan Pharmaceuticals in 1991 as 'Botox' (OnabotulinumtoxinA). Another type A toxin named 'Dysport' (AbobotulinumtoxinA) was marketed world-wide by Ipsen Pharmaceuticals in 1991. 'Xeomin' (IncobotulinumtoxinA) was introduced by Merz Pharmaceuticals; with 'Hengli' (Lanzhou Institute of Biological Products Co., Ltd; Lanzhou, Gansu) and 'Neuronox' (Medytox Inc., South Korea) being the other subtypes available in South Asian countries.[10] Neurobloc/Myobloc (RimabotulinumtoxinB) came into existence in 2000 by Elan Pharmaceuticals as type B toxin.[11]

The toxin complex consists of botulinum neurotoxin, non-toxin proteins and excipients. The neurotoxin is a dipeptide molecule weighing 150 kDa, having a heavy and a light chain attached by a disulphide bond.[12] The other non-toxin proteins weigh from 500 to 900 kDa and prevent absorption through the skin. The excipients consist of lactose, sucrose, and albumin, which determine the pH of the drug and help in stabilisation of the compound. RimabotulinumtoxinB has a pH of 5.4, which makes it painful to inject as compared to the type A toxin, which has a pH of 7.4. IncobotulinumtoxinA is the only variety of the toxin which can be preserved at room temperature, whereas others require refrigeration. RimabotulinumtoxinB is available as a ready-to-use solution, whereas others are freeze dried powders, which require reconstitution with 0.9% normal saline.[11] After reconstitution, the manufactures recommend usage of the compound within four hours, but the reconstituted product can be preserved for a week in the refrigerator.[13]

After injection into a site, the tissue proteases cleave the drug molecule [Figure 2]. The heavy chain helps to bind the toxin to surface glycoproteins at the cholinergic nerve terminal, and thus, it gets internalised at the neuromuscular junction. The toxin inhibits the release of acetylcholine at the neuromuscular junction thereby leading to an efficacious decrement in the neuromuscular transmission at these junctions but not leading to clinically significant weakness.[13]
Figure 2: Botulinum toxin consists of a heavy and light chain. After injection into the muscle, it reaches the neuromuscular junction where tissue proteases cleave the molecule into heavy and light chain. The heavy chain helps in internalization of the toxin by binding to nerve terminal surface glycoprotein receptors. The light chain impairs the binding of the SNARE (soluble N-ethyl maleimide-sensitive factor [NSF], attachment receptors, proteins essential for regulated exocytosis)/VAMP (vesicle associated membrane protein) with the synaptic vesicle containing acetylcholine and further prevents its fusion with the membrane. This inhibits the release of acetylcholine at the junction, and thereby, the muscle cannot contract. This results in muscle weakness. Different botulinum toxins target separate SNARE proteins as illustrated in the figure above

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Not only does it influence the alpha motor neurons, it also influences the gamma motor neurons leading to reduced spindle afferent activity. This causes the muscle to be relaxed and reduces its spasm without weakening the muscle. There is also retrograde transportation of the toxin into the axons and the spinal cord thereby preventing the Renshaw cell inhibition and reciprocal inhibition as well. The toxin is also believed to play a role in modulating the brain plasticity. The brain tends to reduce the size of cortical representation of a particular area that is not in use. Thus, by decreasing the spindle afferent activity, botulinum toxin signals the brain about reduced activity of that area, leading to further decrease in its representational size and thereby causing decreased movement. Secondly, it also decreases the cortical GABAergic levels, thereby reducing the intra-cortical inhibition seen in patients with dystonia.[14]

The potency of the different types varies, with type A being three times more potent than type B. The effect of the toxin starts 2 to 3 days following the injection, peaks by 2 weeks and wanes off by 2.8 months. The immunogenicity of Type B is higher; the intramuscular injections are more painful with a greater effect on the autonomic nervous system; they are mainly used in treating conditions like sialorrhea, hyperhidrosis and non-motor symptoms.[15]

Plan of injection

A meticulous planning before the injection is very important to calculate the toxin dosages for the individual muscles likely to be injected. A written informed consent from the patient is a must before giving the injections. It is advisable to video tape the movements for future reference, and use them as a baseline for comparison to assess for any improvement or side effects.

Having a detailed knowledge about the toxin and its dilution rate is of utmost importance, as it will remarkably influence the results in the patients. The dilution rates in blepharospasm patients varies from 1.25units (U)/0.1 ml to 5 U/0.1 ml for onabotulinumtoxinA and incobotulinumtoxinA, whereas it varies from 10 U/0.1 ml to 20 U/0.1 ml for abobotulinumtoxinA. The recommended dilutions of onabotulinumtoxinA/incobotulinumtoxinA for cervical dystonia patients varies from 50 U/1 ml to 200 U/4 mL with normal saline. This dosage is also dependent on the volume and number of injection sites desired to achieve the treatment objectives. In general, not more than 50 Units per site and 400 U maximum per sitting, should be administered. A sterile needle of an appropriate length (e.g., 27-32 gauge for blepharospasm and 22-24 gauge for cervical dystonia) should be used.[9]

Localization of the involved muscles with electromyographic (EMG) guidance may be useful, but EMG can only reveal if the muscles are hyperactive or not. Bhidayasiri et al., in 2006 stated that the outcome following EMG guided injections were comparable to the manual injections following palpation of muscles.[16] Ultrasound is a new way to localise the muscles to be injected. Various studies have shown the superiority of ultrasound over clinical palpation of muscles.[17],[18],[19],[20],[21],[22],[23] Further injections are guided by the response of the patient to prior injections and the side effects. Higher doses are required if the patient has less than 50 to 60% improvement from the previous injection.[9] The toxin is contraindicated in pregnancy and during breast-feeding. Botulinum toxin injections are generally safe and effective with very few side effects.[24] It is important to note any prior history of bleeding diathesis or a history of blood thinning medications being administered; as the toxin is given intramuscularly, the presence of these conditions can lead to haematoma formation. The toxin can spread to nearby tissues when injected in large doses, rarely leading to weakness of muscles. Also, rare systemic side effects of the toxin that are reported include influenza-like illness, necrotising fasciitis, gall bladder dysfunction, brachial plexopathy and generalised muscular weakness.[24] A subset of patients can develop antibodies against the toxin making them non-responders.[6]

Blepharospasm and hemi-facial spasm

Blepharospasm and hemi-facial spasm are the most common indications for botulinum toxin injection in a movement disorder clinic. Blepharospasm is characterised by repetitive, involuntary, and synchronous contractions of orbicularis oculi leading to forceful closure of both the eyes. It is classified as clonic or tonic, depending upon the duration of muscle contraction.[25] Blepharospasm can be primary or secondary with various underlying aetiologies.[26] Botulinum toxin type A is very effective for the treatment of blepharospasm with a response rate of over 90%.[27] Jankovic and Orman in 1987 were the first to conduct a randomised trial in patients with blepharospasm.[28] The muscle injected predominantly is the orbicularis oculi, but in a few cases, corrugator supercilii and procerus are also injected. It is advisable to start with a minimal effective dose and gradually escalate the dose depending on the response rates. The starting doses for onabotulinumtoxinA and incobotulinumtoxinA is 1.25 to 2.5 U per site and 22.5+-9.5 U per eye [Table 1].[29] There can be a requirement for increasing the dose with each session due to progression of the disease or the appearance of neutralising antibodies, but there is a subset of patients who require the same doses or may not even require further injections.[9] The injection is usually given in the pre-tarsal region of orbicularis oculi at three to four sites as it has been seen to be more effective than the pre-septal injections.[9] The maximum doses used in studies per se ssion average to 40 to 75 U of onabotulinumtoxinA, 62 U of incobotulinumtoxinA and 120-240 U of abobotulinumtoxinA.[25],[30],[31],[32],[33]
Table 1: Muscles injected in patients with focal dystonia

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Hemi-facial spasm (HFS) is characterized by dyskinesia of the facial muscles involving involuntary irregular tonic or clonic twitching of periocular and periorbital muscles innervated by the seventh cranial nerve.[34] Most of the cases are unilateral with only 0.6 to 5% reported incidence in literature of bilateral cases.[35] Yoshimura et al., in 1992, were the first to use botulinum toxin in patients with hemi-facial spasm.[36] The muscles implicated in hemi-facial spasm include the orbicularis oculi, zygomaticus major and minor, risorius, levator labii superiosis, orbicularis oris, mentalis, depressor angularis and platysma; however, the muscle to be injected is based on the physician's observation of the involvement of muscles. The starting doses are 2.5 to 5 U per site for onabotulinumtoxinA/incobotulinumtoxinA, and 15 to 20 U per site for abobotulinumtoxinA.[29] One of the studies reported an overall 80% improvement in patients of hemi-facial spasm injected with botulinum toxin and found no difference in the efficacy of onabotulinumtoxinA and abobotulinumtoxinA.[37] They also reported improvement in symptoms by the second to the fourteenth day after the injection was administered. A study in 2010 showed that botulinum toxin not only improved the motor symptoms in patients with hemi-facial spasm but also markedly reduced the non-motor (tearing, eye irritation, facial paraesthesias and clicking sound in the ear) symptoms in these patients by nearly 75% following the administration of the first injection itself.[38] Another study showed that botulinum toxin type A was effective in improving facial asymmetry present at rest, but worsened the facial symmetry during voluntary movements.[39] The effect of splitting the injection sites into two at the zygomaticus and risorius muscles proved to be equal to administering a non-split injection.[40]

The side effects ranged from 3 to 25% and included ptosis, lagophthalmos, dry eye, entropion, local site bruising, tearing, keratitis and diplopia. These effects were transient and usually reversible.

Cervical dystonia

Cervical dystonia is the most common of the focal dystonias and clinically characterized by involuntary contractions of cervical muscles causing abnormal head movements and postures.[41] The current classification of cervical dystonia includes torticollis (rotation or turning of head towards one side), anterocollis (flexion of head and neck), laterocollis (head tilting towards one side), and retrocollis (extension of head and neck). A combination of these movements is commonly seen in clinical practice. Recently, combinations of complex cervical dystonias have been classified depending on the neck (collis) and head (caput) movements.[42] Besides these, there may be lateral or sagittal (anterior or posterior) deviation of the base of the neck from the midline. The patients with an anterior sagittal shift characteristically have anterocollis and retrocaput causing a gooseneck posturing, whereas those with a posterior sagittal shift have a double chin appearance secondary to retrocollis and anterocaput.

Although cervical dystonia is the most common variety of the focal dystonias, not many physicians are trained in treating the same. A lot of factors need to be considered while injecting the toxin in patients with cervical dystonia. Tsui et al., in 1985 were the first to demonstrate the efficacy of type A botulinum toxin in cervical dystonia patients, whereas in 1997, Lewy et al., showed that type B toxin is also efficacious.[43] Type A and B botulinum toxins have both been approved for treatment of cervical dystonia, and it was seen in studies that there was no significant difference between their efficacies.[44] In a study by Zoons et al., 43 to 68% of the patients with cervical dystonia injected with botulinum toxin reported a beneficial effect. They used Tsui and Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) to record improvement in symptoms.[45] The side effects included focal weakness of the neck muscles and dysphagia, which could be reduced by avoiding injection into the lower part of the sternocleidomastoid (SCM) muscle. The incidence of dysphagia ranged from 10 to 12% and was seen particularly when bilateral SCMs were injected in cases of antecollis and also when higher doses of the toxin were used for cervical dystonia.[46],[47] Despite botulinum toxin being the first line therapy for cervical dystonia, it was found that around 30% of the patients discontinued therapy in various longitudinal studies. The review by Jinnah et al., reported that the physician-estimated benefit was higher than patient-estimated benefit.[48] They also stated that the lack of benefit was usually due to an improper dosage schedule and muscle selection rather than due to actual lack of efficacy of botulinum toxin. The group of patients who responded less to the treatment included those with antecollis, anterior or posterior sagittal shift, or tremor associated cervical dystonia. A previous surgery for cervical dystonia, the use of neuropleptics, and the requirement of higher doses of the toxin was also associated with a poorer response.[48]

Oromandibular dystonia

Oromandibular dystonia (OMD) is a type of cranial dystonia characterized by forceful contractions of the face, jaw and/or tongue, causing a difficulty in jaw opening (jaw opening dystonia) or closing the mouth (jaw closure dystonia) affecting chewing and speech.[49] A patient may have a combination of blepharospasm and OMD, also known as Meige's syndrome.[48],[50],[51] The manifestations may be primary, secondary to other neurological disorders, or tardive in nature (drug induced). The upper facial muscles are usually involved at the start of the symptoms, followed by the lower facial muscles. The contractions of facial and pharyngeal muscles can lead to abnormal vocalisation, which can be confused with tics. Tongue involvement in these patients is a pointer to the dystonia being drug induced.[52]

Jaw opening dystonia, also called as hyoid muscle dystonia, is more difficult to treat as compared to jaw closure dystonia. In the latter condition, nearly two-third of the patients respond well to botulinum toxin.[53] The muscles implicated in jaw opening dystonia are the lateral pterygoids, anterior belly of the digastric, the submentalis complex (anterior and posterior digastric and the mylohyoid, geniohyoid, thyrohyoid, sternohyoid and omohyoid muscles) and platsyma, whereas the masseter, temporalis and medial pterygoids are involved in jaw closure dystonia.[54] These are difficult to treat with oral medications, including tetrabenazine, which showed only a 17.4% improvement in the patient symptoms.[55],[56] There are studies showing that both botulinum toxin A and B are equally effective in oromandibular dystonias.[28],[53],[57],[58],[59],[60],[61],[62],[63] The problems faced are that the muscles to be injected are close to vessels and nerves so theoretically EMG or USG guided injections are preferred. But studies have shown no difference in the incidence of of adverse effects utilizing the two procedures.[57],[58],[59] The injection also helps in relieving the pain associated with temporo-mandibular joint involvement.[64] Injections into the sub-mentalis muscle complex, though difficult to perform, can yield good results in the case of jaw opening dystonia. Oromandibular dystonia has been associated with social embarrassment for the patients as it may cause biting of the lips, tongue, and cheek as well as dental problems. Therefore, botulinum toxin injection may be very rewarding in them.[53] The reported side effects after the injection include dysphagia, dysarthria, and neck swelling. In a study by Jankovic et al., these side effects accounted for 11.1% of all treatment visits.[65] There are studies which do not recommend the use of botulinum toxin in lingual dystonia due to the fear of developing dysphagia, but the number of patients included in these studies have been too small to unequivocally make this recommendation.[57],[66] The muscle predominantly injected in the presence of lingual dystonia in a patient is the genioglossus muscle. In a study published in 2008 that included patients with tardive dyskinesia, 50 U of abobotulinumtoxinA was injected in each genioglossus muscle and a dramatic response was obtained.[67]

Task specific dystonias

A task specific dystonia is a type of focal dystonia, which occurs only during performance of a specific skilled motor task. Writer's cramp is the most common type of task specific dystonia involving the hand.[68] The earliest descriptions of writer's cramp came in the 1600s, but Sheehy and Marsden coined the term in 1982.[69] Other types of focal task specific dystonias affecting the upper limb include the typist's dystonia, musician's dystonia, telegraphist's dystonia, hairdresser's dystonia, golfer's dystonia, surgeon's dystonia, and tailor's dystonia.[70] Most of these dystonias are associated with activities involving the occupation of a person. Their presence can, therefore, be a huge source of disability for them. That is the reason that an early recognition and an accurate treatment of these movement disorders can be very rewarding in these patients. Oral agents hardly produce any benefit in symptoms and their use is declining.[71] Cohen and colleagues in 1992 first demonstrated the efficacy of botulinum toxin in patients with writer's cramp.[72] Since then, it has become the first line therapy, producing benefit in a significant number of treated patients. In a study published from India, 16 patients with writer's cramp were treated with botulinum toxin and the benefit was seen in 50% of the patients related to the pain they were having, as well as abnormal posturing and the ease and speed of writing.[73] In a study by Kruisdjik et al., in 2007, 70% of the patients reported a benefit and wished to continue treatment using botulinum toxin, of which 51% continued to benefit from the treatment administered, even at one year duration.[74] Karp et al., in a study of 53 patients, found the benefit lasting for up to 9 months.[75] When injecting these patients, it is important to first determine the type of writer's cramp. This can be done by the use of mirror movements; an EMG guidance also helps in assessing the hyperactive muscles.[76] These patients tend to adapt compensatory postures to overcome their disability so one may wrongly classify the type of dystonia and the involved muscles. Care must be taken to correctly document the primary abnormality.[77] How much to inject and where to inject is the critical factor in getting a good response; also, there is the constant risk of causing spread of the toxin to the adjacent muscles, resulting in post-injection weakness of that part of the body.[78] Wissel et al., found that 27 out of 31 patients with writer's cramp, when treated with botulinum toxin, developed weakness at least once in the course of the period during which they were receiving these injections.[79] The extensor groups of muscles required lesser doses as compared to the flexor muscles. The starting doses for each muscle needed to be conservative, ranging from 2.5 to 10 U of onabotulinumtoxinA and incobotulinumtoxin A, and 40 to 60 U of abobotulinumtoxinA. The maximum doses administered were 120 U for onabotulinumtoxinA and incobotulinumtoxinA, and 240 U for abobotulinumtoxinA. Injecting the muscles closer to the endplates and selecting fewer muscles provided better results.[68]

Tremor

Tremor is defined as a rhythmic, involuntary oscillation of a body part around one or more of the joints.[80] Tremors may be classified based on the clinical features, the etiology or the origin of the tremor. Essential tremor, Parkinsonian tremor, cerebellar tremor, dystonic tremor, orthostatic tremor, physiologic tremor, and psychogenic tremor are the most common types of tremors encountered in a movement disorder clinic. Tremor is mainly managed by giving oral medications, and botulinum toxin is a good therapeutic option in refractory patients.[81]

In a study by Jankovic et al., 51 patients with tremor (42 with head tremor and 10 with hand tremor; 14 with dystonic tremor, 12 with essential tremor, 22 with a combination of dystonic and essential tremor, and one each with parkinsonian, peripherally induced, and midbrain tremor) were injected with onabotulinumtoxinA, of which 67% had improvement. However, 29% of the patients with head tremor developed dysphagia, 10% had transient neck weakness, and 5% had pain, whereas 60% of the patients with hand tremor developed transient hand weakness.[82] In another study by Henderson et al., 10 out of the 17 non-dystonic tremor patients showed improvement in postural and kinetic tremor.[83] Rezvan et al., used incabotulinumtoxinA in 19 patients with essential tremor in a placebo controlled crossover blinded study and reported improvement in tremor in 63% of the patients. Overall, 53% of the patients were satisfied with the treatment with only one patient developing hand weakness.[84] Rahimi et al., used kinematic measurements to measure the tremor amplitude in 24 Parkinson's disease (PD) patients, and found that injection botulinum toxin improved their tremors.[85] In another study, Trosch et al., reported more subjective benefit rather than objective changes in 26 patients (12 patients with PD and 14 with essential tremor) injected with botulinum toxin.[86] In a double-blind placebo controlled crossover trial at the Mayo clinic, 30 patients with PD were injected with incabotulinumtoxinA in a customised way and there was a statistically significant improvement in the tremor rating and patient perception of the improvement, with low occurrence of significant hand weakness.[87] Apart from head and hand tremors, botulinum toxin has also been used in voice tremor.[88],[89],[90],[91] A study by Charles et al., documented benefit in all the 13 patients having voice tremor treated with type A toxin. The side effects included dysphagia and breathlessness, which were maximum at week 2 with improvement by week 6 in all but one patient.[92]

Parkinson's disease

Botulinum toxin has been used for several manifestations related to Parkinson's disease (PD) including apraxia of eyelid opening, blepharospasm, sialorrheoa, hyperhidrosis, cervical dystonia, truncal dystonia including camptocormia and Pisa syndrome, limb dystonias, freezing, levodopa induced dyskinesias, constipation and urinary problems.[93],[94],[95]

Apraxia of eyelid opening with blepharospasm in PD patients responds well to botulinum toxin injections that are administered at the junction of pretarsal and preseptal portions of the orbicularis oculi.[96],[97] Other forms of focal dystonia like foot dystonia seen in young onset PD, or the OFF-period dystonia have also been treated with botulinum toxin injection.[98] In a study by Pachetti et al., 30 patients with PD were injected with onabotulinumtoxinA in a dose of 40 U into different foot muscles including the tibialis posterior, tibialis anterior, gastrocnemius, flexor digitorum longus, and extensor halluces longus, and nearly 66% of the patients were pain free at 4 months with improvement seen in the dystonic spasms as well.[99] The toxin has also been tried with promising results in the ON- period dystonia like blepharospasm, jaw-closing dystonia, cervical dystonia and other predictable phenomena.[96],[98]

Sialorrheoa is commonly seen in PD patients and indicates excessive salivation occurring secondary to an increased salivary flow (due to impaired parasympathetic control), inability to hold secretions due to hypomimia and forward flexion of the neck, impaired clearance due to lingual bradykinesia, oropharyngeal dysphagia and upper oesophageal dysmotility.[100] Botulinum toxin injection can relieve salivation by inhibition of the acetylcholine release.[101] The surface landmark for injecting the toxin into the parotid area is the mid-point of line joining tragus and angle of mandible, whereas for the submandibular region, it is one fingerbreadth medial to the midpoint of the line joining the angle of mandible to the chin.[100] Injecting botulinum toxin under ultrasound guidance may be beneficial, but the data is not sufficient to recommend its routine use.[102],[103] Two serotypes, type A and type B, have been studied in PD patients with sialorrheoa. Injections are delivered into the parotid and submandibular glands with doses of onabotulinumtoxinA ranging from 5 to 50 U and 5 U per parotid and submandibular gland, respectively. In different studies, injection abobotulinumtoxinA, with its doses ranging from 75 to 146.2 units, and 78.7 units per parotid and submandibular gland, respectively, significantly reduced sialorrheoa in patients with PD. RimabotulinumtoxinB injection has also been used in doses ranging from 500 to 2000 units and 250 units per parotid and submandibular gland, respectively. Many studies have showed the efficacy of botulinum toxin in sialorrheoa, and one study by Guidubaldi et al., compared the two types of toxins (A and B), but reported no significant difference in the beneficial effects produced by them.[104] The most common adverse effect after botulinum toxin injection in PD patients with drooling is dryness of mouth, which is usually mild and is seen more commonly with type B toxin injection.[105],[106],[107],[108],[109],[110],[111],[112],[113],[114],[115],[116]

Hyperhydrosis has been reported in 65% of patients with PD; and, the use of botulinum toxin for the treatment of axillary hyperhidrosis has a level A recommendation. Thus, the toxin may be used for treating axillary hyperhidrosis in patients with PD, although no randomised trials have been conducted to confirm this fact.[93],[117]

Camptocormia is defined as an axial deformity, comprising 45 degree of forward flexion, which reverses on sitting, lying down, walking with support and standing against a wall. In patients with PD, camptocormia has been reported in 4.1 to 17.8% patients. It is postulated to be either a form of focal dystonia affecting the paraspinal musces; or, a paraspinal myopathy considered secondary to the disease pathophysiology and sometimes also secondary to dopaminergic drugs used to treat the disease.[118] Thus, botulinum toxin injections in the paraspinal muscles can probably help to alleviate these symptoms.[118] Studies related to this use of the toxin are too few and have recruited less patients to provide any conclusive evidence related to this stated benefit of the toxin. The muscles usually injected are the rectus abdominis, iliopsoas, and external and internal obliques. Only one study by Jankovic et al., has shown improvement in 50% of the patients treated with abobotulinumtoxinA (150-400 U per site injection), whereas studies by Van Coelln et al., Colosimo et al., and Fietzek et al., did not show any significant improvement in symptoms.[119],[120],[121],[122] In another study, Naumann and colleagues injected botulinum toxin into the paraspinal muscles between the lumbar L2 to L5 levels in 6 patients with PD and reported a good response to the toxin given.[123] Marvulli et al., injected incobotulinumtoxinA (100 U) in the paraspinal muscles of 10 PD patients with Pisa syndrome and found it to be effective with improvement evident on the goniometric grading and the visual analogue scale (VAS) score.[124] The injected muscles were the paraspinal muscles, quadratus lumborum and abdominal obliques. The injection was administered about 2 to 2.5 cm lateral to the midline between the T10 to L3 level.[125]

Freezing of gait is described as interruptions in the gait occurring secondary to lower limb dystonia and its prevalence in PD ranges from 20 to 60%. It is usually seen to occur in the OFF periods and responds well to increasing the dose of levodopa, but the ON period dystonias and freezing of gait are usually resistant to dopaminergic drugs. Botulinum toxin is an alternative that can be used in these patients, but studies have not shown a consistent benefit.[126] In one study, Wieler and colleagues used type A botulinum toxin in 12 PD patients with none showing improvement in their freezing of gait; however, their leg dystonia improved. They were injected at six sites in the gastrocnemius and soleus muscles with 200 to 300 U of onabotulinumtoxinA. There were no prolonged adverse events, but one of them reported that his legs felt like jelly one week post injection.[127] Fernandez et al., used type B botulinum toxin to treat freezing of gait in patients with PD. Only one patient showed some improvement out of the 9 patients participating in the study.[128] Another study by Giladi et al., reported marked improvement in 40% of the patients with PD manifesting with freezing of gait after being injected with type A botulinum toxin.[129] On the contrary, Gurevich et al., did not demonstrate any improvement with type A botulinum toxin in freezing of gait.[130]

The role of botulinum toxin was examined in small cohorts of tremor-predominant PD patients. There was a modest but non-significant improvement in these patients but the side effects of finger muscle weakness dampened the enthusiasm to popularise the use of toxin.[86],[87],[131],[132] Based on these small number of studies, it is difficult to draw a conclusion about the efficacy of botulinum toxin in the treatment of PD patients with focal arm tremor. Jaw tremor in PD patients causes embarrassment and may not respond to the conventional treatment. In a pilot study, botulinum toxin injection into each masseter muscle effectively improved the jaw tremor.[133]

Urinary problems are present in around 35% of patients with PD. Those patients, who are poorly responding to pharmacotherapy can be injected with botulinum toxin. The detrusor overactivity can be reduced for five to nine months after the injection, as has been demonstrated in a number of studies.[134],[135],[136],[137] Transient urinary retention was an adverse effect observed in these patients after the toxin had been injected. Constipation is another disabling non-motor symptom where botulinum toxin has been tried in randomised controlled studies. The toxin was found to reduce the tone of pubo-rectalis muscle leading to improvement in symptoms.[138],[139]

Pain is also an under-recognised non-motor symptom amounting to disability in about 40% patients suffering from PD. In a study by Bruno et al., onabotulinumtoxinA was effective in alleviating pain in these patients.[140]

Tics

Injection botulinum toxin has level C recommendation for use in patients with tics. There is only one randomized controlled study by Marras et al., which has been shown to reduce motor tics in terms of the number and severity of tics, as well as the premonitory urge, with the use of botulinum toxin injections.[141] In 2000, Kwak and his colleagues published a study, which included 35 patients suffering from Tourette's syndrome [TS] (30 male and 5 female patients). 29 of them experienced improvement in their tics following botulinum toxin injection and 23 had marked relief in their premonitory urge.[142] Injection botulinum toxin has also been used in patients with vocal tics. In 2004, Porta and colleagues assessed the effect of onabotulinumtoxinA in 30 patients with TS. The vocal tics improved in 93% of these patients and the mean duration of response was for 102 days.[143]

Based on the current evidence, injection botulinum toxin may be helpful in treating focal motor tics and the effect is more rewarding in patients having dystonic tics.[144]


 » Conclusion Top


Botulinum toxin injection is an effective modality of treatment for treating patients with movement disorders. Although considered safe, there are still many limitations, such as a short duration of response and a high cost. Movement disorder neurologists should try to optimize the benefits and reduce the risk of adverse effects that are observed at each treatment visit. The efficacy of botulinum toxin treatment depends upon the appropriate dosage administered, the proper selection and identification of muscles; and, realistic expectations from the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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