Introduction

Multiple sclerosis (MS) is one of the most common neurological disorders of young adults with 149 out of 100.000 Germans being affected [28]. This equals about 2.5 million MS patients worldwide [41]. MS can affect not only the central nervous system white matter, but also its grey matter. It can, therefore, produce a wide range of motor disorders, reaching from paresis to apraxia or fatigue. Spasticity may be one of them. Around two-third of MS patients are suffering from spasticity [47]. Almost half of them are rating their spasticity as moderate or severe [47]. Conventional treatment of spasticity includes baclofen, tizanidine, diazepam and dantrolene as oral drugs [5]. Continuous intrathecal baclofen application through implanted pumps can be helpful for severe spasticity, especially in the legs [20]. Peripheral surgery is reserved for few special cases. Intramuscular phenol injections are only rarely performed. Botulinum toxin (BT) was originally introduced in the early 1980s as a compound reducing various muscle hyperactivity syndromes. Later on it was also used to reduce hyperactivity of exocrine glands and, most recently, to reduce migraine pain. Other pain conditions are under investigation. Spasticity has long been one of the main muscle hyperactivity syndromes treated with BT [19].

When spasticity is caused by stroke, a large body of literature supports the use of BT [60]. Subsequently, formal registrations for the use of BT to treat stroke spasticity have been granted by the regulatory authorities in most major countries and robust sales figures indicate BT’s actual use for this indication. When spasticity, however, is caused by MS, the literature is scarce, formal registrations are usually lacking and the actual clinical potential seems underused. Therefore, IAB-Interdisciplinary Working Group for Movement Disorders [1] formed a task force to explore the use of BT for treatment of MS spasticity.

Methods

Literature search

The literature search was performed on PubMed (National Center of Biomedical Information, United States National Library, Medicine and National Institutes of Health). Search date was July 19th, 2016. The search included all references published up to this point of time. The search was performed along three axes with the following search words:

Axis 1 Botulinum toxin, botulinum neurotoxin, onabotulinumtoxinA, incobotulinumtoxinA, abobotulinumtoxinA, rimabotulinumtoxinB.

Axis 2 Multiple sclerosis, encephalomyelitis disseminata, MS.

Axis 3 Spasticity.

All publications retrieved had to contain at least one item on each axis. There were no exclusion criteria. The retrieved publications were classified according to the following categories: Randomised Controlled Trial, Interventional Study, Observational Study, Case Study, Review and Guideline.

Results

Literature search

The literature search produced 55 publications containing the above-mentioned search words. Table 1 gives an overview about the retrieved publications.

Table 1 Number of studies retrieved from PubMed for the current literature search
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Randomised controlled trials

Three of the publications were Randomised Controlled Trials. They are shown in Table 2. Snow et al. [62] was the first article published. The authors demonstrated that Botox® reduces MS hip-adductor spasticity as measured by the Ashworth scale and improves hygiene as measured by a hygiene scale [62]. Gradzko et al. demonstrated Botox® induced reduction of MS arm and leg spasticity as measured by the Ashworth Scale. Additionally, they detected reduction of Parkinson’s disease rigidity as measured by the United Parkinson’s Disease Rating Scale [25]. Hyman et al., again, demonstrated reduction of MS hip-adductor spasticity as measured by knee distance, pain score, hygiene score and spasm frequency score. There was no clear dose effect correlation [29].

Table 2 Randomised controlled trials retrieved from PubMed for the current literature search
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Interventional studies

Three publications retrieved were Interventional Studies. They are shown in Table 3. Giovannelli et al. demonstrated that BT therapy alone improves MS spasticity as compared to a control group. Further improvement, however, is seen when BT therapy is combined with physiotherapy [23]. Barnes et al. could not detect an effect of different Xeomin® dilutions on upper limb spasticity of various aetiologies. Only 2 of their 192 patients suffered from MS [4]. Paolini et al. found that BT therapy as well as vibration may improve spasticity in MS [48].

Table 3 Interventional Studies retrieved from PubMed for the current literature search
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Observational studies

Eleven publications were Observational Studies. They are shown in Table 4. Most studies were on spasticity of different aetiologies including MS. Eight studies demonstrated spasticity improvement after BT therapy usually documented by Ashworth scale often complimented by visual analogue scales, spasm frequency scores, pain scores, or hygiene scores or singular functional tests [8, 14, 33, 35, 46, 54, 63, 64]. Two studies pursued other goals. One study demonstrated that the Barthel index does not correlate with spasticity improvement [16]. Another study showed that BT total doses are different in spasticity of different aetiologies [49]. Highest doses were necessary in MS, lower ones in cerebral palsy and stroke.

Table 4 Observational Studies retrieved from PubMed for the current literature search
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Case studies

Two publications were Case Studies. Sławek et al. described a patient with paraspasticity successfully treated with BT. After disease progression to tetraspasticity therapy was intensified to intrathecal baclofen with favourable result [61]. Daelen et al. described a patient with severe tetraspasticity and bruxism successfully treated with BT in the M. masseter bilaterally [15].

Reviews

Thirty-five publications were Reviews. They are summarized in Table 5. Four Reviews were dealing with general treatment of MS and mentioned BT as a spasticity treatment [42–44]. Five Reviews were dealing with treatment of MS spasticity and mentioned BT as one treatment option [5, 27, 55–57]. Two Reviews were dealing with symptomatic treatment of MS and mentioned BT as a spasticity treatment [38, 50]. One Review was dealing with BT and MS [36], 1 with MS and spasticity mentioning BT as a spasticity treatment [9]. Three Reviews were dealing with treatment of spasticity and mentioned BT as a treatment of MS spasticity [12, 34, 51]. Five Reviews were dealing with BT for symptomatic treatment of MS and mentioned BT as a treatment option for spasticity [11, 26, 30, 31, 67]. Most of those sReviews also discussed other uses of BT in MS patients including treatment of hypersalivation, hyperhidrosis, bladder dysfunction, eye motility disorders, tremor and proctologic conditions. Fourteen Reviews were dealing with BT for spasticity treatment and mentioned BT as a treatment option in MS spasticity [2, 6, 7, 10, 22, 32, 39, 40, 45, 58, 59, 65, 66, 68].

Table 5 Reviews retrieved from PubMed for the current literature search
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Guidelines

One publication was a Guideline based on recommendations from committees of the Spanish Society of Neurology and the German Neurological Society [24]. In this publication BT was mentioned as a potential treatment for MS spasticity in selected cases.

Discussion

Spasticity in MS

74% of all MS patients complain of spasticity; 47% present with spasticity with an Ashworth Score ≥2 3. 10% of all MS patients are estimated to be candidates for BT therapy [3]. Spasticity in MS, therefore, is a highly relevant symptom of MS.

Conventional treatment of MS spasticity

Due to the high prevalence of spasticity in MS a considerable number of antispastic therapies emerged over the years including oral baclofen, tizadinine, benzodiazepam/clonazepam, dantrolene, gabapentine, clonidine, intrathecal baclofen and, most recently, cannabidiol/tetrahydrocannabinol (nabiximols, Sativex®). Adjuvant treatments include orthopaedic surgery, physiotherapy, occupational therapy and other physical therapies. Despite the number of conventional treatment options for MS spasticity, treatment effects are often only mild and treatment of more severe forms remains a challenge.

Principal suitability of BT therapy for MS spasticity

Classically, spasticity is defined as ‘a motor disorder characterised by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex as one component of the upper motor neuron syndrome’ [37]. This definition has its merits in neurophysiological discussions. However, it describes only one of the many motor phenomena occurring when supranuclear motor system lesions occur. This was the reason why a broader definition was introduced recently [17]. The spastic syndrome is now defined as a combination of central paresis and various forms of muscle hyperactivity including spasticity as such, dystonia, rigidity and spasms [17]. All of those muscle hyperactivities are responsive to BT therapy. The element with least clinical relevance is probably spasticity in its original definition. It may, as a matter of fact, even be considered an examination artefact.

Treating spastic syndromes, it has to be taken into account that muscle hyperactivity may have positive functional aspects, such as stabilising paretic limbs, and that treating muscle hyperactivity does not improve co-existing paresis. Treating spastic syndromes with BT has a time window: When in the further course of the disease contractures arise, spastic postures turn fixed and BT therapy becomes ineffective. Timely treatment, therefore, is encouraged [52].

BT’s mode of action is based upon the blockade of the cholinergic neuromuscular synapse [18]. Additional effects on muscle spindles are discussed [53]. Transsynaptic spinal transport of active BT has not been demonstrated so far. BT’s action on increased alpha-motoneuron activity should therefore be independent from the kind of supraspinal excitation, be it dystonic or spastic in origin. It should also be independent from the level of supranuclear lesion, be it spinal or supraspinal. Therefore, BT efficacy should not be affected by the kind of supraspinal excitation (dystonic, spastic, tremor, etc.) nor by the localisation of the lesion (spinal, supraspinal), let alone the underlying pathological process (ischemic, traumatic, encephalitic). Altogether, there is no reason why BT should not act upon MS spasticity in a similar way as it is acting upon stroke spasticity.

BT therapy for MS spasticity/literature search

BT has long been used in symptomatic treatment of MS and spasticity has been the earliest, largest and best documented indication. Other muscle hyperactivity phenomena have been tried including tremor, ataxia, myokymia, nystagmus, internuclear ophthalmoplegia and dysphagia, however, so far with ambiguous results. Various forms of bladder dysfunction affecting the detrusor vesicae, the sphincter internus and the sphincter externus have recently been investigated. With robust positive effects, several of these conditions have become licenced indications. Experimentally, various MS-associated pain syndromes have also been treated with BT.

Our literature search produced a robust body of studies on the use of BT in MS spasticity. All 3 Randomised Controlled Trials [25, 29, 62] and all 3 Interventional Studies [4, 23, 48] demonstrated the efficacy of BT to treat hip, arm and leg spasticity in MS. Additional physiotherapy may be helpful. All 11 Observational Studies [8, 13, 14, 16, 33, 35, 46, 49, 54, 63, 64] and all 2 Case Studies confirmed these results [15, 61]. All 35 Reviews dealing with different aspects of MS stated a principal suitability of BT for treatment of MS spasticity.

Altogether, the literature on BT therapy for MS spasticity is scarcer than that on stroke spasticity. The study quality is similar although large registration studies are missing in MS spasticity. All publications unanimously favour the use of BT therapy for MS spasticity. One guideline includes BT therapy as one of the treatment options for MS spasticity [24].

Current situation of BT therapy for MS spasticity

There is no robust published data on the extent of clinical use of BT therapy, neither for MS spasticity, nor for stroke spasticity. Internal data of the BT manufacturers may exist in stroke spasticity; in the off-label use of MS spasticity they would be extremely vague. Regional differences of BT use for spasticity are considerable [21]. The limited number of publications and overall sales figures of BT drugs together with the general feeling that MS spasticity is underrepresented in our BT clinics suggests an under-use of this treatment option.

Causes for the current situation may be manifold. (1) The current prevalence of MS spasticity may be lower than suggested by prevalence data not adapted to the recent improvements in neuromodulatory therapies. (2) Prevalence figures on MS spasticity may erroneously include motor dysfunction unresponsive to BT such as apraxia, ataxia and fatigue. (3) In most countries use of BT therapy is closely linked to the drug’s registration status as only full formal registration for a specified indication guarantees reimbursement by the insurance systems. So far, BT therapy for spasticity is not a registered indication in most countries. Only very recently, registration of BT therapy for spasticity is considered by few registration authorities without restricting the underlying aetiology to stroke only. BT’s high cost reimbursement and registration restrictions are an issue and probably the major obstacle to use BT therapy for MS spasticity.

Unaddressed issues

As large double-stranded protein BT drugs are antigenic. With this they could interfere with the MS relapse frequency. Conversely, increased immunological activity in MS patients could increase the risk of BT antibody formation. Both aspects have not been studied so far.

Recommendations

As an initial step, formal studies should provide exact data on the current prevalence of MS spasticity and its clinical features according to the classification used in movement disorders. In parallel, immunological long-term data on MS patients already treated should be analysed with respect to MS relapse frequency and frequency of BT antibody formation. With this, registration authorities should consider expansion of the current registration status of BT drugs for spasticity to aetiologies other than stroke. Alternatively, specific registration studies should be initiated by the BT manufacturers to limit the off-label problem. Attempts to expand registrations to include MS spasticity are currently under way. MS specialists should consider BT therapy for symptomatic treatment of spasticity.