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Spasticity and walking impairment in MS

Thomas Berger MD MSc
16 May, 2016  

Current drug developments add to improvements of multiple sclerosis-related symptoms and symptom-related burden of disease

Thomas Berger MD MSc 
Clinical Department of Neurology 
Medical University of Innsbruck 
Innsbruck, Austria
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS) in young adults with a prevalence of 120 per 100,000.1 Relapsing-remitting MS (RRMS) is characterised by an individual frequency of relapses followed by complete or incomplete remissions bearing the risk of conversion to secondary progressive MS (SPMS). SPMS and primary progressive MS (PPMS), which indicates disease progression without any relapses from MS onset, are both the most common cause of accumulating, permanent, debilitating and irreversible neurological disability in young adults. 
Disability may affect different CNS functional domains, including vision, coordination, bladder and sexual function, mobility, mood and cognition.1 One of the hallmarks of MS is walking impairment, which affects up to 90% of patients as the disease progresses.2 Leg weakness, spasticity, lack of balance and coordination, slowness of movement, and impaired sensory function contribute to walking impairment in MS.
Spasticity is part of the upper motor neuron syndrome, which includes hyperreflexia, increased muscle tone, loss of dexterity and leads to fatiguability, painful muscle spasms, bladder dysfunction, sleeping disturbances, abnormal posture, limitations in the range of movement, contractures, joint deformities and pressure sores. Thus, spasticity is the major contributor to walking impairment in MS and affects 40–60% of MS patients during their lifetime disease course.3
Walking is the most highly valued functional domain in patients with MS.4 Loss of walking abilities, often followed by wheelchair dependence usually leads to impaired social participation, restrictions in performing activities of daily living, and the need for informal and formal care.3,5
Walking impairments therefore dramatically impact health-related quality of life (HRQoL) and the ability to work. Reduced HRQoL, productivity and employment are suggested to be the greatest contributors to the socio-economic burden of MS patients and their caregivers.6
Therefore, patients with MS have identified maintenance of mobility as a priority and it is ranked as the most important of thirteen bodily functions across all stages of the disease.4
Despite the enormous therapeutic merits of an expanding armamentarium of immunomodulatory or immunosuppressive disease-modifying therapies aiming to reduce relapse rates and to delay disease progression in RRMS, symptomatic treatments – with the explicit therapeutic goal to improve existing neurological symptoms and, in consequence, to reduce disability and impairment – are generally underestimated in terms of medical and non-medicinal treatment innovations, clinical trials, prescription rates and reimbursements. Therefore, they often escape physicians’ attention as an important need of their patients.
However, recent drug approvals enable to focus now much more (again) on symptomatic drug treatment of MS patients, based on the evidence of appropriate clinical trials. 
Treatment of spasticity
The range of treatments for spasticity in MS in clinical practice includes non-medicinal therapies, such as in- and outpatient neurorehabilitation, and drug treatments (Table 1) in a complementary and multimodal approach.3 General treatment goals for improvement of spasticity are shown in Table 2.
Oral baclofen or tizanidine are commonly used as antispasticity drugs and anticonvulsants, such as carbamazepine, gabapentin or lamotrigine, for relief of spasticity related pain. However, formal clinical trial evidence is not established for treatment effects of these medications.7 Systemic reviews and meta-analyses concluded that the overall benefits of these mentioned drugs are small, tolerability has restricted their potential and more effective treatments are needed. 
Local botulinum-A toxin injections have been used for focal spasticity8 and in March 2010, the United States Food and Drug Administration approved a botulinum-A toxin for focal upper limb spasticity in disorders including MS. The use of botulinum-A toxin treatment should be the preserve of specialists.   
As compared to the majority of commonly used antispasticity drugs, cannabinoids demonstrated clinical efficacy in MS patients with spasticity and related pain.9 In addition, safety and tolerability was favourable for different cannabinoid compounds, such as nabilone (a benzopyran derivate synthetic cannabinoid, Cesamet®, Canemes®) and tetrahydrocannabinol (THC)/cannabidiol (CBD) (Sativex®). 
The cannabinoid type I receptor is the most abundant G protein-coupled receptor within the adult nervous system and functions as a regulator of synaptic neurotransmission. This is consistent with the capacity of (synthetic) cannabinoids to control, among other neurological symptoms, spasticity and pain.9
The clinical efficacy and safety of Sativex® was studied in several Phase II and III, randomised, controlled clinical trials.10 The results across these trials demonstrated significant improvements of spasticity (and related symptoms) as measured by the ‘Numerical Rating Scale’. The safety profile of Sativex® was favourable: mild to moderate dizziness and fatigue may occur transiently during the first weeks of treatment and are diminished by stepwise drug dose increases over the first 14 days. Sativex® does not exhibit psychoactive or tolerance effects. In addition, there are no reports of drug abuse or addictive potential.10
Since March 2011 Sativex® has been approved as oromucosal spray containing 2.7mg THC and 2.5mg CBD in several European countries as “add-on treatment for patients with moderate to severe spasticity due to MS who have not adequately responded to other antispasticity medications and who have demonstrated a clinically significant improvement in symptoms related to spasticity during an initial treatment period”. Although available, accessibility of Sativex® for patients is currently still limited due to ongoing reimbursement negotiations in several European countries.
Treatment of walking impairment
In the past, the symptomatic management of walking impairment in patients with MS relied on strategies adapted from other conditions and indications. Historically, no drug therapy was available to achieve functional improvements in walking overall. Non-medicinal neurorehabilitation approaches such as physiotherapy, hippotherapy and balance training are utilised in an attempt to achieve functional improvements.3
Hence, it is important to recognise that many complex interrelating factors are required for walking, such as sensory inputs, including visual control and balance, together with coordination and motor control. Walking impairment may occur due to the disruption of one or more of these factors, making it a challenging and often difficult symptom to treat effectively. 
For example, lower limb power, fatigue, balance, balance confidence, fear of falling are significant independent determinants of walking speed, endurance and distance in patients with MS. Patients perceive limited walking speed as an increase of disability.4 Thus again, a multimodular approach is warranted in MS patients with walking impairment (Table 3). 
Based on the long known effects of immediate release, 4-aminopyridine (4-AP) as a voltage-dependent potassium channel blocker an oral compound with prolonged release (PR), fampridine (Fampyra®), was developed to improve pharmacokinetics and to reduce the side effects associated with immediate release 4-AP.11 The mode of action of PR fampridine is believed to improve conduction velocity in inflammatory demyelinated axons by blocking expressed potassium channels.
Pooled analyses of two Phase III clinical trials of PR fampridine showed that 38% of PR fampridine-treated patients had consistently faster walking speed on the Timed-25-Foot-Walk (T25FW) compared with 9% of placebo-treated patients.11,12 Furthermore, improvement in walking speed in PR fampridine timed-walk responders was associated with improvement in patient-perceived walking ability on the 12-item MS Walking Scale (MSWS-12) and in leg muscle strength.11,12
Treatment benefits have been shown to be maintained in patients for up to 2.5 years in extension studies and in 3.5 years in open-label use,13,14 indicating the potential for prolonged duration of efficacy. Furthermore, a Phase IV trial has investigated the important relationship between response to PR fampridine and HRQoL. Based on the association between increased walking speed and increases in HRQoL, it is anticipated that PR fampridine therapy may help to improve HRQoL, enhance the undertaking of activities of daily living, and reduce healthcare costs. 
During the first weeks of PR fampridine treatment, dizziness and nausea may occur as adverse effects, which are usually mild to moderate and transient.11,12 Although the incidence of seizures in PR fampridine clinical trials was not different from incidence of seizures in MS population, PR fampridine is contraindicated in patients with a history of seizures or epilepsy due to its channel-blocking mechanism of action.11,12 Renal function should be known before initiation of therapy as even mild renal insufficiency represents a contraindication for use.11,12
In July 2011, oral PR fampridine 10mg twice-daily received conditional approval from the European Medicines Agency for the “improvement of walking in adult patients with MS with walking disability and an Expanded Disability Status Scale 4.0–7.0”. As such, it can be used in patients with all types of MS disease courses (RRMS, SPMS, PPMS) and concomitant to MS disease-modifying drugs. 
The European label requires that patients be reassessed for clinical benefit after two weeks of treatment initiation with PR fampridine. Due to the fact that ‘only’ approximately 40% of patients respond to treatment with PR fampridine, extensive subgroup analyses of clinical trials have been done to search for predictive factors for treatment response. 
However, no predictive factor could be identified so far, therefore, neurologists need to evaluate treatment response after two weeks in each individual patient at the clinical setting, primarily based on the patient (narrative) report.12 To quantify a patient’s report it is recommended to use in addition a patient self-reporting outcome assessment (such as the MSWS-12) and document a walking test (such as the T25FW test).12 The ease of application and the usefulness of such assessment tools to document sustained long-term clinical benefit of PR fampridine treatment has been shown for the daily clinical routine setting and illustrated by video examples.15
In summary, PR fampridine is the first medication with an indication for the improvement of walking in adult MS patients and, thus, represents an important treatment option for a substantial number of patients with MS. Although available, accessibility of Fampyra® for patients is also currently limited due to still ongoing reimbursement negotiations in several European countries.
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