**6.1 Pharmacological treatment**

Pharmacological treatment for cerebellar ataxia also remains challenging. Case report studies and small studies offer little support for certain treatments. Although recommendations are difficult to make for the treatment of ataxia and tremor, a variety of medications have been shown to have advantages in small open-label studies or case reports. Several treatments have been used including propranolol [78], isoniazid [76, 77], topiramate [79], carbamazepine [80], clonazepam, and levetiracetam [81] and reported only little success [10]. In a small pilot research involving 14 MS patients, levetiracetam was also found to dramatically lessen tremor and ataxia [82]. Moreover, topiramate has shown significant functional improvement in a sustained, dose-dependent manner [79]. Additionally, fingolimod may have added benefits in MS patients with ataxia [75]. Other drugs tested including glutethimide [83], cannabinoids [84], and dolasetron mesylate [85]. Cannabis extracts have been the subject of several randomized controlled trials, and the results have shown that cannabinoids do not seem to reduce MS tremor [84, 86, 87]. There is some evidence that paroxysmal ataxia and dysarthria may respond to carbamazepine in a manner comparable to other paroxysmal symptoms of MS, such as tonic spasm [88].

Although isoniazid, propranolol, and levetiracetam have been investigated, the findings are inconclusive, and these drugs are not frequently used (the patients included in these trials were typically very small, allowing for few generalizations) [76, 78, 81, 89–91]. Whereas, isoniazide in high doses, carbamazepine, propranolol,


### **Table 4.**

*Treatment modalities and options for the ataxia of multiple sclerosis (MS) patients.*

### *Ataxia in Multiple Sclerosis: From Current Understanding to Therapy DOI: http://dx.doi.org/10.5772/intechopen.112013*

glutethimide, 4-aminopyridine, and topiramate have been reported to provide some benefit in the treatment of ataxia and tremor [20, 79, 92]. As ataxia constitutes a difficult symptom to treat, medications like isoniazid and carbamezepine must be used in high amounts for the treatment to be effective. Since these medications have hepatotoxic effects, many patients are unable to receive the maximum dosage, which limits their ability to be used for extended periods of time [7]. Indeed, pharmacological approaches used to improve ataxic symptoms are generally disappointing, necessitating the need for innovative treatments. In a meta-analysis study performed by Mills et al. [70], the authors have reviewed six randomized placebo-controlled trials (pharmacotherapy) of treatments for ataxia in MS. They concluded that there is insufficient information regarding absolute and comparative efficacy and tolerability of pharmacotherapies [70]. As a result, no recommendations could be given to guide in prescribing these medications [70].

It is worth mentioning that a patient-centered strategy is critical to the efficacy of pharmacological treatment, which is a crucial part of managing MS symptoms. To maximize compliance, particularly with invasive interventions, doctors must properly inform patients, discuss their priorities and expectations, and assist them in making the right treatment decisions [11]. With oral medications, the first dose should be low and gradually increased based on response and tolerability. If one medication is insufficient due to its ineffectiveness or unacceptable side effects, it is advised to combine several medications—possibly at lower doses [11].

### **6.2 Surgical interventions**

Tremors can be both kinetic and postural, and they can be very challenging to manage. In case of tremor resistance to treatment, thalamotomy or thalamic stimulation has been tried to some degree of success [93]. Carefully selected patients with localized tremor with minimum disability could benefit from stereotactic thalamotomy, which targets the nucleus ventralis lateralis and nucleus ventralis intermedius, or DBS, which targets the nuclei ventralis lateralis and nucleus ventralis intermedius, ventralis oralis posterior nucleus, and zona incerta [94–96]. Tremor was abolished by both thalamotomy and thalamic stimulation in all patients immediately postsurgery [97]. However, tremor returned in almost all MS patients after 6 months, albeit of less severity than preoperative levels. Stereotactic thalamotomy seems to be more effective for intractable tremor, but the consequent functional improvement is variable and the intervention is associated with a higher risk of neurological deficit [11].

It is believed that distal tremor with good proximal stability and limb function are particularly responsive to DBS [11]. Successful alleviation of tremor in patients with MS has been achieved using DBS of the ventralis intermedius (VIM) thalamic nucleus [98]. Indeed, DBS is likely to improve tremor, but the effect might be reduced over time. Functional improvement is more often reported after DBS than after stereotactic thalamotomy, and DBS can be better tolerated. It has been reported that both procedures initially suppressed tremor in over 90% of patients, although functional improvement was seen only in 47.8% of those who underwent thalamotomy as opposed to 85.2% of those who had DBS [99]. However, the choice between interventions should be made on an individual basis in consultation with the specialist neurosurgical team [11], and larger trials that compare these two interventions and assess the efficacy are needed.

### **6.3 Rehabilitation approaches**

Beyond pharmacological and surgical approaches, many physiotherapy approaches are used in balance therapy and tremor. Physiotherapy, orthoses, and limb cooling may be beneficial [20]. Indeed, in MS, rehabilitation programs may be helpful to enhance core stability in individuals with balance issues, lumbar stabilization exercises that strengthen the core trunk muscles and have an impact on postural control, ambulation, and skilled motor function [100]. A systemic review of trials with physical therapies showed some beneficial effect [101]. Additionally, Armutlu et al. [72] reported that physiotherapy approaches were effective to decrease the ataxia [7]. There is some evidence, according to a systematic review of research looking into the benefits of treadmill or robot-assisted training, that people with severe disabilities can see improvements in their quality of life and gait [102]. Two of the eight studies that were considered were modest singlegroup studies that only included individuals with progressing MS in their sample [103, 104]. Using weights and heavy walkers may decrease ataxic movements; however, they may increase fatigue [7, 105–107]. Patients with MS who were randomly assigned to physiotherapy showed improved scores on the Expanded Disability Status Scale (EDSS) and the Rivermead Mobility Index [7, 108]. An improvement in the Rivermead Mobility Index was seen in a different study on 42 randomly selected patients when home and outpatient therapy groups were compared to no therapy. However, mobility returned to pretreatment levels after 2 months of follow-up [109]. In MS patients, balance-based torso-weighting has been shown to improve cerebellar ataxia patients [110]. In 45 ataxic relapsing–remitting MS patients, the addition of core stability exercises and task-oriented training to typical balance training was found to potentially enhance stability [111]. Similar to this, task-oriented training and lumbar stabilization enhanced the efficacy of balance therapy in a group of 42 MS patients [74], exhibiting a considerable improvement in the International Cooperative Ataxia Rating Scale and composite balance scores. As measured by the International Cooperative Ataxia Rating Scale, the Mini-Balance Evaluation Systems Test, the smoothness of movement on both sides in a 5-m walk, and balance in a step-to-stand task before and after the intervention, a targeted ballet program aimed at reducing MS-associated ataxia and improving balance in women demonstrated significant clinical improvement [112]. These studies collectively demonstrate the positive effects of physiotherapy in MS-related ataxia [75]. In another study, it was determined that physiotherapy approaches were effective to decrease ataxia and that the combination of suitable physiotherapy techniques is effective in MS rehabilitation [7]. Even though physiotherapy has been shown to improve function in ataxia modestly, its long-term benefits in MS patients remain unclear.

Following task-specific rehabilitation, neural plasticity is enhanced [113, 114]. Thus, it is believed that balance and mobility interventions offer the proper taskspecific stimuli to promote neural reorganization of central sensory integration, resulting in improved stability [6]. Despite the fact that neuroplasticity and motor learning are commonly considered to be more beneficial in the initial stages of MS, they seem to remain even in those with more severe disability [114]. Future research should establish whether or not those with progressive MS, and at different levels of disability, respond differently to these interventions, and if so whether and when interventions should be refocused on compensatory rather than restorative strategies.
