Dalfampridine (Ampyra®) was approved in 2010 for the improvement of walking ability. It is a nonspecific potassium channel blocker that is thought to improve conduction in focally demyelinated axons by delaying repolarization and prolonging duration of action potentials. Enhanced neuronal conduction is thought to strengthen skeletal muscle fiber twitch activity, resulting in improved motor function [168-170].

Spasticity continues to be a major problem in MS patients [2]. Diazepam (Valium®) was the first drug to be proven to reduce spasticity in MS, and it continues to be a very helpful drug. The use of single oral dose of 5 mg at bedtime is convenient and cost-effective treatment in a large proportion of patients with mild- to-moderate spasticity. Occasionally, a small additional dose can be added in the morning, but the long half-life of the drug usually makes that unnecessary or undesirable. Baclofen (Lioresal®) is an important and useful drug that is less frequently associated with sedation than diazepam, even at high doses. The oral form of the drug, which is a racemic mixture, does not seem to have a predictable dose response in many patients, however. In contrast, those patients with severe refractory spasticity predictably respond to intrathecal baclofen [171]. This, in part, reflects the addition of l-baclofen to the racemic forms of baclofen for intrathecal use. Use of the intrathecal drug requires the implantation of a pump to deliver the drug, however [171]. Tizanidine (Zanaflex®), an alpha-2-adrenergic agonist, has good dose- response characteristics [122]. On the negative side, tizanidine has a short half-life and 40% of patients experience prominent fatigue and dry mouth as side effects. In some patients use of tizanidine avoids the necessity of pump implantation and therefore is a welcome alternative [172]. Hopefully, in the future an oral formulation of

l-baclofen will advance to phase III studies and become a clinical option.

Bladder dysfunction occurs in the majority of patients, largely due to hyperre- flexia of the detrusor muscle. However, dyssynergia accompanies this in 90% of cases. Managing urinary frequency is usually attempted with the use of low doses of anticholinergic and oral baclofen, but is often unsatisfactory. Often a single dosage of an anticholinergic drug before retiring at night and prior to occasional social outings is more satisfactory than a multiple doses. Incomplete emptying is usually best handed by intermittent catheterization. The management of infections is very important. Avoidance of antibiotics for unproven infections, and obtaining bacterial sensitivities for each infection, is crucial to avoid pseudomonas infections. Often chronic use of oral ascorbic acid 2-4 g daily with hippuric acid 2 g daily to acidify the urine together with six to eight glasses of water successfully prevents recurrent infections. Mirabegron (Myrbetriq®) is a remarkable new adrenergic drug for hyperreflexic bladder with incontinence [173].

More extensively studied in spinal cord injury, botulinum toxin A has recently been approved as an effective alternative for uncontrolled neurogenic detrusor overactivity resulting in incontinence in patients with MS [174, 175]. It is clear that good bladder management significantly contributes to quality of life [176].

Management of the paroxysmal disorders is relatively simple in most patients once they are recognized and identified by physicians [2]. Paroxysmal dystonia (or tonic spasms), paroxysmal akinesia, trigeminal neuralgia, facial myokymia, and hemifacial spasm are often successfully managed with modest doses of anticonvulsant drugs. However, the response in patients with paroxysmal dysarthria tends is less predictable. For patients requiring treatment, carbamazepine in doses of 100 mg orally three times daily controls about 70% of these disorders and 400 mg daily increases the response rate to 80-85%. Higher doses sometimes are helpful but the addition of a second anticonvulsant is often more effective. Some patients require two or more drugs, including gabapentin and topiramate, to control these symptoms, but often carbamazepine can be withdrawn if the second drug is effective [177]. The use of corticotrophin (ACTH) intravenously or intramuscularly, but not steroids, is sometimes necessary to gain control of the situation [178].

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