Therapeutic Advances in Neurological Disorders

Multifocal motor neuropathy (MMN) is a rare and disabling disease. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis, although underlying mechanisms in MMN seem to be very specific, mainly because of the presence of IgM anti-GM1 serum antibodies and the dramatic response to intravenous immunoglobulins (IVIg). The origin of antiganglioside antibodies and the way in which they act at the molecular level remain unclear. Several studies have demonstrated the key role of complement activation in the underlying mechanisms of MMN, as well as in animal models of acute motor axonal neuropathy (AMAN). Deposition of the membrane attack complex may disrupt the architecture of the nodes of Ranvier and paranodal areas, causing local disruption of nodal sodium-channel clusters. In patients with MMN, muscle weakness is the consequence of conduction blocks (CB), which leads to secondary axonal degeneration, consequently the aim of the treatment is to reverse CB at early stages of the disease. High-dose immunoglobulin is to date the only therapy which has proven efficacy in MMN patients in providing transient improvement of muscle strength, but long-term follow-up studies show a progressive motor decline. Therefore, other therapies are needed to improve the conduction nerve properties in long-term design. The reduction of complement activation and more generally the gain in paranodal stabilization could be directions for future therapeutic strategies.

For decades, persons with multiple sclerosis (MS) were counseled to avoid excessive physical activity and exercise because of concerns about worsening disease activity. Recent studies indicate that, not only can those with MS tolerate physical exercise, but that it is helpful in managing symptoms, preventing complications and comorbidities, and may possibly have neuroprotective actions. This article reviews previous studies on the effects of different exercise protocols in people with MS, and provides summaries of suggested exercise regimens that may be appropriate and beneficial for this patient population.

Topiramate has been widely utilized worldwide as an effective medication against partial- and generalized-onset seizures. Extended-release topiramate was developed to provide patients with the convenience of once-daily dosing and potentially improved tolerability by reducing serum concentration fluctuation. USL255 is a once-daily, extended-release formulation of topiramate, which was recently approved in the USA. Compared with immediate-release topiramate taken twice daily, once-daily USL255 provides equivalent topiramate exposure with a 26% reduction in plasma fluctuations. A multinational, phase III, randomized, double-blind, placebo-controlled clinical trial in patients with refractory partial-onset seizures demonstrated that USL255 (200 mg/day) significantly improved seizure control and was well tolerated with low overall neuropsychiatric and neurocognitive adverse events.

More than 20 antiepileptic drugs (AEDs) are currently available for the medical treatment of epilepsies. However, still about 30% of all epilepsies have a drug-resistant course. Even worse, in the case of some epilepsy syndromes, freedom from seizures is almost never achieved. Therefore, new treatment options are still necessary, especially if theoretical concepts such as a new mode of action offer new horizons. Perampanel is the first-in-class orally active, selective, noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The pharmacokinetic profile offers once-daily dosing in the evening as the best route of administration.

According to the results of three pivotal placebo-controlled, double-blind phase III trials that investigated perampanel as an adjunctive AED in adult and adolescent patients from age 12 years who had ongoing focal epileptic seizures despite receiving one to three AEDs, perampanel has been widely licensed and introduced. Phase III trials showed superiority of adjunctive perampanel over placebo consistently in the range between 4 and 12 mg. Dizziness and somnolence were by far the leading adverse events. This review covers the clinical trial evidence but also clinical experience with perampanel after launch according to observational studies.