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109 Dear Editor, Fampridine or 4-aminopyridine is a broad-spectrum blocker of the Kv1 family of voltage-gated potassium channels that is used as a symptomatic therapy for patients with certain neuromuscular disorders to enhance synaptic neuronal conduction (1). In multiple sclerosis (MS) [Expanded Disability Status Scale (EDSS) 4-7], it is used to improve walking ability and or ataxia. The drug blocks K+ channels involved in the establishment of early membrane hyperpolarization, thereby potentiating and prolonging membrane depolarization and the nerve impulse (2). However, the role of Fampridine in improving the manifestations of MS could be related to the following effects: Interference with the establishment of hyperpolarization in the neuronal cell membrane, allowing for prolonged cell membrane depolarization and accordingly stronger nerve impulse. This is helped by the physiologic subcellular localization of the Kv1 K+ channels at the presynaptic ends of neuronal cell membranes (3). However, this action is responsible for the main adverse effect of the drug that might develop in some patients, which is the development of seizures. Kv1.3 and Kv1.5 have been reported to play a significant role in immunomodulation and cellular activation, proliferation, and migration of lymphocytes (2). Accordingly, inhibition of these channels might contribute to the suppression of the demyelinating autoimmune pathogenesis of the disease. The demyelination associated with MS was found to be associated with the relocation of Kv1.1 and Kv1.2 from the typical juxta-paranodal sites to the nodes, together with a disproportionate increase in the level of KV1.1 (4). Accordingly, inhibition of these channels through the Fampridine therapy could partially restore the physiologic monophasic compound action potential (4). Thus, it seems that the drug is well suited to MS and similar disorders. However, there is another side of the drug that is not well investigated and should be carefully considered. The inhibition of Kv1.3 and Kv1.5, which are important for cellular proliferation and migration, is beneficial for immunomodulation when affecting lymphocytes. However, on the other side, it might impede regenerative abilities that are essential for disease control and or remyelination. Moreover, although the various members of the Kv1 family have different signaling and little is known about their exact roles in disease and physiology, it is well established that these channels are involved in cell membrane hyperpolarization, and their blockade is associated with increased membrane depolarization and cellular excitability with the potential of the development of seizures, atrial fibrillation, and arterial myogenic vasoconstriction (5,6), which might potentiate ischemic events that may accidently occur during the application of the therapy or even help their precipitation. Spreading depression (SD) is a wave of membrane depolarization that occurs in the brain and is accompanied with vascular changes. The reason behind the development of SD is not fully clear, but it might result from differential ionic channels activities in various areas of the brain as a consequence of areal metabolic-perfusion mismatches (7). Under physiologic conditions, the duration of SD is too short to cause tissue injury. However, prolonged SD has

Fampridine Therapy in Multiple Sclerosis: We Should Think Twice!