Phenytoin: neuroprotection or neurotoxicity?

Abstract

Phenytoin is an 80-year young molecule and new indications are still emerging. The neuroprotective potential of phenytoin has been evaluated for decades. Recently, a positive phase II trial supported its further development in the treatment of optic neuritis in multiple sclerosis. In 1942, however, peripheral neuritis was first reported to be an adverse event of phenytoin, and since then a small but steady stream of publications discussed peripheral polyneuropathy as being a possible adverse event of phenytoin. We have reviewed the literature and concluded there is some supportive evidence for a reversible polyneuropathy after the oral use of phenytoin, though with no evidence for clear neurotoxicity on the level of peripheral nerves. This is probably due to the fact that the pharmacological effects of phenytoin, based on the stabilizing effect of the voltage-gated sodium channels, make impairment of nerve conduction in asymptomatic and symptomatic reversible polyneuropathies plausible. Clear toxically-induced phenytoin-related polyneuropathies, however, are extremely rare and are always related to high dose or high plasma levels of phenytoin, mostly developing during many years of therapy. We could only find one case of a probable reversible chronic phenytoin intoxication resulting in a biopsy proven axonal atrophy with secondary demyelination and signs of remyelination. All case series and case reports published are insufficient in detail to prove a clear causal relation between phenytoin intake and the induction of a peripheral polyneuropathy. Phenytoin does not lead to irreversible toxicity of the peripheral nerves and might, on the other hand, have neuroprotective properties.

Phenytoin Cream for the Treatment of Neuropathic Pain: Case Series

“…Although many patients were responders to compounded creams containing for example amitriptyline, ketamine, and baclofen, a number of patients remained treatment-resistant. We therefore introduced phenytoin as a new compound for topical neuropathic pain treatment based on its remarkable history and its various modes of action [ 15 , 16 , 17 ]. Phenytoin, as a broad-acting ion channel blocker with neuroprotective and anti-inflammatory properties, seemed to be an optimal choice as an effective compound that is able to modulate peripheral mechanisms, which are increasingly recognized as important drivers in neuropathic pain [ 18 ].…”

The retinoprotective role of phenytoin

“…However clear toxicity-induced phenytoin-related polyneuropathies are extremely rare, and they are always related to high doses or high plasma levels of phenytoin, that primarily develop over many years of therapy. 13 …”

Incidental Ultrastructural Findings in the Sural Nerve and Dorsal Root Ganglion of Aged Control Sprague Dawley Rats in a Nonclinical Carcinogenicity Study

“…Numerous medications can cause, or are suspected to cause, damage to the PNS. These include medications used to treat heart arrhythmias, 4 bacterial infections, 5,6 retroviral infections, [7][8][9][10][11] cancer, [12][13][14] high blood pressure, 15 autoimmune disorders, 16 epilepsy, 17 high cholesterol, 18,19 alcohol addiction, 20 and vitamin over-/undersupplementation. 21,22 As would be expected, there is no commonality between the structure and/or the mechanism of action between these varied therapeutic agents.…”