> Susceptibility of peripheral nerve > Peripheral nerve is protected by a blood-nerve barrier and would seem to > be > at lesser risk than other organs for toxicity. However, a number of > factors > enhance peripheral nerve vulnerable, especially compared to the central > nervous > system.1 Some examples include: > o Blood flow to peripheral nerve is not autoregulated and is vulnerable > to sudden microenvironment changes. > o Dorsal root ganglia (DRG) lack an efficient vascular barrier to some > large molecules making the cell body and not axon a target in some cases > o Endothelial cells in the epineurium are fenestrated and allow escape of > some blood proteins in the extracellular space. > o The blood-nerve barrier is less efficient than the BBB, allowing easier > access for potential neurotoxins into the periphery. > o Endoneural nerves have no lymphatic system to remove toxins. > o Peripheral nerve has nothing analogous to the sink action of CSF > > A number of other factors render some individuals more vulnerable to > potentially toxic medications. A well-known and increasingly supported > predisposition is the presence of an underlying neuropathy that may be of > unrelated genetic > or acquired cause.2,3 In some conditions (e.g. malignancy and HIV), an > inherent neuropathy can be difficult to distinguish from treatment-induced > neuropathy. Other genetic factors may alter toxicity especially > impairments > in > metabolism which may be either detrimental or protective depending on > whether > exposure to the primary drug or toxic metabolites is the offensive factor. > More > recently, genes known to promote neuronal axon survival have been shown to > blunt > certain neurotoxic effects. For example, presence of the WldS slow > Wallerian degeneration gene, can protect against both axotomy and > vincristine > exposure > neuropathy.4 Transfection of this gene into rat DRG cells in vitro has > conferred this beneficial property onto these neurons, raising intriguing > possibilities for future treatments.5 > Most toxic neuropathies, including medication-induced forms, principally > induce axonal degeneration in a ╲dying back╡ pattern disproportionately > affecting > the distal segments of the most vulnerable, usually longest nerves. > However, a number of agents may cause segmental demyelination or target > Schwann > cells, dorsal root ganglia and autonomic neurons, or peripheral myelin. > A number of agents not discussed in detail bear some mention. Some agents > convincingly associated with neuropathy are generally safe with typical > usage, > but may be used at higher dose or more chronically. One common example is > colchicine typically taken intermittently for gout attacks, but in some > cases > taken chronically for extended periods. Myopathy is the primary effect but > additional neuropathy is usually part of the syndrome. Allopurinol is also > rarely > associated with neuropathy but the effect appears to be an idiosyncratic > hypersensitivity reaction. Metronidazole is usually given in short > courses, > generally less than 14 days, but some infections require extended > treatment. In this > setting monitoring for toxic neuropathy is warranted. Much is known about > disulfiram neuropathy and the toxic mechanism is likely very similar if > not > identical to carbon disulfide. The drug is still used in some settings and > alcoholic neuropathy should not be assumed in treated patients. Phenytoin > neuropathy from chronic exposure remains controversial and based on a > small > number of > reports but affected patients described were generally on much higher than > current doses (>500 mg/d) and blood levels (> 20 µg/ml). A few examples of > important agents with recent developments have been selected for > discussion. > >