MEDICATION-INDUCED NEUROPATHIES

Loui s H. Weimer , M.D.

Introduction Idiopathic polyneuropathy constitutes a significant proportion of peripheral neuropathy cases. In addition, a number of identifiable causes of neuropathy have no preventative or curative interventions available, only symptomatic treatment. Thus, detection of toxic or medication induced neuropathy can be an important diagnosis that impacts quality of life. Medication-induced neuropathies are uncommon (2-4% of cases in one outpatient neurology setting)1, but crucial to recognize because intervention can lead to significant improvement or symptom resolution. Numerous medications have been associated with neuropathy (Table 1), but many more agents are suspected of causing neurotoxicity, including peripheral neuropathy than have convincing proof. Also, many subclinical or unsuspected cases likely remain undiagnosed.

Many iatrogenic neuropathies are due to medications uncommonly prescribed (disulfiram), not used in the U.S. (perhexiline, almitrine), normally used in low doses with minimal toxicity (phenytoin, ara-C), or typically used for short duration (metronidazole). Nevertheless, medications continue to rapidly increase in number and uncommon side effects may not become apparent until after widespread usage. In addition, expansion or changes in usage have increased the importance of toxic neuropathies (e.g. thalidomide). A number of agents produce tolerable neuropathies because the underlying disease is severe, notably malignancies and HIV infection. In these cases evolving research has been directed toward identifying secondary agents or delivery methods to blunt or prevent toxicity.

Identification of a toxic effect is simplest when acute or subacute onset of symptoms occurs soon after the initial drug exposure or a change of medication dosage. Most patients fall into this category. In contrast, it is much more problematic to diagnose a slowly progressive neuropathy starting many months or years after starting a chronic agent. Statin drugs provides a recent case in point and is discussed below.

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:

• Blood flow to peripheral nerve is not autoregulated and is vulnerable to sudden microenvironment changes.

• 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

• Endothelial cells in the epineurium are fenestrated and allow escape of some blood proteins in the extracellular space.

• The blood-nerve barrier is less efficient than the BBB, allowing easier access for potential neurotoxins into the periphery.

• Endoneural nerves have no lymphatic system to remove toxins. • 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

1

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.

Chemotherapeutic agents Treatment of malignancies is one setting where medication toxicity is accepted, assuming the agent is efficacious. Most agents cause neuropathy in a dose-dependent manner. Thus, a lower dose may lessen neurotoxicity but could compromise efficacy. Because a number of important neurotoxic chemotherapeutic drugs are commonly used, therapeutic interventions have focused on elimination or reduction of the neuropathy, preferably by prevention. This field is especially attractive because of the potential capability to pretreat, unlike most neurologic injuries. A separate critical issue is whether preventative agents reduce drug efficacy, especially relevant when the neurotoxicity is mediated by the same mechanisms as the anti-neoplastic effects.6 Selective blocking of the deleterious processes is advantageous, but is only possible if the underlying processes are understood.6 Numerous secondary agents have been tried with cisplatin and to a lesser degree, taxoids and vinca alkaloids. Cisplatin and related analogs remain widely used against a variety of malignancies alone or in combination therapy. The incidence of neuropathy varies between reports and according to dose, but is roughly 12% at conventional dose and 70-100% with higher cumulative doses (540-600 mg/m2) and may be lower (14%) if used as a sole agent.1 The drug likely accumulates over time and the phenomenon of “coasting”, when a neuropathy continues to progress for a time after the drug is stopped can be seen. Usually this effect persists only 2-3 weeks, but longer intervals have been described. The primary drug effect is not precisely known, but the effect on malignant cells appears to be binding to and altering DNA. Cell division is arrested for DNA repair and if damage is extensive, apoptosis is triggered.7 In contrast, the cause of neuronal injury is less clear, but apoptosis

2

also occurs with evidence that neurons enter the cell cycle prior to apoptosis, implying that drugs which block this transition, including nerve growth factor (NGF), could prevent cell death.7

Dorsal root ganglia (DRG) and axons show high platinum levels thus, differential drug access appears to be an important factor, although, autonomic ganglia are relatively spared.6,8 In addition mice with defective DNA repair abilities appear to have increased cisplatin susceptibility.9 Additional clinical, pathological, and electrophysiologic evidence also supports the concept that the process is a dorsal root ganglionopathy rather than a distal axonopathy.8,10 Effects of other drugs, especially taxoids may have additive neurotoxicity. Taxoids comprise a family of diterpene alkaloids, including paclitaxel (Taxol) and docetaxel (Taxotere). Both are widely used in metastatic ovarian and breast cancer and are increasingly used in earlier disease stages and in other cancer types. Higher doses are desirable to oncologists for efficacy but toxicity, including peripheral neuropathy, is a limiting factor. Human paclitaxel neurotoxicity is most commonly a dose-dependent, predominantly sensory neuropathy. Although evident at low doses (<200 mg/m2), symptoms are usually not clinically significant. At high dose, neuropathy is common and has been the major limiting factor in some trials.11 Symptoms may begin after one dose and can appear simultaneously in proximal sites prior to distal foot symptoms, again suggesting a possible neuronopathy. However, the pattern usually coalesces into a more typical distal predominance. Dysautonomia is not uncommon and often overlooked. Motor involvement is much less common but can be seen at high dose. Docetaxel toxicity appears to be similar. Early animal findings did not mimic the human manifestations of predominately small and large fiber sensory and autonomic and lesser motor impairment, but more recent animal studies have better modeled human taxol acute and chronic painful neuropathy.12

The neurotoxic mechanisms are unknown. In fact, it is not even certain whether the primary target is the sensory or autonomic neuron, axon, or myelin. Most likely all three are vulnerable in part. A major effect on tumor cells that may be relevant to neurotoxicity is the assembly of large arrays of disordered microtubules, in contrast to numerous other neuropathy-inducing agents that inhibit microtubular assembly (colchicine, vinca alkaloids, podophyllin resin). Chemoprotectants. Some agents have been empirically tried with anecdotal but unproven benefit including steroids and vitamin E. Glutamate paradoxically has been reported to be a neuropathy protectant against both paclitaxel and cisplatin rat models without apparent inhibition of the therapeutic effects and warrants further study.13 Amifostine is an agent approved specifically for reduction of cisplatin toxicity. Amifostine is a tissue activated prodrug, which decreases renal toxicity by detoxifying cisplatin metabolites and by free radical scavenging, with theoretical higher activity in normal tissue. Any neurologic benefit is likely due to improved toxin clearance. Studies of patients with advanced ovarian and other cancers have shown modest prevention of neuropathy from cisplatin in some series without altering efficacy, but the neurologic benefits are not clearly established at present. Studies with paclitaxel have not been promising to date.14,15 The free radical scavenger Glutathione has been shown to reduce cisplatin nephrotoxcity and possibly secondarily, neurotoxicity by preventing drug accumulation.16 In a blinded placebo-controlled study of patients treated with oxaliplatin, glutathione administration showed improved clinical and sensory nerve conduction outcomes compared to placebo treatment.17 Org 2766 is an ACTH derived hexapeptide that has shown promise in several small trials and animal studies with incomplete blunting of cisplatin and other systemic toxicity. However, a large clinical trial failed to demonstrate any benefit.18

Neuronal growth factors have attracted much interest in various areas of neurology and neuroscience, but are still awaiting proven clinical applications. A number of neurotrophins have been

3

studied in the prevention of toxic neuropathies and show promise and are only agents that can completely prevent neurotoxicity in some models.6,11 Receptors for these agents are unlikely to be present on tumor cells, reducing the risk of blunting chemotherapy efficacy.6 In both tissue culture and animal models, several neurotrophins, including NGF, insulin-like growth factor-1, brain derived neurotrophic factor, leukaemia inhibitory factor (LIF), and neurotrophin-3 (NT-3) have shown protective effects against neurotoxicities of cisplatin and analogs, taxoids, vincristine, and suramin; in some cases, the neuroprotective outcomes are marked. In addition, NT-3 introduced by virally-mediated or non-viral electroporation-mediated genetic transfer has been shown to protect against acrylamide, pyridoxine, and cisplatin-induced neuropathies using in vivo animal models.19,20 Thus, despite the disappointing outcomes of clinical trials of patients with diabetic and HIV neuropathies, these agents may be efficacious if applied as a preventative therapy. No human studies have been reported despite reasonable tolerability of these agents; however, leukaemia inhibitory factor (LIF) is currently being tested in phase II clinical trials.21

A number of other agents have shown some promising results in early studies and more are likely to follow. Glutamine was shown to reduce symptoms but not nerve conduction abnormalities after high-dose paclitaxel.22 Other promising compounds in animal models include Prosaptides (neurotrophic activity) and the antibiotics radicicol and geldanamycin. Suramin is a promising experimental agent used mostly for hormone-refractory or metastatic prostate cancer. The drug was introduced in the 1920s as an antiparasitic agent and later tried unsuccessfully against the HIV virus. During these trials, ancillary benefits against Kaposi sarcoma and lymphoma were noted. The drug currently shows promise against a variety of cancers including prostate, colon, and lymphoma, although the drug is awaiting approval in the U.S. Toxic neuropathy is a primary limiting factor. The drug is tightly protein-bound accounting for an extremely long half-life (40-50 days), which is useful in prophylaxis against protozoal infections but detrimental after the onset of neurotoxicity.

Suramin in rat models induces a length, dose, and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration, atrophy, and accumulation of glycolipid lysosomal inclusions.23 However, detailed electrophysiologic studies of patients on suramin have shown evidence of demyelination as frequently as axonal injury, and many patients had clinical courses resembling Guillain-Barré syndrome (GBS).24,25 In patients with plasma levels of suramin over 350 µg/ml, the incidence of neuropathy appears to be approximately 15%, but may be as high as 40%.25 Suramin treated neuronal cultures have shown accumulation of GM1 gangliosides, and ceramide, as well as other gangliosides.26 Ceramide levels, an important mediator of programmed cell death, are boosted intracellularly in suramin treated cultured neurons, suggesting a possible ceramide-induced apoptotic mechanism of neurotoxicity.26 Suramin also inhibits DNA polymerase and some growth factors including NGF. This growth factor inhibition may be neurotoxic and increasing suramin doses inhibit NGF-specific binding and conversely high-dose NGF can block suramin toxicity on DRG neuron.26,27

Patients using the drug as an antibiotic most often describe distal burning paresthesias, but reports have had limited details. High-dose suramin chemotherapy leads to sensorimotor neuropathy and in some cases progresses to quadriplegia with respiratory compromise. Acute signs of demyelination and high CSF protein have been observed in suramin-treated patients and are reminiscent of GBS.

Cardiovascular agents Statins Cholesterol lowering agent myopathy (CLAM) is well recognized among physicians and patients. Less well known are the small number of patients on HMG-CoA reductase inhibitors (statins) who

4

have shown signs of peripheral neuropathy, either in addition to or separately from CLAM. The significance of these reports is uncertain since millions of individuals worldwide are on statins.28,29,30 However, a recent Danish study concluded that statin users appear to have an overall higher incidence of idiopathic peripheral neuropathy.31 The effect correlated with dose, but individual agents were not separated. Gaist et al had published an earlier English series that did not find a statin-neuropathy effect but concluded their sample size was insufficient. They then conducted a much larger population-based study in one Danish county (465,000 inhabitants) and cross referenced a prescription registry to a national patient diagnosis registry from 1994-1998, when statin use in Denmark dramatically increased. They identified 1084 registered patients with a diagnosis of polyneuropathy. They excluded 492 with onset prior to 1994 or a concurrent cause of neuropathy (diabetes, renal failure, monoclonal gammopathy, etc.). Only cases with clinical signs of distal, symmetric neuropathy and an adequate workup including electrodiagnostic studies were analyzed and categorized as definite, probable, or possible idiopathic neuropathy. Twenty-five controls were randomly chosen per index case. In total 35 definite, 54 probable, and 77 possible neuropathy cases from the registry (166 total) were found. Nine had been exposed to statins including simvastatin, pravastatin, lovastatin, and fluvastatin. Odds ratios of neuropathy were calculated as 4.6 overall with current users of statins compared to controls and 16.1 with definite neuropathy cases compared to controls. They also calculated an interesting number needed to harm measure and found, based on their odds ratios, one excess case of idiopathic peripheral neuropathy for every 2,200 person-years of statin use. In light of these data, neuropathy was suggested as a more important public health concern than myopathy in patients taking statins. One potential pitfall is whether all symptomatic neuropathy causes were in fact excluded including associated conditions for patients requiring statins, for example occult diabetes. In any event the study highlights the difficulties and trial size needed to prove a modest, chronic neurotoxic drug effect and why most associations are made with acute or high dose exposures. Although at most a rare effect, the large numbers of patients on these agents makes this correlation potentially relevant. Amiodarone Amiodarone (Cordone) is benzofuran derivative initially developed as an anti-anginal drug, but found to be better as an anti-arrhythmic. It has been used extensively in Europe for this purpose, but only approved for refractory, life-threatening ventricular arrhythmias in the U.S., mainly because of toxicity. Peripheral neuropathy is one of the primary forms of toxicity, occurring in 6% of patients in one series. Other forms of neurotoxicity are known including tremor (40%) and ataxia, although some tremor and neuropathy cases likely overlap.32 Other neurotoxic effects are much less common including myopathy, optic neuropathy, movement disorders, and encephalopathy, possibly because the drug does not normally cross the blood-brain or blood-nerve barriers. Virtually all patients will experience some side effects many in other organ systems, almost all of which are susceptible. Metabolism is extremely slow in the liver and the plasma half-life may be as long as 100 days. The pharmacology of the main metabolite desethylamiodarone is less well known. Thus improvement after drug cessation can be quite delayed.

Animal studies with high does amiodarone have reproduced weakness and tremor.33 Cytoplamic lysosomal lipid inclusions were found in autonomic, dorsal root, myenteric plexi and other areas with a missing BBB, e.g. area postrema, choroids plexus, and pituitary. Levels were also seen in areas with injured BNB, such as after crush injury. Intraneural injections induced demyelination and conduction block in rats. Higher doses caused axonal degneration.

Peripheral neuropathy is the second most common neurotoxic effect after tremor and correlates poorly with daily dose or treatment duration. Most have received medication for months to years in moderately high doses, but cases after 200 mg for <1 month are known. Symmetrical sensorimotor neuropathy is most common in some cases with a motor predominance. Autonomic neuropathy is also reported. A variety of patterns are described both clinically and on electrodiagnostic studies.

5

Cases with a predominant axonopathy with low amplitude and distal denervation are seen. Patients with almost pure demyelination are also seen or a mixture of both processes. Many cases show slow velocity. Small and large fibers are affected on biopsy samples. Nerve biopsies also demonstrate lysosomal inclusion in Schwann cells and axons as well as adjacent cells such as fibroblasts, endothelial cells, and perineural cells. Measures of amiodarone and desethylamiodarone were found 80 fold higher than serum in one case where intraneural levels were measured. Lesser signs of myopathy are also seen in animal and human cases with proximal weakness and modest CK increases, and also lipid inclusions, and myopathic EMG changes in some cases. Optic neuropathy is also well known with abundant recent examples.

The mechanism of toxicity is less clear. Amiodarone is lipophilic similar to perhexiline maleate, which also causes a toxic demyelinating neuropathy. Thus the drug may gain entry to lysosomes and bind to polar lipids. Both drugs form intralysosomal lipid complexes leading to the inclusions seen in many tissues. The drug is still frequently used but patients need to be watched closely for toxicity. Antibiotics Nucleoside Analogs Antiviral nucleoside analogs are a class of drugs resembling nucleotide bases. When phosphorylated, they compete with nucleotides for reverse transcriptase binding and help terminate HIV DNA elongation. The class is a mainstay of highly active artiretroviral therapy (HAART).34 In some, peripheral neuropathy is an important limiting factor, primarily zalcitabine (ddC, Hivid), didanosine (ddI, Videx), and stavudine (d4T, Zerit). Other group members, including lamivudine (3TC), abacavir (ABC, Ziagen), and zidovudine (AZT), cause minimal or no clinically significant neuropathy. All, however, appear to be toxic to mitochondria and can produce increased lactate levels, severe in some cases.35,36 The mitochondrial toxicity is associated with reduced mtDNA content through inhibition of γ-DNA polymerase, which can improve after drug cessation.35,36 The neuropathy, as well as acquired lipodystrophy, may be manifestations of these mitochondrial effects.34,37,38,39 However, the development of neuropathy is likely multifactorial with other considerations including unmasking of subclinical HIV neuropathy, low CD4 count and viral load, other coincident neurotoxins, or poor drug clearance.37

Animal models in this field have focused on rabbits, not traditional mice or rats, and animals given zalcitabine develop pathologic and electrophysiologic signs of demyelination, possibly through Schwann cell mitochondrial toxicity.40 Didanosine and stavudine models have been less impressive even at high dose. However, a sensory neuropathy similar to humans was induced in cynomolgus monkeys with decreased large and small fiber sensory axons.34

Humans most commonly develop distal, predominantly axonal sensory neuropathy closely resembling primary HIV-related distal small fiber neuropathy, which is sometimes difficult to distinguish.39,41,42 Burning and shooting pain with decreased small more than large fiber sensory modalities is typical.34 The rapidity of onset and eventual improvement may help distinguish the processes, but not in all cases. Lower doses reduce toxicity, but may blunt efficacy. Aggressive HAART including these agents may lessen symptoms and improve quantitative sensory thresholds of primary HIV neuropathy by reducing viral load.43

Effects are dose related and nearly all will develop neuropathy if the dose is sufficiently high. At conventional doses (2.25 mg/day) roughly a third develop evidence of neuropathy on zalcitabine, but many continue to take the medication until the neuropathy reaches sufficient severity.44 Moyle and Sadler reported approximately 10% of patients receiving zalcitabine or stavudine and 1-2% of patients on didanosine stopped therapy because of severe neuropathy, but some have reported

6

incidence as high as 60%.44 Similar to other conditions, underlying neuropathy may enhance neurotoxicity.

Newer considerations to help blunt neuropathy progression include NGF and levacecarnine (acetyl-L-carnitine). Carnitine levels were preliminarily reported reduced in HIV patients on nucleoside analogs with neuropathy suggesting possibly beneficial carnitine supplementation; 36,45 however, recent attempts failed to show this effect in patients with or without neuropathy irrespective of nucleoside analog use.46 Similarly, administration of NGF to HIV neuropathy patients, the majority of who were on nucleoside analogs, produced blunting of pain but no improvement in other measures including clinical exam, quantitative sensory testing, or epidermal nerve fiber density.47,48 Other than dosage adjustments, current symptomatic treatment is similar to other painful neuropathies.

Miscellaneous medications Thalidomide Thalidomide use has slowly increased over the last 10-12 years due to its antiangiogenic and anti-inflammatory properties. Current applications are for a wide variety of disorders including Behçets and HIV-related ulcers, discoid lupus and other dermatological conditions, ulcerative colitis, rheumatoid arthritis, leprosy, graft-vs-host disease, and others.1,49 It is also increasingly used as a chemotherapeutic agent, notably in prostate and renal cancers. In addition to the infamous teratogenic effects, sensory neuropathy reached near epidemic levels in 1960-61, before the drug was withdrawn. Animal and in vitro models of thalidomide neuropathy have revealed mild and unconvincing effects. For example, a recent negative study in dogs treated with various doses of thalidomide for over a year and included nerve conduction studies, thus highlighting the limitations of animal models with some toxins.50

The true incidence and dose response relationships of thalidomide induced neuropathy remain unknown. Over the years, reports have claimed widely variable incidence rates, in part due to differences in dosage levels, treatment duration, and neuropathy ascertainment. Some patients appear to tolerate higher doses for extended periods, and genetic differences in metabolism have been suspected but not demonstrated.51 Molloy et al recently performed an open-label prospective study of 67 metastatic prostate cancer patients.52 Many (55) stopped the drug early due to lack of effect, but 24 continued thalidomide for at least 3 months. Of these, 6 developed neuropathy. Virtually all individuals treated for more than six months developed either clinical or electrophysiologic signs of neuropathy. Because the neuropathies were generally in early stages when the drug was discontinued, recovery generally occurred. However, in other studies recovery has been variable and may be incomplete, arguing for a presumed effect on DRG neurons. Electrophysiology has shown reduced or absent sensory potentials with minor motor changes.52,53 Autopsy findings have shown loss of sensory axons, DRG neurons, and dorsal column fibers. Physicians prescribing the drug, namely rheumatologists, immunologists, oncologists, and dermatologists, should be aware of these toxic effects and closely monitor patients for evidence of neuropathy.

Tacrolimus (ProGraf, FK-506) This agent is a novel immunosuppresant increasingly used in transplant medicine, largely replacing cyclosporin A (CSA). The agent is a macrolide antibiotic that suppresses both cellular and humoral mediated immune responses. Neurotoxicity is common in part because of relatively high doses usually given. Central toxicity is more common with a variety of findings including leukoencephalopathy, seizures, behavioral changes, headache, or other cortical signs, many of which are dose dependant. Peripheral neuropathy appears to take the form of a severe multifocal demyelinating neuropathy resembling chronic inflammatory demyelinating neuropathy (CIDP)

7

although two cases with acute motor axonal neuropathy are also reported.54,55 Some patients have responded to IVIg or plasmapheresis.

Both CSA and tacrolimus act through calcineurin inhibition, though by different means (tacrolimus binding protein: FKBP-12). The calcineurin inhibition through several steps decreases T-cell proliferation. This pathway is also the likely cause of much of the central neurotoxicity and possibly the peripheral effects. Tacrolimus also has an additional separate function through a different binding protein (FKBP-52) that acts as a nerve stimulator and is beneficial to nerve regeneration in nerve axotomy and ischemia models.56 FKBP-52 is part of a steroid receptor complex and may represent a target for future regenerative therapies separate from the growth factor/Trk pathways. The mechanism of why in some patients an immune attack resembling CIDP or possibly trigger of an underlying condition occurs, but additional patients will likely be uncovered as use widens. A similar agent sirolimus is also approved but no analogous cases have been reported to date.

Conclusions Many more agents are suspected of causing neuropathy than discussed. Despite the lengthy and fastidious drug approval process, rare and idiosyncratic causes of medication-induced neuropathy may only become evident after wide-usage. Medication-induced toxicity should be at least considered in new cases of neuropathy including apparent idiopathic forms. Also importantly, patients with existing neuropathy of known or presumed cause should have their current regimen and planned therapy considered for potential neurotoxicity. Some preventative agents against chemotherapy toxicity show promise, but none are yet approved for routine use against neurotoxic effects. 57

References 1. Jain KK. Drug-induced peripheral neuropathies. In: Jain KK, ed. Drug-induced neurological disorders,

2nd ed. Seattle: Hogrefe & Huber. 2001:263-294. 2. Chaudhry V, Chaudhry M, Crawford TO, Griffin JW. Toxic neuropathy in patients with pre-

existing neuropathy [abstract]. Neurology 2002;58(suppl 3):A19 3. Graf WD, Chance PF, Lensch MW, et al. Severe vincristine neuropathy in Charcot-Marie-Tooth

disease type 1A. Cancer 1996;77:1356-1362. 4. Wang M, Culver DG, Glass JD. The gene for slow Wallerian degeneration (Wld(s)) is also

protective against vincristine neuropathy. Neurobiol Dis 2001;8:155-161. 5. Wang MS, Fang G, Culver DG, et al. The WldS protein protects against axonal degeneration: a

model of gene therapy for peripheral neuropathy. Ann Neurol 2001;50:773-779. 6. Windebank AJ: Chemotherapeutic neuropathy. Curr Opin Neurol 1999;12:565-571. 7. Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglia neurons is

associated with attempted entry in the cell cycle. J Clin Invest 1998;101:2842-2850. 8. Krarup-Hansen A, Rietz B, Krarup C, et al. Histology and platinum content of sensory ganglia

and sural nerves in patients treated with cisplatin and carboplatin. an autopsy study. Neuropath Appl Neurobiol 1999;25:29-40.

9. Makhalova J, Katsarava Z, Liedert B, et al. Cisplatin-induced neurotoxicity. Formation and repair of specific cisplatin-DNA lesions in different cell types of nervous tissue in wild type and XPC-knockout mice. Neurology 2002;58(suppl 3):A19 [Abstract]

10. Krarup-Hansen A, Fugleholm K, Lelweg-Larsen S, et al. Examination of distal involvement in cisplatin-induced neuropathy in man. Brain 1993;116:1017-1041.

11. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 2002;249:9-17.

8

12. Cliffer KD, Siuciak JA, Carson SR, et al. Physiological characterization of Taxol-induced large-fiber sensory neuropathy in the rat. Ann Neurol 1998;43:46-55.

13. Boyle FM, Wheeler HR, Shenfield GM. Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate. J Neurooncol 1999;41:107-116.

14. Gelmon K, Eisenhauer E, Bryce C, et al. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol 1999;17:3038-3044.

15. Openshaw H, Slatkin N, Beamon K, et al. The effect of amifostine on peripheral neuropathy after high dose paclitaxel. Neurology 2002;58(suppl 3):A50 [Abstract].

16. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of double-blind randomized trial. Ann Oncol 1997;8:569-573.

17. Cascinu S, Catalano V, Cordella L, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002;20:3478-3483.

18. Roberts JA, Jenison EL, Kim K, et al. A randomized, multicenter, double-blind, placebo-controlled, dose-finding study of ORG 2766 in the prevention or delay of cisplatin-induced neuropathies in women with ovarian cancer. Gynecol Oncol 1997;67:172-177.

19. Chattopadhyay M, Wolfe D, Huang S, et al. In vivo gene therapy for pyridoxine-induced neuropathy by herpes simplex virus-mediated gene transfer of neurotrophin-3. Ann Neurol 2002;51:19-27.

20. Pradat PF, Finiels F, Kennel P, et al. Partial prevention of cisplatin-induced neuropathy by electroporation-mediated nonviral gene transfer. Hum Gene Ther 2001;12:367-75

21. Boyle FM, Beatson C, Monk R, et al. The experimental neuroprotectant leukaemia inhibitory factor (LIF) does not compromise antitumour activity of paclitaxel, cisplatin and carboplatin. Cancer Chemother Pharmacol 2001;48:429-434.

22. Vahdat L, Papadopoulos K, Lange D, et al. Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 2001;7:1192-1197.

23. Russell JW, Gill JS, Sorenson EJ, et al. Suramin-induced neuropathy in an animal model. J Neurol Sci 2001;192:71-80.

24. Chaudhry V, Eisenberger MA, Sinibaldi VJ, et al. A prospective study of suramin-induced peripheral neuropathy. Brain 1996;119:2039-2052.

25. Soliven B, Dhand UK, Kobayashi K, et al. Evaluation of neuropathy in patients on suramin treatment. Muscle Nerve 1997;20:83-91.

26. Gill JS, Windebank AJ. Suramin induced ceramide accumulation leads to apoptotic cell death in dorsal root ganglion neurons. Cell Death Differ 1998;5:876-883.

27. Gill JS, Windebank AJ. Direct activation of the high-affinity nerve growth factor receptor by a non-peptide symmetrical polyanion. Neuroscience 1998;87:855-860.

28. Jacobs MG. HMG-CoA reductase inhibitor therapy and peripheral neuropathy. Ann Intern Med 1994;120:970.

29. Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol 1999;54:835-838.

30. Phan T, McLeod JG, Pollard JD, et al. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry 1995;58:625-628.

31. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology 2002;58:1333-1337.

32. Fraser AG, McQueen INF, Watt AH, et al. Peripheral neuropathy during long-term high-dose amiodarone therapy. J Neurol Neurosurg Psychiatry 1985;48:576-578.

33. Santoro L, Barbieri F, Nucciotti R, et al. Amiodarone-induced experimental acute neuropathy in rats. Muscle Nerve 1992;15:788-795.

34. Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Periph N Syst 2001;6:14-20. 35. Coté HC, Brumme ZL, Craib KJ, et al. Changes in mitochondrial DNA as a marker of

nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811-820.

9

36. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995;1:417-422. 37. Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related

mitochondrial toxicity. Clin Ther 2000;8:911-936. 38. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-

analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:1112-1115.

39. Pardo CA, McArthur JC, Griffin JW. HIV neuropathy: insights in the pathology of HIV peripheral nerve disease. J Peripher Nerv Syst 2001;6:21-27.

40. Anderson TD, Davidovich A, Feldman D, et al. Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity. Lab Invest 1994;70:724-739.

41. Berger AR, Arezzo JC, Schaumburg HH, et al. 2’, 3’-Dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology 1993;43:358-362.

42. Williams D, Geraci A, Simpson M. AIDS and AIDS-treatment neuropathies. Curr Neurol Neurosci Rep 2001;1:533-538.

43. Martin C, Solders, G, Sonnerborg A, et al. Antiretroviral therapy may improve sensory function in HIV-infected patients: a pilot study. Neurology 2000;54:2120-2127.

44. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998;19:481-494.

45. Scarpini E, Sacilotto G, Baron P, et al. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst 1997;2:250-252.

46. Simpson DM, Katzenstein D, Haidich B, et al. Plasma carnitine in HIV-associated neuropathy. AIDS 2001;15:2207-2208.

47. McArthur JC, Yiannoutsos C, Simpson DM, et al. A phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. Neurology 2000;54:1080–1088.

48. Schifitto G, Yiannoutsos C, Simpson DM, et al. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 2001;57:1313-1316.

49. Eriksson T, Bjorkman S, Hoglund P. Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 2001;57:365-376.

50. Teo S, Evans M, Ehrhart J, et al. Lack of peripheral neuropathy in Beagle dogs after 53 weeks oral administration of thalidomide capsules. Hum Exp Toxicol 2000;19:615-622.

51. Harland CC, Steventon GB, Marsden JR. Thalidomide-induced neuropathy and genetic differences in drug metabolism. Eur J Clin Pharmacol 1995;49:1-6.

52. Molloy FM, Floeter MK, Syed NA, et al. Thalidomide neuropathy in patients treated for metastatic prostate cancer. Muscle Nerve 2001;24:1050-1057.

53. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide neuropathy: an electrophysiologic study. Muscle Nerve 1994;9:837-844.

54. Wilson JR, Conwit RA, Eidelman PH, et al. Sensorimotor neuropathy resembling CIDP in patients receiving FK-506. Muscle Nerve 1994;17:528-532.

55. Ayres RCS, Dousset B, Wixon S, et al. Peripheral neurotoxicity with tacrolimus. Lancet 1994;343:863-864.

56. Kihara M, Kamijo M, Nakasaka Y, et al. A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration. Muscle Nerve 2001;24(12):1601-1606.

57. Weimer LH. Medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep. Jan 2003 [in press].

10

Table. Drugs associated with peripheral neuropathy CHEMOTHERAPY 5-Azacytidine 5-Fluouracil Cisplatin and analogs Cytarabine (high dose) Etoposide (VP-16) Gemcitabine Hexamethylmelamine Ifosphamide Misonidazole Suramin VM-26 Taxoids Vinca alkaloids ANTIBIOTICS Nucleoside analogs Chloroquine Chloramphenicol Clioquinil Dapsone Ethambutol Fluoroquinolones Griseofulvin INH Mefloquine Metronidazole Nitrofurantoin Podophyllin resin Sulfonamides CARDIOVASCULAR Amiodarone Enalapril Hydralazine Statins Perhexiline Propafenone

CNS ACTING Amitriptyline Phenytoin Chlorprothixene Gangliosides Gluthethimide Lithium Nitrous oxide Phenelzine Thalidomide MISCELLANEOUS Allopurinol Almitrine Botulinum toxin Cimetidine Clofibrate Colchicine Cyclosporin A Dichoroacetate Disulfiram Etretinate Gold salts Interferons α-2A,2B Penacillamine Pyridoxine abuse Sulphasalazine Tacrolimus (FK506, ProGraf) Zimeldine

Drugs with more common, more important, and better established associations are highlighted in bold

11