M E D I C A T I O N -I N D U C E D N EUR O PATHIE S

Louis 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, araC), 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

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Thus. apoptosis is triggered. However. Allopurinol is also rarely associated with neuropathy but the effect appears to be an idiosyncratic hypersensitivity reaction. For example. More recently. but is only possible if the underlying processes are understood.4 Transfection of this gene into rat DRG cells in vitro has conferred this beneficial property onto these neurons. but apoptosis 2 . but longer intervals have been described. Because a number of important neurotoxic chemotherapeutic drugs are commonly used. including medication-induced forms. raising intriguing possibilities for future treatments.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. Chemotherapeutic agents Treatment of malignancies is one setting where medication toxicity is accepted.7 In contrast.1 The drug likely accumulates over time and the phenomenon of “coasting”. Much is known about disulfiram neuropathy and the toxic mechanism is likely very similar if not identical to carbon disulfide. when a neuropathy continues to progress for a time after the drug is stopped can be seen. This field is especially attractive because of the potential capability to pretreat. A separate critical issue is whether preventative agents reduce drug efficacy.5 Most toxic neuropathies. generally less than 14 days. genes known to promote neuronal axon survival have been shown to blunt certain neurotoxic effects. 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).6 Selective blocking of the deleterious processes is advantageous. presence of the WldS slow Wallerian degeneration gene. taxoids and vinca alkaloids. but may be used at higher dose or more chronically. a number of agents may cause segmental demyelination or target Schwann cells. but in some cases taken chronically for extended periods. a lower dose may lessen neurotoxicity but could compromise efficacy. In this setting monitoring for toxic neuropathy is warranted. Myopathy is the primary effect but additional neuropathy is usually part of the syndrome. The incidence of neuropathy varies between reports and according to dose. usually longest nerves. dorsal root ganglia and autonomic neurons. A few examples of important agents with recent developments have been selected for discussion. principally induce axonal degeneration in a “dying back” pattern disproportionately affecting the distal segments of the most vulnerable. One common example is colchicine typically taken intermittently for gout attacks. The primary drug effect is not precisely known. Some agents convincingly associated with neuropathy are generally safe with typical usage. unlike most neurologic injuries. Cell division is arrested for DNA repair and if damage is extensive. therapeutic interventions have focused on elimination or reduction of the neuropathy. 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. Usually this effect persists only 2-3 weeks. or peripheral myelin. The drug is still used in some settings and alcoholic neuropathy should not be assumed in treated patients. Cisplatin and related analogs remain widely used against a variety of malignancies alone or in combination therapy. A number of agents not discussed in detail bear some mention.6 Numerous secondary agents have been tried with cisplatin and to a lesser degree. can protect against both axotomy and vincristine exposure neuropathy. especially relevant when the neurotoxicity is mediated by the same mechanisms as the anti-neoplastic effects. Most agents cause neuropathy in a dose-dependent manner. but some infections require extended treatment. preferably by prevention. Metronidazole is usually given in short courses. assuming the agent is efficacious. the cause of neuronal injury is less clear. but the effect on malignant cells appears to be binding to and altering DNA.

Early animal findings did not mimic the human manifestations of predominately small and large fiber sensory and autonomic and lesser motor impairment. Some agents have been empirically tried with anecdotal but unproven benefit including steroids and vitamin E. However. Both are widely used in metastatic ovarian and breast cancer and are increasingly used in earlier disease stages and in other cancer types. Chemoprotectants. vinca alkaloids. At high dose. including nerve growth factor (NGF). a large clinical trial failed to demonstrate any benefit.18 Neuronal growth factors have attracted much interest in various areas of neurology and neuroscience.8 In addition mice with defective DNA repair abilities appear to have increased cisplatin susceptibility. symptoms are usually not clinically significant.6. which decreases renal toxicity by detoxifying cisplatin metabolites and by free radical scavenging. A major effect on tumor cells that may be relevant to neurotoxicity is the assembly of large arrays of disordered microtubules. neuropathy is common and has been the major limiting factor in some trials. implying that drugs which block this transition. However. the pattern usually coalesces into a more typical distal predominance.12 The neurotoxic mechanisms are unknown. but are still awaiting proven clinical applications.11 Symptoms may begin after one dose and can appear simultaneously in proximal sites prior to distal foot symptoms. A number of neurotrophins have been 3 .also occurs with evidence that neurons enter the cell cycle prior to apoptosis.15 The free radical scavenger Glutathione has been shown to reduce cisplatin nephrotoxcity and possibly secondarily. Amifostine is a tissue activated prodrug. it is not even certain whether the primary target is the sensory or autonomic neuron.9 Additional clinical. including paclitaxel (Taxol) and docetaxel (Taxotere). but more recent animal studies have better modeled human taxol acute and chronic painful neuropathy.16 In a blinded placebo-controlled study of patients treated with oxaliplatin. in contrast to numerous other neuropathy-inducing agents that inhibit microtubular assembly (colchicine. podophyllin resin). autonomic ganglia are relatively spared.10 Effects of other drugs. Docetaxel toxicity appears to be similar.13 Amifostine is an agent approved specifically for reduction of cisplatin toxicity. but the neurologic benefits are not clearly established at present. although. predominantly sensory neuropathy. neurotoxicity by preventing drug accumulation. Human paclitaxel neurotoxicity is most commonly a dose-dependent. pathological. glutathione administration showed improved clinical and sensory nerve conduction outcomes compared to placebo treatment. axon. 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. is a limiting factor.7 Dorsal root ganglia (DRG) and axons show high platinum levels thus. In fact. Studies with paclitaxel have not been promising to date. differential drug access appears to be an important factor. and electrophysiologic evidence also supports the concept that the process is a dorsal root ganglionopathy rather than a distal axonopathy. Taxoids comprise a family of diterpene alkaloids.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. Motor involvement is much less common but can be seen at high dose. including peripheral neuropathy. Most likely all three are vulnerable in part. Although evident at low doses (<200 mg/m2). with theoretical higher activity in normal tissue. Dysautonomia is not uncommon and often overlooked. or myelin.14. Higher doses are desirable to oncologists for efficacy but toxicity. could prevent cell death. Any neurologic benefit is likely due to improved toxin clearance. again suggesting a possible neuronopathy. Studies of patients with advanced ovarian and other cancers have shown modest prevention of neuropathy from cisplatin in some series without altering efficacy.8. especially taxoids may have additive neurotoxicity.

6. the incidence of neuropathy appears to be approximately 15%. High-dose suramin chemotherapy leads to sensorimotor neuropathy and in some cases progresses to quadriplegia with respiratory compromise. Suramin is a promising experimental agent used mostly for hormone-refractory or metastatic prostate cancer. including NGF. these agents may be efficacious if applied as a preventative therapy. detailed electrophysiologic studies of patients on suramin have shown evidence of demyelination as frequently as axonal injury. insulin-like growth factor-1. pyridoxine. the neuroprotective outcomes are marked. The drug currently shows promise against a variety of cancers including prostate.S. leukaemia inhibitory factor (LIF) is currently being tested in phase II clinical trials. Less well known are the small number of patients on HMG-CoA reductase inhibitors (statins) who 4 . colon. which is useful in prophylaxis against protozoal infections but detrimental after the onset of neurotoxicity. and neurotrophin-3 (NT-3) have shown protective effects against neurotoxicities of cisplatin and analogs.studied in the prevention of toxic neuropathies and show promise and are only agents that can completely prevent neurotoxicity in some models. ancillary benefits against Kaposi sarcoma and lymphoma were noted. reducing the risk of blunting chemotherapy efficacy. and cisplatin-induced neuropathies using in vivo animal models. vincristine. The drug was introduced in the 1920s as an antiparasitic agent and later tried unsuccessfully against the HIV virus.21 A number of other agents have shown some promising results in early studies and more are likely to follow. 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.23 However. atrophy. Toxic neuropathy is a primary limiting factor.11 Receptors for these agents are unlikely to be present on tumor cells.20 Thus. During these trials. Glutamine was shown to reduce symptoms but not nerve conduction abnormalities after highdose paclitaxel. in some cases. however.22 Other promising compounds in animal models include Prosaptides (neurotrophic activity) and the antibiotics radicicol and geldanamycin. and accumulation of glycolipid lysosomal inclusions. NT-3 introduced by virallymediated or non-viral electroporation-mediated genetic transfer has been shown to protect against acrylamide.24. No human studies have been reported despite reasonable tolerability of these agents. Suramin in rat models induces a length.27 Patients using the drug as an antibiotic most often describe distal burning paresthesias.26 Ceramide levels. although the drug is awaiting approval in the U. and lymphoma. leukaemia inhibitory factor (LIF). and suramin.26 Suramin also inhibits DNA polymerase and some growth factors including NGF. brain derived neurotrophic factor. and time-dependent axonal sensorimotor polyneuropathy associated with axonal degeneration. are boosted intracellularly in suramin treated cultured neurons. suggesting a possible ceramide-induced apoptotic mechanism of neurotoxicity. taxoids. In addition. Cardiovascular agents Statins Cholesterol lowering agent myopathy (CLAM) is well recognized among physicians and patients. several neurotrophins. an important mediator of programmed cell death.19. as well as other gangliosides.26. but may be as high as 40%. but reports have had limited details.6 In both tissue culture and animal models. and many patients had clinical courses resembling Guillain-Barré syndrome (GBS).25 In patients with plasma levels of suramin over 350 µg/ml.25 Suramin treated neuronal cultures have shown accumulation of GM1 gangliosides. dose. despite the disappointing outcomes of clinical trials of patients with diabetic and HIV neuropathies. The drug is tightly protein-bound accounting for an extremely long halflife (40-50 days). and ceramide. Acute signs of demyelination and high CSF protein have been observed in suramin-treated patients and are reminiscent of GBS.

lovastatin. pravastatin.). a recent Danish study concluded that statin users appear to have an overall higher incidence of idiopathic peripheral neuropathy. neuropathy was suggested as a more important public health concern than myopathy in patients taking statins. and encephalopathy. one excess case of idiopathic peripheral neuropathy for every 2..200 person-years of statin use. and 77 possible neuropathy cases from the registry (166 total) were found. possibly because the drug does not normally cross the blood-brain or blood-nerve barriers. In total 35 definite. It has been used extensively in Europe for this purpose. The pharmacology of the main metabolite desethylamiodarone is less well known. Higher doses caused axonal degneration. symmetric neuropathy and an adequate workup including electrodiagnostic studies were analyzed and categorized as definite. probable.6 overall with current users of statins compared to controls and 16. Thus improvement after drug cessation can be quite delayed. Other forms of neurotoxicity are known including tremor (40%) and ataxia. for example occult diabetes. optic neuropathy. movement disorders. although some tremor and neuropathy cases likely overlap. choroids plexus. 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 individual agents were not separated. when statin use in Denmark dramatically increased. They identified 1084 registered patients with a diagnosis of polyneuropathy. based on their odds ratios. life-threatening ventricular arrhythmias in the U.have shown signs of peripheral neuropathy. Animal studies with high does amiodarone have reproduced weakness and tremor. They then conducted a much larger population-based study in one Danish county (465.1 with definite neuropathy cases compared to controls. and fluvastatin. the large numbers of patients on these agents makes this correlation potentially relevant. Symmetrical sensorimotor neuropathy is most common in some cases with a motor predominance. In light of these data. etc.30 However. Peripheral neuropathy is one of the primary forms of toxicity. dorsal root. 54 probable. but cases after 200 mg for <1 month are known. such as after crush injury. myenteric plexi and other areas with a missing BBB. Amiodarone Amiodarone (Cordone) is benzofuran derivative initially developed as an anti-anginal drug. Odds ratios of neuropathy were calculated as 4. chronic neurotoxic drug effect and why most associations are made with acute or high dose exposures. They excluded 492 with onset prior to 1994 or a concurrent cause of neuropathy (diabetes. Only cases with clinical signs of distal. almost all of which are susceptible. but only approved for refractory.000 inhabitants) and cross referenced a prescription registry to a national patient diagnosis registry from 1994-1998. Intraneural injections induced demyelination and conduction block in rats.31 The effect correlated with dose. either in addition to or separately from CLAM.29. Virtually all patients will experience some side effects many in other organ systems. but found to be better as an anti-arrhythmic. Gaist et al had published an earlier English series that did not find a statin-neuropathy effect but concluded their sample size was insufficient. or possible idiopathic neuropathy. A variety of patterns are described both clinically and on electrodiagnostic studies. renal failure. Twenty-five controls were randomly chosen per index case. monoclonal gammopathy. Metabolism is extremely slow in the liver and the plasma half-life may be as long as 100 days.g. Although at most a rare effect. In any event the study highlights the difficulties and trial size needed to prove a modest. They also calculated an interesting number needed to harm measure and found. mainly because of toxicity.28. 5 .S.33 Cytoplamic lysosomal lipid inclusions were found in autonomic. The significance of these reports is uncertain since millions of individuals worldwide are on statins. Levels were also seen in areas with injured BNB. occurring in 6% of patients in one series. and pituitary. One potential pitfall is whether all symptomatic neuropathy causes were in fact excluded including associated conditions for patients requiring statins. area postrema. Nine had been exposed to statins including simvastatin. Autonomic neuropathy is also reported. e.32 Other neurotoxic effects are much less common including myopathy.

other coincident neurotoxins. severe in some cases. abacavir (ABC. Lesser signs of myopathy are also seen in animal and human cases with proximal weakness and modest CK increases. and stavudine (d4T.25 mg/day) roughly a third develop evidence of neuropathy on zalcitabine.37 Animal models in this field have focused on rabbits. At conventional doses (2. The drug is still frequently used but patients need to be watched closely for toxicity. Thus the drug may gain entry to lysosomes and bind to polar lipids.35. Ziagen).43 Effects are dose related and nearly all will develop neuropathy if the dose is sufficiently high. Amiodarone is lipophilic similar to perhexiline maleate.34 Humans most commonly develop distal.35. but many continue to take the medication until the neuropathy reaches sufficient severity. the development of neuropathy is likely multifactorial with other considerations including unmasking of subclinical HIV neuropathy. and zidovudine (AZT). or poor drug clearance. they compete with nucleotides for reverse transcriptase binding and help terminate HIV DNA elongation.34. cause minimal or no clinically significant neuropathy. Patients with almost pure demyelination are also seen or a mixture of both processes. and also lipid inclusions. primarily zalcitabine (ddC.42 Burning and shooting pain with decreased small more than large fiber sensory modalities is typical.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. When phosphorylated.37.Cases with a predominant axonopathy with low amplitude and distal denervation are seen. All.39 However. but may blunt efficacy. predominantly axonal sensory neuropathy closely resembling primary HIV-related distal small fiber neuropathy. possibly through Schwann cell mitochondrial toxicity. Zerit). which is sometimes difficult to distinguish. didanosine (ddI. and perineural cells.36 The neuropathy. Other group members. including lamivudine (3TC). Nerve biopsies also demonstrate lysosomal inclusion in Schwann cells and axons as well as adjacent cells such as fibroblasts. which also causes a toxic demyelinating neuropathy. peripheral neuropathy is an important limiting factor. not traditional mice or rats.40 Didanosine and stavudine models have been less impressive even at high dose. Aggressive HAART including these agents may lessen symptoms and improve quantitative sensory thresholds of primary HIV neuropathy by reducing viral load.34 The rapidity of onset and eventual improvement may help distinguish the processes. Small and large fibers are affected on biopsy samples. endothelial cells. a sensory neuropathy similar to humans was induced in cynomolgus monkeys with decreased large and small fiber sensory axons. Lower doses reduce toxicity.39. which can improve after drug cessation. The mechanism of toxicity is less clear. may be manifestations of these mitochondrial effects. Measures of amiodarone and desethylamiodarone were found 80 fold higher than serum in one case where intraneural levels were measured. however. Antibiotics Nucleoside Analogs Antiviral nucleoside analogs are a class of drugs resembling nucleotide bases. The class is a mainstay of highly active artiretroviral therapy (HAART). but some have reported 6 . However.41. but not in all cases. Both drugs form intralysosomal lipid complexes leading to the inclusions seen in many tissues. Optic neuropathy is also well known with abundant recent examples. appear to be toxic to mitochondria and can produce increased lactate levels. low CD4 count and viral load.38. Hivid). and animals given zalcitabine develop pathologic and electrophysiologic signs of demyelination. and myopathic EMG changes in some cases.36 The mitochondrial toxicity is associated with reduced mtDNA content through inhibition of γ-DNA polymerase.34 In some. as well as acquired lipodystrophy. Videx). Many cases show slow velocity.

and neuropathy ascertainment. or epidermal nerve fiber density. The agent is a macrolide antibiotic that suppresses both cellular and humoral mediated immune responses. Miscellaneous medications Thalidomide Thalidomide use has slowly increased over the last 10-12 years due to its antiangiogenic and antiinflammatory properties. 36. ulcerative colitis. Virtually all individuals treated for more than six months developed either clinical or electrophysiologic signs of neuropathy. in part due to differences in dosage levels. However. immunologists. produced blunting of pain but no improvement in other measures including clinical exam.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. Peripheral neuropathy appears to take the form of a severe multifocal demyelinating neuropathy resembling chronic inflammatory demyelinating neuropathy (CIDP) 7 .46 Similarly. or other cortical signs. Because the neuropathies were generally in early stages when the drug was discontinued. Some patients appear to tolerate higher doses for extended periods.48 Other than dosage adjustments. oncologists. In addition to the infamous teratogenic effects.53 Autopsy findings have shown loss of sensory axons. quantitative sensory testing. many of which are dose dependant. and dorsal column fibers. FK-506) This agent is a novel immunosuppresant increasingly used in transplant medicine. in other studies recovery has been variable and may be incomplete. headache. Electrophysiology has shown reduced or absent sensory potentials with minor motor changes. For example. Newer considerations to help blunt neuropathy progression include NGF and levacecarnine (acetylL-carnitine). and genetic differences in metabolism have been suspected but not demonstrated. notably in prostate and renal cancers. Tacrolimus (ProGraf. thus highlighting the limitations of animal models with some toxins. should be aware of these toxic effects and closely monitor patients for evidence of neuropathy.50 The true incidence and dose response relationships of thalidomide induced neuropathy remain unknown. Central toxicity is more common with a variety of findings including leukoencephalopathy. Carnitine levels were preliminarily reported reduced in HIV patients on nucleoside analogs with neuropathy suggesting possibly beneficial carnitine supplementation. recovery generally occurred. underlying neuropathy may enhance neurotoxicity. and others. reports have claimed widely variable incidence rates.incidence as high as 60%. before the drug was withdrawn. rheumatoid arthritis.44 Similar to other conditions.1. Animal and in vitro models of thalidomide neuropathy have revealed mild and unconvincing effects. current symptomatic treatment is similar to other painful neuropathies. but 24 continued thalidomide for at least 3 months. largely replacing cyclosporin A (CSA). 6 developed neuropathy.45 however. sensory neuropathy reached near epidemic levels in 1960-61. administration of NGF to HIV neuropathy patients. behavioral changes. discoid lupus and other dermatological conditions. treatment duration.49 It is also increasingly used as a chemotherapeutic agent. and dermatologists. Neurotoxicity is common in part because of relatively high doses usually given. graft-vs-host disease. a recent negative study in dogs treated with various doses of thalidomide for over a year and included nerve conduction studies. DRG neurons. arguing for a presumed effect on DRG neurons. the majority of who were on nucleoside analogs. leprosy.47. Physicians prescribing the drug. Of these. recent attempts failed to show this effect in patients with or without neuropathy irrespective of nucleoside analog use.52. Current applications are for a wide variety of disorders including Behçets and HIV-related ulcers. seizures. namely rheumatologists. Over the years.

Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Graf WD. J Neurol 2002. Some preventative agents against chemotherapy toxicity show promise. Jain KK. 8. et al. 8 . 6. 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. Fang G. Glass JD. Windebank AJ: Chemotherapeutic neuropathy. Examination of distal involvement in cisplatin-induced neuropathy in man. This pathway is also the likely cause of much of the central neurotoxicity and possibly the peripheral effects. Griffin JW. 2.58(suppl 3):A19 [Abstract] 10. Curr Opin Neurol 1999. Neurobiol Dis 2001. Windebank AJ. 7. Despite the lengthy and fastidious drug approval process.although two cases with acute motor axonal neuropathy are also reported. 11. Brain 1993. rare and idiosyncratic causes of medication-induced neuropathy may only become evident after wide-usage. Liedert B. 57 References 1. et al.54. J Clin Invest 1998.116:1017-1041. Hartung HP. et al. In: Jain KK. The calcineurin inhibition through several steps decreases T-cell proliferation. Drug-induced neurological disorders. Medication-induced toxicity should be at least considered in new cases of neuropathy including apparent idiopathic forms.8:155-161. ed. patients with existing neuropathy of known or presumed cause should have their current regimen and planned therapy considered for potential neurotoxicity. Lensch MW. Lelweg-Larsen S. Formation and repair of specific cisplatin-DNA lesions in different cell types of nervous tissue in wild type and XPCknockout mice. Katsarava Z.77:1356-1362. Chaudhry V. Both CSA and tacrolimus act through calcineurin inhibition. 2nd ed. Wang M. Ann Neurol 2001. 9. The gene for slow Wallerian degeneration (Wld(s)) is also protective against vincristine neuropathy.249:917.12:565-571. The WldS protein protects against axonal degeneration: a model of gene therapy for peripheral neuropathy. 5. but additional patients will likely be uncovered as use widens. Seattle: Hogrefe & Huber. Krarup-Hansen A. A similar agent sirolimus is also approved but no analogous cases have been reported to date. Quasthoff S. 4. Neurology 2002. Drug-induced peripheral neuropathies. Culver DG. an autopsy study.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. but none are yet approved for routine use against neurotoxic effects. Conclusions Many more agents are suspected of causing neuropathy than discussed.50:773-779. Cancer 1996. Krarup C. Culver DG. et al. Krarup-Hansen A. Chance PF.55 Some patients have responded to IVIg or plasmapheresis. Makhalova J. Fugleholm K. Cisplatin-induced neurotoxicity. though by different means (tacrolimus binding protein: FKBP-12). Also importantly. Gill JS. Neuropath Appl Neurobiol 1999. Chaudhry M. The mechanism of why in some patients an immune attack resembling CIDP or possibly trigger of an underlying condition occurs. Crawford TO. et al. Wang MS. Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin. Rietz B. Toxic neuropathy in patients with preexisting neuropathy [abstract]. Chemotherapy-induced peripheral neuropathy.25:29-40.101:2842-2850. Neurology 2002. Cisplatin-induced apoptosis in rat dorsal root ganglia neurons is associated with attempted entry in the cell cycle.58(suppl 3):A19 3. 2001:263-294.

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2B Penacillamine Pyridoxine abuse Sulphasalazine Tacrolimus (FK506. more important.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 Drugs with more common. ProGraf) Zimeldine 11 . and better established associations are highlighted in bold 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.