Drug-induced neuropathies …

Louis H Weimer MD

Neuropharmacology & Neurotherapeutics

Updated 12.24.2023
Released 11.02.1999
Expires For CME 12.24.2026

Drug-induced neuropathies

Author: Louis H Weimer MD

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Drug-induced neuropathies

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Introduction

Overview

Although uncommon, medication-induced neuropathies are critical to identify because of potential reversibility and limitation of toxicity. Numerous medications have well-established neuropathy links, but many others have only occasional temporal associations. Neuropathy-inducing medications are continually approved, including some that are not known to cause neuropathy prior to release, for example, the rheumatoid arthritis drug leflunomide and tumor necrosis alpha inhibitors. The importance of some, such as phenytoin, is likely overestimated. Peripheral neuropathy from chronic drug exposure is more problematic to establish, and the association with idiopathic neuropathy and statin drugs is a prime example. The author discusses the best evidence available for neuropathy and many commonly used medications.

Key points

	• Medication-induced neuropathy is a potentially reversible form of neuropathy.
	• Identification of toxicity is critical before significant axonal injury occurs.
	• Many medications have limited or dubious evidence for toxicity.
	• Certain individuals are more susceptible to neurotoxicity, especially those with existing neuropathy, specific genetic predispositions, or renal or hepatic insufficiency.

Historical note and terminology

Despite considerable increases in the number of identifiable peripheral neuropathy causes in recent years, idiopathic polyneuropathy still accounts for a significant proportion of cases. Moreover, many identifiable causes can only be treated symptomatically. Medication and toxin-induced neuropathies constitute a minority of cases, probably around 2% to 4%, but they are crucial to identify because of potentially reversibility, especially if uncovered prior to significant nerve injury.

Numerous medications and toxins have been associated with neuropathy, but objective proof is lacking for many. Suspicion of a current medication or unnamed environmental toxin is a natural and common patient concern, especially if they are informed the cause of their peripheral neuropathy is unknown despite an exhaustive diagnostic evaluation. However, a simple temporal relationship between an exposure to an agent and onset of neuropathy is the only evidence in some cases without other findings to support the claim of peripheral neurotoxicity. Symptomatic and preferably electrophysiologic improvement or resolution after cessation is also diagnostically helpful. The list of agents is not static; new medications are continually added (bortezomib, leflunomide, ixabepilone) and others have changes in usage patterns (thalidomide), some of which are discussed here and some in other sections (eg, chemotherapeutic agent neuropathy, antibiotic-induced neuropathies). Agents not covered elsewhere are discussed in this section, ranging from commonly encountered to rare, or even questionable, associations.

Clinical manifestations

Presentation and course

Symptoms, with some exceptions, are indistinguishable from prototypic toxic neuropathies including initial distal paresthesias and sensory loss in a stocking distribution affecting large or small fiber modalities or both, and lesser and later onset distal motor impairment. Some cases never progress to demonstrable motor changes or have purely or predominantly sensory manifestations. Tendon reflexes are distally depressed or absent. In some cases, the neuropathic manifestations improve but chronically persist after stopping the agent, clouding the association. Also included are presentations similar or identical to Guillain-Barré syndrome, such as with tacrolimus, zimeldine, and lithium overdose as well as a number of other agents discussed in other sections. Some agents may preferentially target dorsal root ganglia or autonomic ganglia neurons, but manifestations usually coalesce into the typical distal predominant pattern. Thus, sensory symptoms, which may be small or large diameter fiber-mediated or both, can occur. Associations are easiest with acute or subacute symptoms beginning soon after exposure to a new medication or dosage increase and subsequent improvement after cessation; however, some progression for several weeks may occur due to “coasting,” when persistent toxicity is present in some cases due to slow toxin clearance. However, in some cases, recovery is delayed even without persistent elevated levels of toxin, such as with pyridoxine neurotoxicity (14). Of interest are cases of possible occult toxic idiopathic neuropathy due to chronic medications. The example of statin drugs is a case in point. In general, although unusual, these entities are important to uncover because, unlike many neuropathy etiologies, removal of a toxic agent may lead to significant recovery (188; 144).

Prognosis and complications

Prognosis depends on the severity of involvement and the degree of axonal injury.

Biological basis

Etiology and pathogenesis

No broad etiology or pathogenic mechanism has been suggested, but isolated cases may be part of an acute hypersensitivity reaction (71). Most of the potentially pathogenic mechanisms in this section are speculative.

Specific agents.

Allopurinol. Allopurinol has been used for the treatment of gout since its approval in 1966. Allopurinol inhibits the enzyme xanthine oxidase, which blocks the metabolism of hypoxanthine and xanthine (oxypurines) to uric acid, interfering with the catabolism of purines. A number of cases of neuropathy have been associated with this agent in reports with various strengths of association (71; 194; 10). The initial description included a hypersensitivity reaction with later drug rechallenge with a subsequent repeat allergic reaction, which included symptoms and signs of peripheral neuropathy. The patient also received colchicine after symptom onset with unclear timing related to neuropathy onset. Symptoms improved but persisted after cessation (71). Fewer than 10 cases have been noted in the literature with at least two cases having complicating issues (uremia). One included some electrophysiologically and pathologically demyelinating features (10). These features were not previously noted, and regression occurred after drug cessation. Most cases occur after several or many years of therapy. No predisposition or ancillary factors are currently known. No experimental evidence supports the association, making this a possible, but not a definite, rare idiosyncratic association. In fact, the agent has been used to preserve nerve and vascular function in streptozotocin-induced diabetic neuropathy in rats (81). Inhibition of xanthine oxidase produced reactive oxygen species is the suspected beneficial effect. Blood flow declines caused by the experimental diabetes were also partially corrected.

Almitrine. Almitrine bismesylate is not FDA approved for use in the United States, but it is available in many other countries for treatment of chronic obstructive pulmonary disease and some vascular disorders including stroke prophylaxis. Almitrine acts as a peripheral chemoreceptor agonist. The component is noteworthy because it appears to commonly induce a predominantly sensory neuropathy. In one small placebo-controlled study of seven controls and five treated chronic obstructive pulmonary disease patients, three of five treated patients and none of the controls developed significant neuropathy (06). Bouche and colleagues reported 46 cases of almitrine-associated neuropathy in one series (25). The range of onset described is nine to 25 months after medication onset. Sensory symptoms restricted to distal legs involving all modalities are typical. Electrophysiology and nerve biopsy findings were consistent with sensory axonopathy (69; 141). Improvement is described in most cases and is usually complete after a year (25). Numerous other reports have been made that support the high incidence of neurotoxicity with this agent (109; 21; 141; 05; 195; 06; 70). Small placebo control studies have reported variable, but significant, percentages of patients stopping trials because of neuropathic symptoms. Gherardi and colleagues have reported nerve biopsy and ultrastructural studies of eight cases. The primary finding is axonal loss of large myelinated fibers with signs of regeneration in one delayed biopsy. In addition, signs including segmental demyelination on teased fiber preparations suggested a demyelinating component in a variable percentage of fibers. No animal studies are available for consideration. No predisposing conditions are known. Moreover, the severity of hypoxemia from the pulmonary disease does not appear to correlate with the appearance of neuropathy or subsequent improvement after cessation. One series did describe a shorter latency to neuropathy onset in chronic obstructive pulmonary disease versus vascular patients, but most were receiving higher doses. However, some additional neuropathological signs seen in isolated cases (microangiopathy) could be secondary to chronic hypoxemia. Weight loss is commonly associated with the appearance of neuropathy. Some studies using a lower dosage (< 100 mg/day) have shown no significant neuropathy, including electrophysiologic changes (189). Series have reported no dropout due to neuropathy of patients who used similar dosages, but these series are without specific methods to detect sensory loss.

Amitriptyline. Amitriptyline is a useful drug in the treatment of painful conditions including peripheral neuropathy, especially conditions with marked small fiber mediated pain involvement. However, several reports have associated this agent and, even more rarely, other tricyclic antidepressants including imipramine with inducing peripheral neuropathy (105; 106). Many of the cases described are in the setting of overdose with other complications including rhabdomyolysis and cholinergic effects on the CNS and periphery; however, a small number have described suspected neuropathy on conventional amitriptyline dosages with improvement after cessation (83; 133; 197). There is limited experimental evidence of ultrastructural lesions in cultured neurons and astrocytes, but this relation to human toxicity is speculative at best and has not altered use in patients with neuropathy.

Chloroquine. Chloroquine is an agent used to treat malaria prophylaxis and some autoimmune conditions. The primary neuromuscular complication is a vacuolar myopathy, which can be fulminant (160); however, rare cases of neuropathy with demyelinating features and axonal loss have been described (186; 167). Onset is typically 1 to 2 years after starting medication and involves both sensory and motor fibers. Severity is not typically marked. Schwann cells have shown dense and laminar cytoplasmic inclusions similar to those seen with amiodarone and perhexiline, notable other causes of demyelinating toxic neuropathy. Sural biopsies have shown axonal loss and segmental demyelination and remyelination (173). Electrodiagnostic studies have also suggested a neurogenic component superimposed on the predominant myopathy. Some have noted the pattern could mimic a polyradiculopathy. This effect has been reproduced in rats. Neuromuscular toxicity from short-term use of hydroxychloroquine or this agent against COVID19 is speculative at present. A review using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) compared adverse reports comparing chloroquine and hydroxychloroquine spurred by increased hydroxychloroquine usage for COVID-19 (138). Over 6.6 million reports were assessed. Relative odds ratio of 3.3 was found for chloroquine but no increase (1.0) for hydroxychloroquine.

Cyclosporin. Cyclosporin A has been used as an immunosuppressive agent in numerous conditions including organ transplantation and even some cases of immune mediated neuropathy. Limited information has associated cyclosporin A with otherwise unexplained peripheral neuropathy. The evidence rates this agent at best as a possible, but not probable, causative agent at present (20; 34).

Dichloroacetate. Dichloroacetate is used experimentally to treat chronic lactic acidemia from mitochondrial diseases. Peripheral neuropathy is common with chronic dichloroacetate treatment. Clinical and electrophysiologic signs of sensorimotor neuropathy are found (165; 09; 91). The neuropathy is significant but can be reversible over months if the drug is stopped. Neuropathy also develops in younger children with lactic acidosis but was said to be tolerated by most in one trial of 36 impaired children (166). The neurotoxic mechanism is not fully known, but the agent causes reversible demyelination in cultured rat Schwann cells and dorsal root ganglia neurons exposed to dichloroacetate for up to 12 days (64). The heme precursor delta-aminolevulinate is implicated in neurologic complications associated with porphyria and tyrosinemia type I. The compound is elevated in the urine of animals and humans on dichloroacetate and appears to damage Schwann cells in part by reducing the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22 (63). It is currently unclear but suspected that patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) may be at increased risk of developing the toxic neuropathy. The drug is also under investigation in the treatment of glioblastoma multiforme and other oncology effects. Dichloroacetate may help minimize treatment resistance mediated by changes in mitochondria that reduce cancer cell apoptosis in part by a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. However, studies in humans have been limited by dose-dependent peripheral neuropathy (123). Dichloroacetate has the interesting property of inhibiting its own metabolism on repeat dosing, resulting in alteration of its pharmacokinetics. This dichloroacetate effect on its own metabolism complicates the selection of an effective dose with minimal side effects (85).

Glutethimide. Glutethimide is a sedative-hypnotic agent originally used as an ethanol substitute, but it proved to be highly addictive in its own right. The compound was reclassified as schedule II and withdrawn from general availability in 1991. Chemically, the compound is structurally similar to thalidomide, an agent that more commonly induces sensory neuropathy. Rarely, neuropathy has been associated with chronic glutethimide use at high doses (134; 76). Cerebellar ataxia is also described and may be marked and persistent. Manifestations are predominantly but not exclusively sensory and are supported by limited electrodiagnostic data. Improvement or resolution over ensuing months is described. No experimental evidence or nerve biopsy data are available for correlation.

Ixabepilone. The epothilones are a relatively new class of chemotherapeutic agent with currently low tumor resistance. The class includes the natural agents, epothilone B (patupilone) and epothilone D, which are not yet FDA approved as well as the semisynthetic analog, ixabepilone (16; 170); ixabepilone was FDA approved in October 2007. This agent is also discussed in the separate chemotherapy neuropathy section. Breast cancer is the primary indication, but phase 2 studies are completed or are ongoing for a variety of cancer types. The group binds to tubulin similarly to certain other chemotherapeutic agents, such as vinca alkaloids and taxanes, but at differing binding sites. Similar to taxanes, the drugs promote dysfunctional stabilization of microtubules but with a differing mechanism, in contrast to microtubular destabilizing agents such as vincristine, colchicine, and podophyllotoxin (49). Peripheral neuropathy from ixabepilone is a major dose-limiting side effect. Mild-to-moderate (grade 1 to 2), predominately sensory neuropathy that improves or resolves is most common, but more severe grades (grade 3) occur rarely in monotherapy and at rates of 10% to 15% with combination therapy or in patients previously exposed to taxanes or capecitabine; grade 4 neuropathy appears to be very rare (54; 152; 176). Dose reduction may be adequate in many, but treatment discontinuation occurs as well; more dispersed treatment protocols may have lesser toxicity (175). Twenty-one percent of patients treated with ixabepilone plus capecitabine discontinued treatment because of sensory neuropathy in one large, phase-3 trial (175). Severity increases with cumulative dosing, especially after an average of four treatment cycles. The overall neuropathy incidence varies depending on dose and coincident treatments but is as high as 67%. The reported reversibility of sensory neuropathy is surprising considering the experience with other microtubule targeting agents such as vincristine and taxanes. One patient is reported who developed significant weakness associated with neuropathy after one treatment cycle (24). Review of all phase 2 and phase 3 clinical trials found a 1% incidence of severe neuropathy in patients previously untreated and up to 24% of breast cancer patients treated with other agents (180). Carefully monitoring for neuropathy and timely dose adjustment or treatment discontinuation is advocated depending on the neuropathy severity (170). Neuropathy is increasingly recognized as a dose-limiting side effect and 20% dose reduction is one proposed strategy (181). This entity is also discussed in the section on chemotherapy-induced neuropathy.

Leflunomide and teriflunomide. The immunosuppressive prodrug leflunomide was FDA approved in late 1998 as a disease-modifying rheumatoid arthritis treatment. It was subsequently recognized that an axonal, sometimes painful, sensorimotor polyneuropathy is associated with leflunomide (30; 23; 122). Eighty cases reported to the FDA were uncovered and described (23). After this report, additional series have been reported identifying numerous additional probable cases (15; 116; 93). Bharadwaj and Haroon describe 150 prospectively tracked rheumatoid arthritis patients in India. Fifty received leflunomide either as monotherapy or in combination with other drugs. Five developed new neuropathy (10%) in contrast to two of 100 receiving other treatments (2%). Nerve biopsy in three demonstrated epineural perivascular inflammation around small and medium-sized arterioles patchily affecting large and small myelinated nerve fibers suggesting a predominant axonopathy with features of vasculitis. All showed clinical improvement and were said to become asymptomatic within 3 months, but residual nerve conduction abnormalities remained (15). Kopp and colleagues describe a case and suggest a potential interaction between 5-FU and leflunomide and include the possible mechanism (96). Onset is usually after 3 to 6 months of drug use, although symptoms may appear sooner. Another study compared 16 rheumatoid arthritis patients treated with leflunomide with 16 others receiving alternative disease-modifying therapies. Neuropathy symptoms scores increased in 54% of the leflunomide group compared with 8% of the others; however, electrophysiology did not correlate with clinical symptoms (149). Stopping therapy within 30 days of symptom onset gives a better chance of improvement, though recovery is typically slow. Sural nerve biopsies have shown nonspecific axonal loss in most, but signs of perivascular inflammation have been described. Primary rheumatoid arthritis is an independent neuropathy risk factor often associated with vasculitis, but leflunomide reports have not generally described this type of pattern. Neuropathy incidence is higher than with rheumatoid arthritis alone or with other rheumatoid arthritis medications. One retrospective analysis found increased associated neuropathy risk with increasing age, diabetes, and the use of other potentially neurotoxic medication (117). The mechanism of neurotoxicity is not known; neuropathy cases were not detected in clinical trials. The drug remains an effective treatment and efficacy appears to be similar to methotrexate and better than sulfasalazine. However, withdrawal rates are higher than methotrexate because of toxicity; peripheral neuropathy is one of several forms of toxicity (03). Comparison of 94 rheumatoid arthritis patients treated with either leflunomide or other disease modifying agents found significant differences in quantitative cold but not vibration perception measures; leflunomide-treated patients were roughly twice as likely to have increased cold perception measures (95).

Teriflunomide, an active metabolite of leflunomide, is approved in the United States to treat multiple sclerosis. Paresthesia and peripheral neuropathy based on nerve conduction study data are associated with this agent as well. Clinical trial data suggest an incidence of 1% to 2% depending on dose, but no aftermarket reports of significant neuropathy cases are known. The TOWER extension study of 751 relapsing remitting multiple sclerosis patients treated with teriflunomide for a median of 4.25 years found four patients discontinued treatment because of clinical neuropathy (124). Three cases of small fiber neuropathy attributed to teriflunomide treatment of relapsing remitting multiple sclerosis have been reported (59). Symptom onset began 6 months, 1 year, and 4 years after treatment initiation. All failed other therapies. One had metabolic syndrome. All had a limited search for other neuropathy causes, and all had reduced epidermal nerve fiber density on skin biopsy.

Lipid lowering agents. The statin-class of cholesterol medications acts by inhibiting the rate-limiting step in cholesterol synthesis, hydroxymethylglutaryl coenzyme A. The predominant neuromuscular complication with these agents is a toxic myopathy referred to as cholesterol-lowering agent myopathy, which is well appreciated by physicians and patients. An increasingly recognized acute necrotizing myositis with rhabdomyolysis associated with antibodies against the HMG CoA enzyme can develop. However, a number of cases of peripheral neuropathy temporally associated with conventional doses of simvastatin and other agents in the class have been reported (84; 01; 143; 198; 87; 108). Partial or complete recovery after drug cessation is described. One report described sural biopsy data demonstrating small and large fiber axonal loss (143). Several cases have serial electrophysiological studies showing sensorimotor axonal neuropathy with variable levels of subsequent improvement. No experimental model to support the effect is known. Symptom onset has been described within days to as long as several years after onset. One case described neuropathy onset after several years of treatment with lovastatin; when treatment stopped, the condition improved (198). Rechallenge with pravastatin, simvastatin, and later atorvastatin each caused a subacute recurrence of burning dysesthesias that improved with cessation. Similar rapid worsening with rechallenge has been noted in other reports. One speculative mechanism proposed is that inhibition of mitochondrial hydroxymethylglutaryl coenzyme A reductase causes a subsequent decrease of ubiquinone synthesis, which potentially may disturb neuronal energy utilization (183).

Thus, only the temporal association with the neuropathy development and subsequent improvement was available to support a causative link until a case control study reported by Gaist and colleagues (67). Gaist and colleagues suspected a possible link between these agents and cases of idiopathic neuropathy, despite an earlier negative United Kingdom study (68). 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 to 1998, when statin use in Denmark increased from 11,547 to 50,318 nationwide. Gaist and colleagues identified 1084 registered patients with a diagnosis of polyneuropathy. They excluded 492 with onset prior to 1994 or 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. Thirty-five 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 were calculated as 4.6% overall with current users of statins compared to controls and 16.1% with definite neuropathy cases compared to controls. The researchers 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 2200 person-years of statin use. Considered in this way, neuropathy was suggested as a more important public health concern than myopathy in patients taking statins. However, potential pitfalls complicate the study, such as whether all symptomatic neuropathy causes were in fact excluded. Examples of complicating disorders include conditions associated with statin use, such as occult diabetes, glucose intolerance, or metabolic syndrome. (56); however, not all series found a clear association with statins and idiopathic neuropathy (08). Despite the rarity of the association, the large number of patients who take these medications makes the association potentially clinically relevant. Further uncertainty was raised in 2007 by the announcement at the meeting of the American Diabetes Association of the large 8-year long Australian Fremantle study of nearly 1300 diabetic patients that demonstrated significantly decreased risk of developing neuropathy in patients treated with statins or fibrates compared to untreated patients. The reduction was 35% and 48%, respectively (51). Experimental evidence suggests that the statin rosuvastatin improves a mouse model of diabetic neuropathy through improved microcirculation independent of cholesterol lowering effects (80). The combination of studies and evidence challenges the importance of the earlier Gaist results; statin neuropathy likely occurs but may be much less frequent than recently thought and appears to be neuroprotective in some settings. A large Danish study of over 135,000 type 2 diabetes patients on new or chronic statin treatment found no significant risk of statin induced neuropathy (98). In contrast, a study of a large cohort from Korean health insurance data of type II diabetes patients found a 1.22 neuropathy odds ratio associated with statin use and reduced odds ratio for metformin-treated patients (125). A systematic review of nearly 5000 studies including two metaanalyses examined statin use and neuropathy (184). When pooled, no significant association between statin use and neuropathy was found, though they acknowledge high heterogeneity between the metaanalyses. Hyperlipidemia, notably triglycerides, is increasingly suspected as an important neuropathy factor that complicates the statin link to neuropathy (82; 139). A later Taiwanese study of 2448 patients, of which 21.4% had baseline diabetic neuropathy, has been reported. Multivariate analysis of risk factors found that hyperlipidemia, low-density lipoprotein, and total cholesterol, lipid lowering therapy, statin, or fibrate use were not associated with neuropathy prevalence (38). A systematic literature review of available trials and reports found the evidence for statin induced neuropathy to be minimal (50).

One possible case following initiation of simvastatin rapidly developed into neuropathy mimicking Guillain-Barré syndrome; a pravastatin challenge six months earlier had led to milder symptoms. The combination suggested a possible hypersensitivity reaction (146). In contrast, lovastatin attenuated nerve injury in an experimental model of experimental allergic neuritis. The effect was blocked by mevalonate (156).

There is no supportive experimental model of the potentially toxic effects, but alteration of membrane function though inhibition of cholesterol synthesis, reduction of axon transport, and inhibition of mitochondrial function have been suggested as possible factors. Oddly, some animal models support statin-induced benefit in neuropathic pain despite discussed concerns of increased neuropathic pain in humans (140). A streptozotocin (STZ)-induced diabetic rat model found that atorvastatin significantly reduced the hyperalgesia in diabetic rats, suggesting it is mediated by the nitric oxide pathway (02).

Interference with selenoprotein synthesis, a well-established pathway also implicated in some hereditary muscle disorders, has been postulated to be causative but probably relates better to myotoxicity. Myopathy from severe selenium deficiency shares some features with statin-induced myopathy (128).

Lithium. Lithium is rarely associated with neuropathy. Isolated reports describe the onset of typical toxic neuropathy manifestations after prolonged exposure on a convention dose (177; 127); however, most reports are after acute intoxication or overdose (28; 179; 136; 41; 182; 88; 121; 35). Excessive levels can occur due, in part, to the narrow therapeutic range of the drug; moreover, neuropathic findings may be underrecognized. Some reported cases are complicated by more generalized toxicity including cerebral impairment with the neuropathy becoming evident only with subsequent recovery. A chronically treated 72-year-old bipolar patient was found to have weakness, myoclonus, encephalopathy, and sensorimotor neuropathy attributed to lithium toxicity; both her EMG and EEG were notably abnormal. She improved after lithium cessation (168). Secondary infections are also problematic, raising the issue of critical illness neuromyopathy in some instances. No convincing experimental evidence is known other than an isolated report suggesting a tendency toward reduced nerve fiber area in rats chronically given lithium over control animals (107). In fact, in a small series, lithium has been reported to blunt the symptoms of vincristine-associated neuropathy in both mice and humans (142). Lithium pretreatment was found to attenuate neuropathy in paclitaxel-treated mice possibly by interacting with paclitaxel-related intracellular calcium signaling pathways (126). A double-blind placebo versus lithium 300 mg pretreatment trial of 36 breast cancer patients was reported (129). Treatment or placebo was given for 5 days in each chemotherapy cycle, starting the day prior to chemotherapy. Assessment was done by EMG, clinical symptoms, and examination at 3 and 9 months. Both groups had neuropathic signs and symptoms that improved by month 9. No significant differences between groups was noted (129). A larger multicenter, randomized phase 2 trial (N=84 subjects) including lithium versus placebo pretreatment in paclitaxel-treated patients to assess differences with chemotherapy-induced neuropathy prevention is ongoing (79).

Phenelzine. Phenelzine is a rarely used monoamine oxidase inhibitor for atypical or refractory depression. Side effects such as hypertensive crises and serious reactions with other agents are well known. Rarely, this agent (but not other MAOIs) has been implicated in inducing peripheral neuropathy. Phenelzine has been shown to affect pyridoxine metabolism and reduce measurable active pyridoxal phosphate levels in humans (113). The compound is in the same chemical class as hydralazine and isoniazid, which both reduce pyridoxal phosphate levels and can cause peripheral neuropathy. Whether this effect is clinically relevant remains to be seen. Malcolm and colleagues demonstrated pyridoxal phosphate levels reduced, on average, by half in 19 patients on phenelzine, but none developed clinical symptoms (113). Several reports of neuropathy associated with phenelzine have been published (77; 74). The neuropathy is described as a typical toxic neuropathy with sensorimotor axonal involvement with predominantly sensory manifestations.

Phenytoin. Peripheral neuropathy from chronic phenytoin use has been long recognized and generally accepted. However, despite many reported patient series, the phenomenon is based on relatively few uncomplicated prospective studies. Most likely, there is a probable effect of protracted use, especially with serum levels chronically higher than 20 µg/ml (in excess of the standard therapeutic range). Peripheral neuropathy was more commonly seen early in the history of phenytoin use when doses of 500 mg/day or higher were not uncommon. However, many of the earlier series had relatively few patients on phenytoin monotherapy, and the contributions of acute reversible phenomena were not taken into account. At current dosages with monitored serum levels, peripheral neuropathy is rare and typically produces only asymptomatic examination findings or minimally discernible neuropathy after many years of therapy. The incidence of neuropathy in epileptics on phenytoin varies considerably depending on patient populations and criteria employed (110; 58; 171; 159; 172). Several variables have been proposed as risk factors for neuropathy development, including supra-therapeutic serum levels (greater than 20 µg/ml), protracted use (less than 10 years), and low folate levels (110; 58; 44; 159). Other series have not found any significant association with phenytoin use compared with other anticonvulsants or these risk factors (171; 172). Swift and colleagues found signs of neuropathy in epileptic patients on various therapies and showed a higher incidence among patients on phenobarbital (171). One case with long-term chronically elevated serum levels (31 to 38.5 µg/ml) had clinically symptomatic neuropathy, and sural nerve biopsy demonstrated mild decreases in large diameter axonal number, axonal shrinkage, and secondary demyelination (147). This patient improved clinically and on electrophysiologic studies subsequent to phenytoin cessation. A review of the literature questioned the relevance of this association at currently utilized doses (92).

In addition, there appears to be separate acute effects on nerve function. Acute exposure to high-dose phenytoin causes reversible slowing of nerve conduction velocity. Phenytoin affects sodium permeability across neuronal membranes by stabilizing inactive sodium channels (112). Phenytoin in myelinated nerve preparations produces a voltage-dependent block of sodium channels, a shift of the sodium channel inactivation curve to more negative voltages, and a reduced rate of sodium channel recovery from inactivation (157). However, carbamazepine produced some of these effects as well. Several animal studies have examined the effects of phenytoin on peripheral nerve function. Acute reversible effects have been produced with reduced conduction velocity and compound motor action potentials with acute high dose phenytoin administration in rats (115) and slow velocity after several days in guinea pigs (104). Serum levels were higher than 50 µg/ml. This reversible phenomenon likely represents a physiologic effect but is not a model of long-term toxicity. Some degree of acute reversible effects may have complicated some prior studies that examined chronic toxicity on high dose therapy. A human report has described similar reversible symptomatic effects three hours after a phenytoin loading dose (196). This may represent an additional acute or subacute idiosyncratic syndrome, but a separate syndrome is not well established. The acute reversible effects on nerve function are well established, but the chronic neuropathy is considered a probable association (114).

Podophyllin. Extracts of various plants containing podophyllin resin have been used in Asia for hundreds and even thousands of years for a multitude of purported therapeutic benefits including snake bites, general weakness, lymphadenopathy, tumors, and warts. Similar uses arose in the West over a hundred years ago, commonly as a laxative. The active resin is derived from the roots or rhizomes of the mandrake or mayapple plant (podophyllum peltatum). Additionally, podophyllin is a component of herbs used in Chinese herbal medicines including Bajiaolian (dsyosma pleianthum) and Guijiu (podophyllum emodi wall). The chemotherapeutic agents etoposide and teniposide are semisynthetic derivatives of podophyllotoxin.

Kaplan first introduced the resin as an effective medical treatment for condyloma acuminata, for which it is still commonly used (90). Furthermore, alternative uses are still commonplace in both Asia and the West. Peripheral neuropathy from podophyllin is an unusual complication of exposure to podophyllin resin from a variety of prescription and nonprescription sources. However, despite the numerous clinical reports, this entity is typically omitted from lists of medication or toxic neuropathies. In the West, toxicity from nonprescription sources is known. Dobb and Edis reported a case in Australia of severe podophyllin toxicity with neuropathy from a simple over-the-counter dietary supplement (55). Numerous cases have followed ingestion of Chinese herbal broth containing podophyllin (132; 89; 36; 45) as well as other preparations. Confusion of intended herbs is not rare due to superficial similarities, and toxic reactions have resulted from substitution of Guijiu for other intended ingredients (89).

Conventional medical application of podophyllin is for treatment of condyloma acuminata. Treatment typically involves topical use on the wart or direct intralesional injection. Care is taken not to expose healthy tissue, especially surrounding mucosa, which produces systemic dosage and can lead to toxicity; also, application on friable skin, recent biopsy sites, or over large areas is vulnerable to toxicity. Cases of intentional overdosage have been described as well (31; 22; 135; 103).

Acute manifestations within the first 1 to 2 hours of exposure consist of nausea, vomiting, abdominal pain, and subsequent diarrhea (185; 66; 45). Exposure can be topical (185; 163; 66) oral (47; 118; 190; 55; 22; 75; 78; 37; 42; 132; 40; 89; 45), or intralesional (111; 178). There is a lone report of intramuscular exposure (187). During the first day, central nervous system impairment may ensue, including altered mental status ranging from mild confusion to frank coma. Hallucinations and seizures can also occur. Paresthesias heralding the onset of peripheral neuropathy may begin within the first 2 days but can be delayed for over a week. The neuropathy may progress to marked sensory loss of all modalities, especially large fiber light touch and proprioception. Severe sensory ataxia with wide-based gait and pseudoathetosis may develop (75; 135; 187). Patients generally develop areflexia with a distal stocking-glove pattern of sensory loss.

Autonomic neuropathy has been reported in numerous cases, with findings including sinus tachycardia, urinary retention, paralytic ileus, orthostatic hypotension, diaphoresis, and syncope (66; 187). Peripheral neuropathy has been found in all but a handful of reports; however, central involvement may be absent or transient (75; 187). Non-neurologic involvement may include hepatic dysfunction, pancytopenia, renal insufficiency, and lesser toxicity in other organ systems.

Podophyllin resin contains numerous compounds, some of which have yet to be fully elucidated, but podophyllotoxin, a highly lipid soluble alkaloid, has been shown to be the primary active agent. Other constituents include picropodophyllum, podophyllic acid, alpha and beta peltatin, and the mutagens quercetin and kaempferol (154). Quercetin may have independent neurotoxic effects (46). The resin, as well as purified podophyllotoxin, has been shown to cause parallel toxicity in experimental animals, including marked axonal neuropathy and morphologic changes in the dorsal root ganglia as well as central and peripheral nervous system axons (192; 39). Correspondingly, electrodiagnostic studies have suggested a sensory neuronopathy in addition to the peripheral dying-back form of toxic axonopathy (40).

Podophyllotoxin has a chemical structure similar to colchicine and vinblastine, which are other causes of axonal neuropathy as well as agents that arrest mitosis in metaphase. All of these compounds disrupt microtubular function and inhibit axonal transport. Both podophyllotoxin and colchicine bind to tubulin leading to axonal transport disruption. Dorsal root and autonomic ganglia may also be susceptible to circulating toxin and lead to the neuronopathy. Evidence of both effects is seen in experimental models and clinical reports (75; 39). Toxicity is rare with careful medical application. Manufacturers recommend strict guidelines for medication availability and usage techniques, including application procedures and subsequent drug removal. Added risk from application on friable areas or recent biopsy sites is also critical. Risk from nonmedical sources is less controllable. Additionally, peripheral neuropathy is prevalent in the population at large. Many patients choose to self-medicate with complimentary or alternative medical remedies without informing their treating physicians, most commonly patients with diabetic neuropathy. Some remedies could potentially contain podophyllin resin and have a detrimental effect. In one series, 43% of neuropathy patients tried some form of alternative treatment (27).

Treatment with podophyllin is contraindicated in pregnancy and may lead to miscarriage or stillbirth. One case of intrauterine death at week 32 after mucosal application has been reported (33), as has another with limb malformations (154). However, no controlled human studies are available.

Proton pump inhibitors. A rare effect of commonly used medications can be particularly problematic to resolve and substantiate. One example is the proton pump inhibitors omeprazole and lansoprazole. Rajabally and Jacob reported a 42-year-old woman who developed predominantly sensory neuropathy after three months of lansoprazole use (145). Some partial improvement was noted after later stopping the medication, and no worsening was seen after switching to rabeprazole and then to ranitidine. Three other cases are reported with omeprazole, two of which have adequate electrophysiology and clinical information (62). Additional carefully studied examples are needed to further substantiate this possible link with medication-induced neuropathy in this widely used class of medications. No new cases have been published as of the most recent literature search since these reports despite continued widespread use of these agents. However, these agents and histamine-2 blockers may affect vitamin B12 absorption and lead to secondary neurologic complications (101).

Slaughterhouse workers progressive inflammatory neuropathy. Although not technically a medication-induced neuropathy, this local toxic epidemic at several pork processing plants in Minnesota and surrounding states produced considerable activity and investigation by numerous researchers, mostly at the Centers for Disease Control (32). Twelve workers in a swine slaughterhouse in Minnesota developed a progressive inflammatory neuropathy with symptoms ranging from acute paralysis to gradually progressive symmetric weakness predominantly in the legs from eight to 213 days with varying severity between November 2006 and 2007. Eleven patients had evidence of axonal or demyelinating features by electrodiagnostic testing. Spinal fluid from seven patients showed elevated protein (mean 120 mg/dl) with no or minimal pleocytosis. Ten patients had evidence of inflammation on spinal magnetic resonance imaging (nine patients in peripheral nerves or roots and one patient in the anterior spinal cord). Three patients with sural nerve biopsy showed mild perivascular inflammation. In summary, patients were characterized with a sensory greater than motor polyradiculopathy, predominantly at the root or distal nerve level. The CDC researchers identified that all patients were working in close proximity to swine heads. A compressed air device used to liquefy porcine brain material may have generated aerosolized brain material, which may have induced an immune neurotoxic response. Ultimately work at the Mayo Clinic led by Vanda Lennon found a complex autoantibody profile dominated by neural cation channel IgGs that most significantly affected voltage-gated potassium channels (120).

Tacrolimus. Prograf, previously known as FK-506, is a novel immunosuppressant that is widely used in transplant medicine and for suppression of some inflammatory disorders. The agent is a macrolide antibiotic that suppresses both cellular and humoral mediated immune responses. Neurotoxicity is common in treated patients, in part, because of the 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 dependent. Peripheral neuropathy appears to take the form of a severe multifocal demyelinating neuropathy that resembles chronic inflammatory demyelinating neuropathy (191; 26; 100). Patients have responded to IVIG or plasmapheresis as well. Optic neuropathy is also uncommon but described (148). A possible case of cyclosporine-induced erythromelalgia in a patient with myasthenia gravis is reported (29).

Both cyclosporin A and tacrolimus act through inhibition of calcineurin, though by different means (tacrolimus binding protein: FKBP-12) (164). The calcineurin inhibition, through several steps, decreases IL-2 and eventually 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, increases growth associated protein (GAP-43), and is beneficial to nerve regeneration in nerve axotomy and ischemia models (73; 94). FKBP-52 is part of a steroid receptor complex and may represent a target for future regenerative therapies separate from the growth factor and Trk pathways. The mechanism of why, in some patients, an immune attack that resembles chronic inflammatory demyelinating neuropathy or other autoimmune neuropathy is unclear; however, the number of reported examples is small. Interestingly, tacrolimus has also been shown to have significant and potentially therapeutic neuroregenerative activity, possibly derived from a separate pathway from the immunosuppressive calcineurin inhibition--FKBP-52 binding protein (99; 72). Schwann cells may play an important intermediary role (18). A similar agent, sirolimus, appears to have less risk of this reaction but at least one case is reported (17).

Tumor necrosis factor-alpha blockers. Tumor necrosis factor-alpha (TNF-alpha) blockers are used in the treatment of various forms of inflammatory arthritis and inflammatory bowel diseases but are also associated with inducing or worsening other autoimmune disorders including multiple sclerosis (169). One agent (etanercept) has been reported to improve chronic inflammatory demyelinating neuropathy (CIDP) (102; 43). Postmarketing reporting identified 15 patients diagnosed with Guillain-Barré syndrome or Miller Fisher syndrome from 6 weeks to 2 years after starting a TNF-alpha blocker, although associated infection may be a more important risk factor (151; 158). One case developed acute sensorimotor neuropathy and concomitant encephalopathy (61). Richez and colleagues reported two cases that developed a CIDP-like illness (150). One treated with etanercept for rheumatoid arthritis developed a demyelinating neuropathy 17 months later. The other received infliximab for ankylosing spondylitis and developed CIDP 3 months later. Both incompletely improved after drug cessation without specific treatment for CIDP. Infliximab is also associated with several other CIDP-like cases with underlying rheumatoid arthritis (86; 174; 07) and three cases with underlying psoriatic arthritis, a condition that is much less likely to induce spontaneous or vasculitic neuropathy (169; 57). One reported patient on chronic adalimumab for rheumatoid arthritis developed significant demyelinating neuropathy on initiation of steroids that may have unmasked the inflammatory neuropathy (193). Chronic adalimumab therapy was also implicated in a case of distal acquired demyelinating symmetric neuropathy for the treatment of rheumatoid arthritis (119). Numerous cases resembling multifocal motor neuropathy are reported in association with infliximab (162; 48; 153; 137; 65; 155; 11). However, others question whether some of these cases were actually a form of vasculitic mononeuritis multiplex triggered by the infliximab (19). One case of proposed infliximab-associated immune-mediated sensory polyradiculopathy was successfully treated with intravenous gammaglobulin (131). There are additional less-clear associations with mononeuropathy and axonal sensory or sensorimotor neuropathy (86). In any event, it seems that infliximab and etanercept can contribute to or trigger an immune-mediated neuropathy in some possibly susceptible patients (97). Adalimumab is not clearly associated with chronic neuropathy but was associated with one possible Guillain-Barré syndrome case. Ipilimumab, a monoclonal antibody that is not a TNF alpha antagonist but instead blocks a natural inhibitor of cytotoxic T-cell response to cancer cells, is approved to treat melanoma and is undergoing trials for other cancer types. A case of acute neuropathy mimicking Guillain-Barré syndrome is reported; acute enteric neuropathy is also recognized. A case of adalimumab inducing sensory vasculitic neuropathy is reported (161). A very large observational study in five Nordic countries separately tracked patients with rheumatoid arthritis and spondyloarthritis treated with TNF-alpha monoclonal antibody treatments from 2001 to 2020 (53). The primary outcome measure was development of a neuroinflammatory complication using ICD-10 neuropathy codes. They found 314 such events out of about 62,000 total patients. Central demyelinating events and multiple sclerosis were most common, but 86 cases of probable inflammatory neuropathy were reported. No difference in various treatments were detected, though comparing etanercept to other agents was a primary study goal. Unexpectedly, spondyloarthritis patients had a higher complication rate than rheumatoid arthritis patients.

Interestingly, in light of fluoroquinolone patient-derived reports, peripheral neuropathy associated with TNF-alpha agents was the most common adverse neurologic event reported to the Food and Drug Administration Adverse Event Reporting System (296 reports, 38.3%), exceeding central nervous system and/or spinal cord demyelination (153 reports, 19.8%) (52). The majority of reports (71%) were labeled as “possibly associated” and not higher grades of certainty.

In contrast, these agents may have other protective properties. A mouse model of bortezomib neuropathy found that upregulation of TNF-alpha was neuroprotective, possibly by limiting certain inflammatory cytokines (04).

Zimeldine. Zimeldine is another agent never approved for use in the United States but available transiently as an antidepressant in Sweden, functioning as a 5-HT reuptake inhibitor with purported fewer side effects. The drug is best known as a probable precipitating factor of an outbreak of Guillain-Barré syndrome in Sweden in 1983. The drug was withdrawn from the market 18 months after introduction because of this outbreak. A subsequent Bayesian analysis concluded that the association was supported by relevant data (130). No additional cases, however, were identified in a retrospective review of 761 patients on zimeldine reported from the same region (12). Hypersensitivity reactions are relatively common with this agent (1.4% to 13%), raising the question of potential immune-mediated mechanisms in this phenomenon. Zimeldine appears to affect T-cell function and blunt experimental allergic neuritis in a rat model of Guillain-Barré syndrome (13). The risk of developing Guillain-Barré syndrome from zimeldine was estimated as increased 25-fold compared to natural incidence controls (60).

References

01: Ahmad S. Lovastatin and peripheral neuropathy. Am Heart J 1995;130:1321. PMID 7484806
02: Akbarian R, Chamanara M, Rashidian A, et al. Atorvastatin prevents the development of diabetic neuropathic nociception by possible involvement of nitrergic system. J Appl Biomed 2021;19(1):48-56. PMID 34907715
03: Alcorn N, Saunders S, Madhok R. Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthritis 10 years after licensing. Drug Saf 2009;32(12):1123-34. PMID 19916579
04: Ale A, Bruna J, Morell M, et al. Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model. Exp Neurol 2014;253C:165-73. PMID 24406455
05: Allen MB. Almitrine and peripheral neuropathy. Lancet 1988;2:571. PMID 2900954
06: Allen MB, Prowse K. Peripheral nerve function in patients with chronic bronchitis receiving almitrine or placebo. Thorax 1989;44:292-7. PMID 25473867
07: Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-alpha antagonists. Muscle Nerve 2010;41(5):723-7. PMID 20405504
08: Anderson JL, Muhlestein JB, Bair TL, et al. Do statins increase the risk of idiopathic polyneuropathy. Am J Cardiol 2005;95(9):1097-9. PMID 15842981
09: Anselm IA, Darras BT. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006;67(7):1313. PMID 17030784
10: Azulay JP, Blin O, Valentin P, Abegg P, Pellissier JF, Serratrice G. Regression of allopurinol-induced peripheral neuropathy after drug withdrawal. Eur Neurol 1993;33:193-4. PMID 8385614
11: Bayrak AO, Ulusoy H, Bolat N, Doğan B, Ozbenli T. Multifocal motor neuropathy associated with infliximab: a case report and a literature review. Neurologist 2017;22(4):144-46. PMID 28644258
12: Bengtsson BO, Wiholm BE, Myrhed M, Walinder J. Adverse experiences during treatment with zimeldine on special license in Sweden. Int Clin Psychopharmacol 1994;9:55-61. PMID 8195584
13: Bengtsson BO, Zhu J, Thorell LH, Olsson T, Link H, Walinder J. Effects of zimeldine and its metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis in Lewis rats. J Neuroimmunol 1992;39(1-2):109-22. PMID 1535634
14: Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology 1992;42(7):1367-70. PMID 1620347
15: Bharadwaj A, Haroon N. Peripheral neuropathy in patients on leflunomide. Rheumatology (Oxford) 2004;43(7):934. PMID 15213340
16: Bhushan S, Walko CM. Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer. Ann Pharmacother 2008;42(9):1252-61. PMID 18648018
17: Bilodeau M, Hassoun Z, Brunet D. Demyelinating sensorimotor polyneuropathy associated with the use of sirolimus: a case report. Transplant Proc 2008;40(5):1545-7. PMID 18589148
18: Birge RB, Wadsworth S, Akakura R, et al. A role for schwann cells in the neuroregenerative effects of a non-immunosuppressive fk506 derivative, jnj460. Neuroscience 2004;124(2):351-66. PMID 14980385
19: Birnbaum J. Infliximab-associated neuropathy in RA patients--the importance of considering the diagnosis of mononeuritis multiplex. Clin Rheumatol 2007;26(2):281-2. PMID 17063281
20: Blin O, Desnuelle C, Pellissier JF, et al. [Peripheral neuropathy and cyclosporin. Apropos of 2 cases]. Therapie 1989;44(1):55-7. PMID 2544035
21: Blondel M, Arnott G, Defoort S, et al. [11 cases of neuropathy induced by almitrine, of which one had optic neuropathy]. Rev Neurol (Paris) 1986;142(8-9):683-8. PMID 2880378
22: Boillot A, Cordier A, Guerault E, et al. A rare case of severe toxic peripheral neuropathy: poisoning by podophyllin. Apropos of 1 case. J Toxicol Clin Exp 1989;9:409-12. PMID 2561370
23: Bonnel RA, Graham DJ. Peripheral neuropathy in patients treated with leflunomide. Clin Pharmacol Ther 2004;75(5):580-5. PMID 15179412
24: Bosch-Barrera J, Espinós J, Gómez-Ibáñez A, Gállego Pérez-Larraya J, Iriatre J. Sensory-motor axonal peripheral neuropathy in an advanced breast cancer patient treated with ixabepilone. Clin Transl Oncol 2009;11(11):765-7. PMID 19917541
25: Bouche P, Lacomblez L, Leger JM, et al. Peripheral neuropathies during treatment with almitrine: report of 46 cases. J Neurol 1989;236(1):29-33. PMID 2536801
26: Bronster DJ, Yonover P, Stein J, Scelsa SN, Miller CM, Sheiner PA. Demyelinating sensorimotor polyneuropathy after administration of FK506. Transplantation 1995;59(7):1066-8. PMID 7535959
27: Brunelli B, Gorson KC. The use of complementary and alternative medicines by patients with peripheral neuropathy. J Neurol Sci 2004;218:59-66. PMID 14759634
28: Brust JC, Hammer JS, Challenor Y, Healton EB, Lesser RP. Acute generalized polyneuropathy accompanying lithium poisoning. Ann Neurol 1979;6:360-2. PMID 233413
29: Caiza-Zambrano F, Galarza J, Benetti M, et al. Cyclosporine-induced erythromelalgia. Pract Neurol 2023;23(4):343-5. PMID 37391230
30: Carulli MT, Davies UM. Peripheral neuropathy: an unwanted effect of leflunomide? Rheumatology (Oxford) 2002;41(8):952-3. PMID 12154221
31: Cassidy DE, Drewry J, Fanning JP. Podophyllin toxicity: a report of a fatal case and a review of the literature. J Toxicol Clin Toxicol 1982;19:35-44. PMID 6759681
32: Centers for Disease Control and Prevention. Investigation of progressive inflammatory neuropathy among swine slaughterhouse workers--Minnesota, 2007-2008. MMWR Morb Mortal Wkly Rep 2008;57(5):122-4. PMID 18256584
33: Chamberlain MJ, Reynolds AI, Yeomen WB. Toxic effect of podophyllin application in pregnancy. Br Med J 1972;3:391-2. PMID 5070166
34: Chan CY, DasGupta K, Baker AL. Cyclosporin A: drug discontinuation for the management of long-term toxicity after liver transplantation. Hepatology 1996;24:1085-9. PMID 8903380
35: Chan CH, Leung AK, Cheung YF, et al. A rare neurological complication due to lithium poisoning. Hong Kong Med J 2012;18(4):343-5. PMID 22865182
36: Chan TY, Critchley JA. Usage and adverse effects of Chinese herbal medicines. Hum Exp Toxicol 1996;15:5-12. PMID 8845209
37: Chan YW. Magnetic resonance imaging in toxic encephalopathy due to podophyllin poisoning. Neuroradiology 1991;33:372-3. PMID 1922761
38: Chang KC, Pai YW, Lin CH, Lee IT, Chang MH. The association between hyperlipidemia, lipid-lowering drugs and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus. PLoS One 2023;18(6):e0287373. PMID 37319238
39: Chang LW, Yang CM, Chen CF, Deng JF. Experimental podophyllotoxin (bajiaolian) poisoning: I. Effects on the nervous system. Biomed Environ Sci 1992b;5:283-92. PMID 1489522
40: Chang MH, Lin KP, Wu ZA, Liao KK. Acute ataxic sensory neuronopathy resulting from podophyllin intoxication. Muscle Nerve 1992a;15:513-4. PMID 1314329
41: Chang YC, Yip PK, Chiu YN, Lin HN. Severe generalized polyneuropathy in lithium intoxication. Eur Neurol 1988;28:39-41. PMID 3130252
42: Chapon F, Dupuy B, Gosset S, et al. Intoxication accidentelle a la podophylline: Un cas avec etude du nerf peripherique. Rev Neurol (Paris) 1991;147:240-3. PMID 1648254
43: Chin RL, Sherman WH, Sander HW, Hays AP, Latov N. Etanercept (Enbrel) therapy for chronic inflammatory demyelinating polyneuropathy. J Neurol Sci 2003;210(1-2):19-21. PMID 12736082
44: Chokroverty S, Sayeed ZA. Motor nerve conduction study in patients on diphenylhydantoin therapy. J Neurol Neurosurg Psychiatry 1975;38:1235-9. PMID 176326
45: Chu CC, Huang CC, Chu NS. Sensory neuropathy due to Bajiaolian (podophyllotoxin) intoxication. Eur Neurol 2000;44:121-3. PMID 10965167
46: Chui FC. Podophyllotoxin and related compounds. In: Spencer PS, Schaumburg HH, Ludolph AC, editors. Experimental and clinical neurotoxicology, 2nd ed. New York: Oxford University Press, 2000:1008-10.
47: Clark AN, Parsonage MJ. A case of podophyllum poisoning with involvement of the nervous system. Br Med J 1957;16:1155-7. PMID 13472072
48: Cocito D, Bergamasco B, Tavella A, et al. Multifocal motor neuropathy during treatment with infliximab. J Peripher Nerv Syst 2005;10(4):386-7. PMID 16279990
49: Cortes J, Baselga J. Targeting the microtubules in breast cancer beyond taxanes: the epothilones. Oncologist 2007;12(3):271-80. PMID 17405891
50: Daliri M, Johnston TP, Sahebkar A. Statins and peripheral neuropathy in diabetic and non-diabetic cases: a systematic review. J Pharm Pharmacol 2023;75(5):593-611. PMID 36843566
51: Davis TM, Yeap BB, Davis WA, Bruce DG. Lipid-lowering therapy and peripheral sensory neuropathy in type 2 diabetes: the Fremantle Diabetes Study. Diabetologia 2008;51(4):562-6. PMID 18193189
52: Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther 2013;38(4):388-96. PMID 23802849
53: Delcoigne B, Kopp TI, Arkema EV, et al. Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis: a collaborative observational study across five Nordic rheumatology registers. RMD Open 2023;9(1):e002924. PMID 36854568
54: Denduluri N, Low JA, Lee JJ, et al. Phase II trial of ixabepilone, an epothilone B analog, in patients with metastatic breast cancer previously untreated with taxanes. J Clin Oncol 2007;25(23):3421-7. PMID 17606971
55: Dobb GJ, Edis RH. Coma and neuropathy after ingestion of herbal laxative containing podophyllin. Med J Aust 1984;140:495-6. PMID 6323937
56: Donaghy M. Assessing the risk of drug-induced neurologic disorders. Statins and neuropathy. Neurology 2002;58:1321-2. PMID 12011272
57: Eguren C, Díaz Ley B, Daudén E, García-Diez A, Losada M. Peripheral neuropathy in two patients with psoriasis in treatment with infliximab. Muscle Nerve 2009;40(3):488-9. PMID 19623630
58: Eisen AA, Woods JF, Sherwin AL. Peripheral nerve function in long-term therapy with diphenylhydantoin. Neurology 1974;24:411-7. PMID 4363815
59: Elrefaey A, Memon AB. Painful small fiber neuropathy associated with teriflunomide: a case series and literature review related to teriflunomide and leflunomide. Cureus 2023;15(9):e45079. PMID 37705563
60: Fagius J, Osterman PO, Siden A, Wiholm BE. Guillain-Barre syndrome following zimeldine treatment. J Neurol Neurosurg Psychiatry 1985;48:65-9. PMID 3156214
61: Faivre A, Franques J, De Paula AM, et al. Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J Neurol Sci 2010;291(1-2):103-6. PMID 20116808
62: Faucheux JM, Tournebize P, Viguier A, Arne-Bes MC, Larrue V, Geraud G. Neuromyopathy secondary to omeprazole treatment. Muscle Nerve 1998;21(2):261-2. PMID 9466609
63: Felitsyn N, McLeod C, Shroads AL, Stacpoole PW, Notterpek L. The heme precursor delta-aminolevulinate blocks peripheral myelin formation. J Neurochem 2008;106(5):2068-79. PMID 18665889
64: Felitsyn N, Stacpoole PW, Notterpek L. Dichloroacetate causes reversible demyelination in vitro: potential mechanism for its neuropathic effect. J Neurochem 2007;100(2):429-36. PMID 17241159
65: Fernández-Menéndez S, González Nafría N, Redondo-Robles L, et al. Multifocal-motor-neuropathy-like disease associated with Infliximab treatment in a patient with Crohn's disease. J Neurol Sci 2015;349(1-2):246-8. PMID 25592414
66: Filley CM, Graff-Richard NR, Lacy JR, Heitner MA, Earnest MP. Neurologic manifestations of podophyllin toxicity. Neurology 1982;32:308-11. PMID 7199647
67: Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology 2002;58(9):1333-7. PMID 12011277
68: Gaist D, Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology 2001;12(5):21-5. PMID 11505177
69: Gherardi R, Baudrimont M, Gray F, Louarn F. Almitrine neuropathy. A nerve biopsy study of 8 cases. Acta Neuropathol (Berl) 1987;73:202-8. PMID 3037844
70: Gherardi R, Belec L, Louarn F. Almitrine-induced peripheral neuropathy and weight loss [letter]. J Neurol 1989;236:374. PMID 2571682
71: Glyn JH, Crofts PA. Peripheral neuropathy due to allopurinol. Br Med J 1966;2:1531-2.
72: Gold BG, Voda J, Yu X, Gordon H. The immunosuppressant FK506 elicits a neuronal heat shock response and protects against acrylamide neuropathy. Exp Neurol 2004;187(1):160-70. PMID 15081597
73: Gold BG, Yew JY, Zeleny-Pooley M. The immunosuppressant FK506 increases GAP-43 mRNA levels in axotomized sensory neurons. Neurosci Lett 1998;241:25-8. PMID 9502207
74: Goodheart RS, Dunne JW, Edis RH. Phenelzine associated peripheral neuropathy--clinical and electrophysiologic findings. Aust N Z J Med 1991;21:339-40. PMID 1659356
75: Gorin F, Kindall D, Seyal M. Dorsal radiculopathy resulting from podophyllin toxicity. Neurology 1989;39:607-8. PMID 2538779
76: Haas DC, Marasigan A. Neurological effects of glutethimide. J Neurol Neurosurg Psychiatry 1968;31:561-4. PMID 5709841
77: Heller CA, Friedman PA. Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Am J Med 1983;75:887-8. PMID 6638055
78: Holdright DR, Jahangiri M. Accidental poisoning with podophyllin. Hum Exp Toxicol 1990;9:55-6. PMID 2328153
79: Huehnchen P, Bangemann N, Lischewski S, et al. Rationale and design of the prevention of paclitaxel-related neurological side effects with lithium trial - Protocol of a multicenter, randomized, double-blind, placebo- controlled proof-of-concept phase-2 clinical trial. Front Med (Lausanne) 2022;9:967964. PMID 36035422
80: Ii M, Nishimura H, Kusano KF, et al. Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy. Circulation 2005;112(1):93-102. PMID 15983249
81: Inkster ME, Cotter MA, Cameron NE. Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats. Eur J Pharmacol 2007;561(1-3):63-71. PMID 17291486
82: Iqbal Z, Bashir B, Ferdousi M, et al. Lipids and peripheral neuropathy. Curr Opin Lipidol 2021;32(4):249-57. PMID 34101657
83: Isaacs AD, Carlish S. Peripheral neuropathy after amitriptyline [letter]. Br Med J 1963;1:1739.
84: Jacobs MB. HMG-CoA reductase inhibitor therapy and peripheral neuropathy [letter]. Ann Intern Med 1994;120:970. PMID 8172444
85: James MO, Jahn SC, Zhong G, Smeltz M, Hu Z, Stacpoole PW. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol Ther 2017;170:166-80. PMID 27771434
86: Jarand J, Zochodne DW, Martin LO, Voll C. Neurological complications of infliximab. J Rheumatol 2006;33(5):1018-20. PMID 16511935
87: Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol 1999;54:835-8. PMID 10027656
88: Johnston SR, Burn D, Brooks DJ. Peripheral neuropathy associated with lithium toxicity [letter]. J Neurol Neurosurg Psychiatry 1991;54:1019-20. PMID 1666123
89: Kao WF, Hung DZ, Tsai WJ, Lin KP, Deng JF. Podophyllotoxin intoxication: toxic effect of Bajiaolian in herbal therapeutics. Hum Exp Toxicol 1992;11:480-7. PMID 1361136
90: Kaplan IW. Condyloma acuminata. New Orl Med Surg J 1942;94:388-90.
91: Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006;66(3):324-30. PMID 16476929
92: Keppel Hesselink JM, Kopsky DJ. Phenytoin: neuroprotection or neurotoxicity? Neurol Sci 2017;38(6):1137-41. PMID 28497312
93: Kho LK, Kermode AG. Leflunomide-induced peripheral neuropathy. J Clin Neurosci 2007;14(2):179-81. PMID 17107800
94: Kihara M, Kamijo M, Nakasaka Y, Mitsui Y, Takahashi M, Schmelzer JD. A small dose of the immunosuppressive agent FK506 (tacrolimus) protects peripheral nerve from ischemic fiber degeneration. Muscle Nerve 2001;24(12):1601-6. PMID 11745968
95: Kim HK, Park SB, Park JW, et al. The effect of leflunomide on cold and vibratory sensation in patients with rheumatoid arthritis. Ann Rehabil Med 2012;36(2):207-12. PMID 22639744
96: Kopp HG, Kanz L, Hartmann JT, Moerike K. Leflunomide and peripheral neuropathy: a potential interaction between uracil/tegafur and leflunomide. Clin Pharmacol Ther 2005;78(1):89-90. PMID 16003297
97: Kotyla PJ, Sliwinska-Kotyla B, Kucharz EJ. Treatment with infliximab may contribute to the development of peripheral neuropathy among the patients with rheumatoid arthritis. Clin Rheumatol 2007;26(9):1595-6. PMID 17549580
98: Kristensen FP, Christensen DH, Callaghan BC, et al. Statin therapy and risk of polyneuropathy in type 2 diabetes: a Danish cohort study. Diabetes Care 2020;43(12):2945-52. PMID 32998990
99: Kvist M, Danielsen N, Dahlin LB. Effects of FK506 on regeneration and macrophages in injured rat sciatic nerve. J Peripher Nerv Syst 2003;8(4):251-9. PMID 14641649
100: Labate A, Morelli M, Palamara G, Pirritano D, Quattrone A. Tacrolimus-induced polyneuropathy after heart transplantation. Clin Neuropharmacol 2010;33(3):161-2. PMID 20502136
101: Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013;310(22):2435-42. PMID 24327038
102: Latov N, Sherman WH. Improvement with etanercept (Enbrel) in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2000;48:473.
103: Leitner J, Hofbauer F, Ackerl M. Poisoning with a podophyllin-containing wart-treating tincture. Dtsch Med Wochenschr 2002;127:1516-20. PMID 12111657
104: LeQuesne PM, Goldberg V, Vajda F. Acute conduction velocity changes in guinea-pigs after administration of diphenylhydantoin. J Neurol Neurosurg Psychiatry 1976:39:995-1000. PMID 1003245
105: LeWitt PA, Forno LS. Peripheral neuropathy following amitriptyline overdose. Muscle Nerve 1985;8:723-4. PMID 2997606
106: Leys D, Pasquier F, Lamblin MD, Dubois F, Petit H. Acute polyradiculoneuropathy after amitriptyline overdose. Br Med J (Clin Res Ed) 1987;294(6572):608. PMID 3103821
107: Licht RW, Smith D, Braendgaard H. The effect of chronic lithium treatment on the calibre of axons and nerve fibers in the rat sural nerve. Eur Neuropsychopharmacol 1997;7(2):95-8. PMID 9169296
108: Lo YL, Leoh TH, Loh LM, Tan CE. Statin therapy and small fibre neuropathy: a serial electrophysiological study. J Neurol Sci 2003;208(1-2):105-8. PMID 12639733
109: Louarn F, Gherardi R. Almitrine and peripheral neuropathy. Lancet 1985;2:1068. PMID 2865544
110: Lovelace RE, Horwitz SJ. Peripheral neuropathy in long-term diphenylhydantoin therapy. Arch Neurol 1968;18:69-77. PMID 4293820
111: Lund O, Marstrander J, Smeby B, Monstad I, Gadeholt G. Podophyllin. Systemic poisoning after intracutaneous injection in plantar warts. Tidsskr. Nor Laegeforen 1988;108:1293-4. PMID 3388357
112: Macdonald RL, Kelly KM. Mechanism of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 1994;35(Suppl 4):S41-50. PMID 7513639
113: Malcolm DE, Yu PH, Bowen RC, O'Donovan C, Hawkes J, Hussein M. Phenelzine reduces plasma vitamin B6. J Psychiatry Neurosci 1994;19:332-4. PMID 7803366
114: Mann A, Sinnett MJ, Shinnar S. Phenytoin. In: Spencer PS, Schaumburg HH, Ludolph AC, editors. Experimental and Clinical Neurotoxicology, 2nd edition. New York: Oxford University Press, 2000:988-98.
115: Marcus DJ, Swift TR, McDonald TF. Acute effects of phenytoin on peripheral nerve function in the rat. Muscle Nerve 1981;4:48-50. PMID 7231445
116: Martin K, Bentaberry F, Dumoulin C, et al. Neuropathy associated with leflunomide: a case series. Ann Rheum Dis 2005;64(4):649-50. PMID 15769926
117: Martin K, Bentaberry F, Dumoulin C, et al. Peripheral neuropathy associated with leflunomide: is there a risk patient profile. Pharmacoepidemiol Drug Saf 2007;16(1):74-8. PMID 16845649
118: McFarland MF, McFarland J. Accidental ingestion of podophyllum. Clin Toxicol 1981;18:973-7. PMID 7318384
119: McGinty RN, McNamara B, Moore H. DADS neuropathy associated with anti-TNF-α therapy. BMJ Case Rep 2015;2015. PMID 26607186
120: Meeusen JW, Klein CJ, Pirko I, et al. Potassium channel complex autoimmunity induced by inhaled brain tissue aerosol. Ann Neurol 2012;71(3):417-26. PMID 22451206
121: Merwick A, Cooke J, Neligan A, McNamara B, Sweeney BJ. Acute neuropathy in setting of diarrhoeal illness and hyponatraemia due to lithium toxicity. Clin Neurol Neurosurg 2011;113(10):923-4. PMID 21763067
122: Metzler C, Arlt AC, Gross WL, Brandt J. Peripheral neuropathy in patients with systemic rheumatic diseases treated with leflunomide. Ann Rheum Dis 2005;64(12):1798-800. PMID 16284351
123: Michelakis ED, Sutendra G, Dromparis P, et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2010;2(31):31-4. PMID 20463368
124: Miller AE, Olsson TP, Wolinsky JS, et al. Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: results from the TOWER extension study. Mult Scler Relat Disord 2020;46:102438. PMID 32911306
125: Min HK, Kim SH, Choi JH, Choi K, Kim HR, Lee SH. Impacts of statin and metformin on neuropathy in patients with type 2 diabetes mellitus: Korean Health Insurance data. World J Clin Cases 2021;9(33):10198-207. PMID 34904090
126: Mo M, Erdelyi I, Szigeti-Buck K, Benbow JH, Ehrlich BE. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. FASEB J 2012;26(11):4696-709. PMID 22889832
127: Mohapatra S, Sahoo MR, Rath N. Lithium-induced motor neuropathy: an unusual presentation. Indian J Psychol Med 2016;38(3):252-3. PMID 27335523
128: Moosmann B, Behl C. Selenoprotein synthesis and side-effects of statins. Lancet 2004;363(9412):892-4. PMID 15031036
129: Najafi S, Heidarali Z, Rajabi M, et al. Lithium and preventing chemotherapy-induced peripheral neuropathy in breast cancer patients: a placebo-controlled randomized clinical trial. Trials 2021;22(1):835. PMID 34819131
130: Naranjo CA, Lane D, Ho-Asjoe M, Lanctot KL. A Bayesian assessment of idiosyncratic adverse reactions to new drugs: Guillain-Barre syndrome and zimeldine. J Clin Pharmacol 1990;30:174-80. PMID 2138168
131: Naruse H, Nagashima Y, Maekawa R, et al. Successful treatment of infliximab-associated immune-mediated sensory polyradiculopathy with intravenous immunoglobulin. J Clin Neurosci 2013;20(11):1618-9. PMID 23906523
132: Ng TH, Chan YW, Yu YL, et al. Encephalopathy and neuropathy following ingestion of a Chinese herbal broth containing podophyllin. J Neurol Sci 1991;101:107-13. PMID 2027023
133: Nimmo Smith RC, Grieve RC. Peripheral neuropathy after amitriptyline. Br Med J 1963;2:254.
134: Nover R. Persistent neuropathy following chronic use of glutethimide. Clin Pharmacol Ther 1967;8:283-5. PMID 4290074
135: O’Mahony S, Keohane C, Jacobs J, O’Riordain D, Whelton M. Neuropathy due to podophyllin intoxication. J Neurol 1990;237:110-2. PMID 2162382
136: Pamphlett RS, Mackenzie RA. Severe peripheral neuropathy due to lithium intoxication. J Neurol Neurosurg Psychiatry 1982;45:656. PMID 6288882
137: Paolazzi G, Peccatori S, Cavatorta FP, Morini A. A case of spontaneously recovering multifocal motor neuropathy with conduction blocks (MMNCB) during anti-TNF alpha therapy for ankylosing spondylitis. Clin Rheumatol 2009;28(8):993-5. PMID 19350342
138: Papazisis G, Siafis S, Cepatyte D, et al. Safety profile of chloroquine and hydroxychloroquine: a disproportionality analysis of the FDA Adverse Event Reporting System database. Eur Rev Med Pharmacol Sci 2021;25(19):6003-12. PMID 34661260
139: Pasha R, Azmi S, Ferdousi M, et al. Lipids, lipid-lowering therapy, and neuropathy: a narrative review. Clin Ther 2022;44(7):1012-25. PMID 35810030
140: Pergolizzi JV Jr, Magnusson P, LeQuang JA Razmi R, Zampogna G, Taylor R Jr. Statins and neuropathic pain: a narrative review. Pain Ther 2020;9(1):97-111. PMID 32020545
141: Petit H, Leys D, Hurtevent JF, et al. [Neuropathies and almitrine. 14 cases]. Rev Neurol (Paris) 1987;143(6-7):510-9. PMID 2889253
142: Petrini M, Vaglini F, Cervetti G, et al. Is lithium able to reverse neurological damage induced by vinca alkaloids. J Neural Transm 1999;106(5-6):569-75. PMID 10443559
143: Phan T, McLeod JG, Pollard JD, Peiris O, Rohan A, Halpern JP. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry 1995;58:625-8. PMID 7745415
144: Pratt RW, Weimer LH. Medication and toxin-induced peripheral neuropathy. Semin Neurol 2005;25(2):204-16. PMID 15937736
145: Rajabally YA, Jacob S. Neuropathy associated with lansoprazole treatment. Muscle Nerve 2005;31(1):124-5. PMID 15468341
146: Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain-Barré syndrome on initiation of statin therapy. Muscle Nerve 2004;30(5):663-6. PMID 15389662
147: Ramirez JA, Mendell JR, Warmolts JR, Griggs RC. Phenytoin neuropathy: structural changes in the sural nerve. Ann Neurol 1986;19:162-7. PMID 3008637
148: Rasool N, Boudreault K, Lessell S, Prasad S, Cestari DM. Tacrolimus optic neuropathy. J Neuroophthalmol 2018;38(2):160-6. PMID 29420328
149: Richards BL, Spies J, McGill N, et al. Effect of leflunomide on the peripheral nerves in rheumatoid arthritis. Intern Med J 2007;37(2):101-7. PMID 17229252
150: Richez C, Blanco P, Lagueny A, et al. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology 2005;64(8):1468-70. PMID 15851749
151: Robinson WH, Genovese MC, Moreland LW. Demyelinating and neurologic events reported in association with tumor necrosis factor antagonism: by what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis. Arthritis Rheum 2001;44(9):1977-83. PMID 11592357
152: Roche H, Yelle L, Cognetti F, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, as first-line therapy in patients with metastatic breast cancer previously treated with anthracycline chemotherapy. J Clin Oncol 2007;25(23):3415-20. PMID 17606972
153: Rodriguez-Escalera C, Belzunegui J, Lopez-Dominguez L, Gonzalez C, Figueroa M. Multifocal motor neuropathy with conduction block in a patient with rheumatoid arthritis on infliximab therapy. Rheumatology 2005;44(1):132-3. PMID 15611308
154: Rosenstein G, Rosenstein H, Freeman M, Weston N. Podophyllum – a dangerous laxative. Pediatrics 1976;57:419-21. PMID 1256956
155: Rowan CR, Tubridy N, Cullen G. Multifocal motor neuropathy associated with infliximab. J Crohns Colitis 2015;9(12):1174-5. PMID 26223843
156: Sarkey JP, Richards MP, Stubbs EB Jr. Lovastatin attenuates nerve injury in an animal model of Guillain-Barré syndrome. J Neurochem 2007;100(5):1265-77. PMID 17286627
157: Schwarz J, Grigat G. Phenytoin and carbamazepine: potential- and frequency-dependent block of Na currents in mammalian myelinated nerve fibers. Epilepsia 1989;30:286-94. PMID 2542011
158: Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor antagonist therapy. Arthritis Rheum 2006;54(5):1429-34. PMID 16645971
159: Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J Neurol Neurosurg Psychiatry 1982;45:620-6. PMID 6288881
160: Siddiqui AK, Huberfeld SI, Weidenheim KM, Einberg KR, Efferen LS. Hydroxychloroquine-induced toxic myopathy causing respiratory failure. Chest 2007;131(2):588-90. PMID 17296665
161: Sim NK, Ismail A, Alam T, Shanmugarajah PD. Adalimumab-induced sensory vasculitic neuropathy. BMJ Case Rep 2022;15(1):e246401. PMID 35039360
162: Singer OC, Otto B, Steinmetz H, Ziemann U. Acute neuropathy with multiple conduction blocks after TNF monoclonal antibody therapy. Neurology 2004;63(9):1754. PMID 15534279
163: Slater GE, Rumack BH, Peterson RF. Podophyllin poisoning. Systemic toxicity following cutaneous application. Obstet Gynecol 1978;52:94-6. PMID 683634
164: Snyder SH, Lai MM, Burnett PE. Immunophilins and the nervous system. Neuron 1998;21:283-94. PMID 9728910
165: Spruijt L, Naviaux RK, McGowan KA, et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve 2001;24(7):916-24. PMID 11410919
166: Stacpoole PW, Gilbert LR, Neiberger RE, et al. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 2008;121(5):e1223-8. PMID 18411236
167: Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol 2000;27(12):2927-31. PMID 11128688
168: Stetkarova I, Bocek V, Gismatullina A, Svobodova Z, Peisker T. Severe chronic lithium intoxication in patient treated for bipolar disorder. Neuro Endocrinol Lett 2017;38(6):397-400. PMID 29298279
169: Stubgen JP. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve 2008;37(3):281-92. PMID 18041052
170: Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol 2008;6(6):455-67. PMID 18567992
171: Swift TR, Gross JA, Ward LC, Crout BO. Peripheral neuropathy in epileptic patients. Neurology 1981;31:826-31. PMID 6264351
172: Taylor JW, Murphy MJ, Rivey MP. Clinical and electrophysiological evaluation of peripheral nerve function in chronic phenytoin therapy. Epilepsia 1985;26:416-20. PMID 2995024
173: Tegner R, Tome FM, Godeau P, Lhermitte F, Fardeau M. Morphological study of peripheral nerve changes induced by chloroquine treatment. Acta Neuropathol 1988;75:253-60. PMID 2831692
174: Tektonidou MG, Serelis J, Skopouli FN. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin Rheumatol 2007;26(2):258-60. PMID 16683176
175: Thomas E, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007b;25(33):5210-7. PMID 17968020
176: Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol 2007a;25(23):3399-406. PMID 17606975
177: Tomasina C, Manzino M, Torrazza A, Pastorino P. [Polyneuropathy in lithium therapy]. Riv Neurol 1990;60:113-6. PMID 1964743
178: Tomczak RL, Hake DH. Near fatal systemic toxicity from local injection of podophyllin for pedal verrucae treatment. J Foot Surg 1992;31:36-42. PMID 1573168
179: Uchigata M, Tanabe H, Hasue I, Kurihara M. Peripheral neuropathy due to lithium intoxication. Ann Neurol 1981;9:414. PMID 6261676
180: Vahdat LT, Thomas ES, Roché HH, et al. Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials. Support Care Cancer 2012;20(11):2661-8. PMID 22382588
181: Valero V. Managing ixabepilone adverse events with dose reduction. Clin Breast Cancer 2013;13(1):1-6. PMID 23098573
182: Vanhooren G, Dehaene I, Van Zandycke M, et al. Polyneuropathy in lithium intoxication. Muscle Nerve 1990;13(3):204-8. PMID 2157151
183: Walravens PA, Greene C, Seerman FE. Lovastatin, isoprenes, and myopathy. Lancet 1989;2:1097-8. PMID 2572816
184: Wannarong T, Chaikijurajai T, Preston DC, Naweera W, Sukpornchairak P, Ungprasert P. Statins and the risk of polyneuropathy: A systematic review and two meta-analyses. Muscle Nerve 2022;65(1):120-5. PMID 34693541
185: Ward JW, Clifford WS, Monaco AR, Bickerstaff HJ. Fatal systemic poisoning following podophyllin treatment of condyloma acuminatum. South Med J 1954;47:1204-6. PMID 13216409
186: Wasay M, Wolfe GI, Herrold JM, Burns DK, Barohn RJ. Chloroquine myopathy and neuropathy with elevated CSF protein. Neurology 1998;51:1226-7. PMID 9781573
187: Weimer LH, Arnaudo E, Freeman MC, Lovelace RE, Brust JM. Electrophysiologic and autonomic findings after intramuscular podophyllin injection. Muscle Nerve 1997;20:1059.
188: Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep 2009;9(1):69-75. PMID 19080756
189: Weitzenblum E, Arnaud F, Bignon J, et al. Sequential administration of a reduced dose of almitrine to patients with chronic obstructive bronchopneumopathies. A controlled multicenter study [Article in French] Rev Mal Respir 1992;9(4):455-63. PMID 1509190
190: West WM, Ridgeway NA, Morris AJ, Sides PJ. Fatal podophyllin ingestion. South Med J 1982;75:1269-70. PMID 7123303
191: Wilson JR, Conwit RA, Eidelman BH, Starzl T, Abu-Elmagd K. Sensorimotor neuropathy resembling CIDP in patients receiving FK-506. Muscle Nerve 1994;17(5):528-32. PMID 7512691
192: Wisniewski H, Shelanski ML, Terry RD. Effects of mitotic spindle inhibitors on neurotubules and neurofilaments in anterior horn cells. J Cell Biol 1968;38:224-9. PMID 5691976
193: Wong SL, Rajabally YA. Steroid-induced inflammatory neuropathy in a patient on tumor necrosis factor-α antagonist therapy. J Clin Neuromuscul Dis 2010;12(2):88-90. PMID 21386777
194: Worth CT, Hussein SM. Peripheral neuropathy due to long-term ingestion of allopurinol. Br Med J 1985;291:1688.
195: Wouters EF, Greve LH, Steenhuis ES, Gimeno F. Almitrine and peripheral neuropathy. Lancet 1988;2:336. PMID 2899747
196: Yoshikawa H, Tokinari A, Yoshihiko O. Extremely acute phenytoin-induced peripheral neuropathy. Epilepsia 1999;40:528-9. PMID 10219285
197: Zampollo A, Sozzi G, Basso F. Amitriptyline-related peripheral neuropathy. Case report. Ital J Neurol Sci 1988;9:89-91. PMID 2833464
198: Ziajka PE, Wehmeier T. Peripheral neuropathy and lipid-lowering therapy. South Med J 1998;91:667-8. PMID 9671841

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Drug-induced neuropathies

Differential Diagnosis

other causes of neuropathy

Also Relevant

Antibiotic-induced neuropathy
Chemotherapy-induced neuropathies
Chemotherapy: neurologic complications
Clinical evaluation of peripheral neuropathies
Drug-induced neurologic disorders
- Phenytoin
- Toxic and nutritional deficiency optic neuropathies
- Toxic peripheral neuropathies

Drug-induced neuropathies …

Drug-induced neuropathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Patient Profile

ICD & OMIM codes

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Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Disulfiram neuropathy

Mercury neuropathy

Clinical evaluation of peripheral neuropathies

Serotonin syndrome

Drug-induced neuropathies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Disulfiram neuropathy

Mercury neuropathy

Clinical evaluation of peripheral neuropathies

Serotonin syndrome

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