Peripheral neuropathies can have a wide variety of etiologies, including but not limited to, metabolic, nutritional, infectious, and autoimmune. These causes vary in the severity and duration of symptoms. Toxic peripheral neuropathies can be environmental, occupational, recreational, or iatrogenic. The prevalence of their cause is influenced by geographical and economic factors. For instance, in developed countries, the most common cause of toxic neuropathy is drug toxicity, particularly associated with chemotherapy treatments. Toxic neuropathies are primarily characterized as length dependent, symmetric, sensory polyneuropathies with possible motor or autonomic involvement.1
A clinically and functionally important complication as a result of drug use, chemotherapy, or toxin exposure is the development of a subacute or chronic peripheral neuropathy. This is primarily characterized as a length dependent, symmetric, sensory polyneuropathy with possible motor or autonomic involvement.
There are more than 200 chemicals known to be neurotoxic to humans.2 Many of these chemicals are organic solvents commonly used in occupational and recreational settings and unfortunately the immediate source of drug toxicity may not always be evident. There are a number of prescribed medications, including chemotherapeutic agents, that cause neurotoxicity.3 Peripheral neurotoxicity can be a limiting factor in the use of many chemotherapy agents.4 Alcohol as an etiology of peripheral neuropathy is often overlooked. According to the WHO, 5.1 % of the global burden of disease and injury is attributable to alcohol. Some herbal medicine products commercially available have been shown to contain heavy metals such as lead, mercury, and arsenic. Using these herbal products may lead to heavy metal toxicity and secondary peripheral neuropathy.5 A 2014 Boston study found that 20% of locally available traditional Indian herbal medicine products contained harmful levels of lead, mercury and/or arsenic.6
It can be difficult to show a causal relationship between an agent and a resultant neuropathy. Bradford Hill’s criteria for causation is generally required to provide adequate evidence.7 This includes a temporal relationship, some dose response effect, and stabilization or improvement after removal of the agent.
- Drugs associated with peripheral neuropathies
- Chemotherapeutic agents – cisplatin, oxaliplatin, taxanes, vinca alkaloids, bortezomib, suramin, misonidazole
- TNF-alpha inhibitors (infliximab, etanercept)
- Antiretroviral agents (zalcitabine, didanosine, stavudine)8
- Cardiac medications (amiodarone, perhexiline, statins)9
- Antibiotics (metronidazole, dapsone, podophyllin,10,11 fluoroquinolones,12 isoniazid,12 nitrofurantoin)
- Pyridoxine excess
- Phenytoin, Lithium
- Chloroquine, hydroxychloroquine
- Organic solvents – aliphatic, aromatic, cyclic, and halogenated hydrocarbons; alcohols, ethers, esters, ketones, and glycols
- Heavy metals such as arsenic, thallium, lead, mercury, gold via environmental exposure (e.g., occupation, living conditions, or consumption)
Most toxic exposures (including heavy metals, organophosphates, and biologics) are small scale, or from suicidal or homicidal incidents. A large proportion of neuropathies have an unknown etiology, and 24% of all peripheral neuropathies are attributed to drugs or toxins.14 In the United States, chemotherapeutic agents are the most commonly thought of drug to cause neuropathy. Overall prevalence of chemotherapy induced peripheral neuropathy (CIPN) is variable with a time dependent course. In a systematic review of 4139 patients, 68% of patients were found to have CIPN within the first month, which subsequently decreased to 60% at 3 months and 30% after 6 months. Variables increasing the risk of neuropathic deterioration include duration of treatment, combination therapy, baseline neuropathy, history of smoking, comorbidities, and cumulative dose.15
|Agent||Incidence of Peripheral Neuropathy|
|Amiodarone||6% incidence of neuropathy.16, 17|
|Bortezomib||In the treatment of multiple myeloma with bortezomib there is a 63% incidence of neuropathy, with up to 30% requiring dose reduction or alternate treatment secondary to neuropathic pain. However, this neuropathy can be improved on completion of treatment.18|
|Chronic alcohol use||Neuropathy affects 25-66% of patients19|
|Cisplatin||30-65% incidence of symptomatic neuropathy.14 The first symptoms usually appear about one month after treatment. After discontinuation, the neuropathy may continue to progress for another two months.|
|Lead||Axonal damage of motor nerves, primarily extensors when exposed to excessive levels. In workers with an average of 18.3mcg/dL, there was a 30% incidence.20|
|Oxaliplatin||10-20% with moderate doses, and 50% at high doses.21|
|Phenytoin||Neuropathy associated with chronic treatment (18%), particularly at higher levels.22 This is somewhat counterintuitive as it can be used to treat painful peripheral neuropathy.|
|Taxols||Subclinical neuropathy at low dosages (60 to 90%), but significant neuropathy at high dosages that can limit the use of this medication in 30% of cases. Tingling of toes and fingertips can start as soon as 24 hours after infusion.23|
|Thalidomide||Associated with neuropathy in 50% of cases but severe in less than 10%.24|
|Vincristine||Almost all patients exposed to vinca alkaloids, like vincristine, develop a neuropathy, limiting treatment in 30% of cases.|
|Zalcitabine and Stavudine||10% incidence of neuropathy.25|
Peripheral axons are susceptible to agents that interfere with axonal transport or energy metabolism. Toxic exposure causes axonal degeneration, which primarily affects distal nerve segments. However, certain agents primarily affect the proximal nerve segment.
The precise mechanism for the development of the neuropathy is often unclear. There are different proposed neurotoxicity mechanisms depending on the drug.26
- Dorsal root ganglion toxicity
- Pyridoxine excess
- Microtubular axon transport function abnormalities
- Vinca alkaloids
- Voltage gated
- Sodium channel abnormalities
Most symptoms have an insidious onset or occur very shortly after exposure with few exceptions. Organophosphates and cisplatin may take many weeks post administration to develop symptoms.2,6
In CIPN, most symptoms plateau and show gradual improvement, especially after discontinuation, such as with paclitaxel. In contrast, oxaliplatin neuropathy may worsen for up to three months after discontinuation.27
Frequently it is difficult to attribute a subclinical neuropathy to prolonged, low-level toxic exposure.
Specific secondary or associated conditions and complications
Sensory deficits can lead to balance difficulties and increased fall risk. Additionally, insensate skin can lead to burns, wounds, and pressure ulcers that indirectly increase the risk of infections. Motor deficits can decrease activity levels increasing the fall risk and development of contractures. Autonomic impairments from neuropathy can also cause dizziness and falls.
Essentials of Assessment
- Positive or negative sensory findings including numbness, tingling, neuropathic pain, and stocking glove pattern sensory loss.
- Distal motor weakness potentially leading to foot drop, gait abnormalities, hand weakness, and muscle atrophy. (e.g. lead toxicity often resembles radial motor neuropathy with wrist drop and weak finger extension)
- Autonomic dysfunction (e.g. orthostatic hypotension)
- Drugs causing toxic neuropathies can lead to other systemic manifestations such as fatigue, anemia, renal failure, gastrointestinal symptoms, seizures, and cognitive changes.
- Depending on the severity of the neuropathy, there can be significant quality of life issues including problems with activities of daily living and instrumental activities of daily living. Additionally, vocation can be adversely impacted by neuropathy.
- Impaired monofilament testing
- Impaired vibratory sensation and proprioception
- Impaired balance testing
- Coordination/dexterity deficits
- Impaired ability to discern temperature differences
- Depressed or absent distal symmetric tendon reflexes
- Distal motor weakness
Clinical functional assessment: mobility, self-care cognition/behavior/affective state
Grading Systems for Neuropathies28,29
Multiple grading systems in assessing for CIPN exist.
- National Cancer Institute Common Toxicity Criteria (NCICTC)
Most commonly used grading system
5 grade scale29
- Total Neuropathy Score
Primarily used in clinic research with electrophysiological and clinical components
- Chemotherapy Induced Neurotoxicity Questionnaire
- Neuropathy Symptom Score
- Neuropathy Impairment Score
- Patient Neurotoxicity Questionnaire
NCI-CTC Grading Criteria
|1||Asymptomatic or loss of deep tendon reflexes or paresthesias; no functional impairment||asymptomatic, weakness on testing only|
|2||Sensory alteration or paresthesia interfering with function but not ADL||Symptomatic weakness interfering with function but not ADL|
|3||Sensory alteration with ADL limitations||weakness interfering with ADL; bracing or assistive devices indicated|
|4||Severe sensory loss, disabling||life-threatening; disabling|
Standard workup of peripheral neuropathies includes hemoglobin A1C, fasting glucose, TSH, BUN, creatinine, vitamin B1, vitamin B6, and vitamin B12. Heavy metal screening should be performed if a toxin is suspected. However, this is usually not helpful unless obtained immediately after an exposure.26
Supplemental assessment tools
The most common finding is a length dependent sensorimotor axonopathy with the NCS being the most informative with SNAP and CMAP potential amplitudes being reduced or absent. Needle EMG abnormalities may reveal a length dependent distribution with typical neuropathic findings including abnormal spontaneous activity, large amplitude motor units, and reduced recruitment. A limitation of nerve conduction studies is that they do not detect small fiber abnormalities.26
|Electrophysiological Findings||Toxic Agent|
|Motor more than sensory findings||organophosphates, lead, vincristine, dapsone, nitrofurantoin, disulfiram|
|Sensory more than motor findings||cisplatin, arsenic, thallium, pyridoxine, thalidomide, polychlorinated biphenyls, metronidazole, mercury, isoniazid|
|Segmental demyelination||amiodarone, perhexiline, diphtheria or tetanus toxin administration, phenytoin|
Quantitative sensory testing (QST)
This may help evaluate vibratory and thermal impairments and define current perception threshold. QST can test small fiber neuropathies.
Histopathology and intradermal nerve fiber density assessment
Skin biopsies provide a detailed view of neuropathology.30,31
Punch biopsy assessment of nerve fiber density is considered a reliable technique to diagnose small fiber neuropathy.
Rehabilitation Management and Treatments
Available or current treatment guidelines
There are three different components to treatment: prevention, rehabilitation of functional impairments, and symptomatic pain management.2
- Dosage reduction or change in the drug
- Avoidance of the occupational toxin
- Neuropathic pain management
Anticonvulsants/nerve membrane stabilizers (gabapentin, pregabalin)
Tricyclic antidepressants (amitriptyline)
Serotonin-noradrenalin reuptake inhibitor (SNRI) drugs (duloxetine and venlafaxine)
- Topical Capsaicin; Topical lidocaine
- Opiate analgesics and mixed opioids with serotonin-norepinephrine reuptake inhibition (tramadol and tapentadol)
- Home and outpatient rehabilitation: An increase in chemo related exercise regimens continue to provide evidence for decrease of neuropathy symptoms. CIPN patients have been found to have significantly increased TUG (timed up and go test) times due to shorter step length and gait velocity.32 In a multicenter, randomized control trial of 355 predominantly female cancer patients undergoing active chemo, a customized 6 week progressive walking and low to moderate intensity resistance home exercise program group demonstrated reduced numbness, tingling, and hot/coldness.33
- Orthoses and assistive devices: can aide weakness and impaired balance and sensation. For instance, an Ankle Foot Orthosis can serve as a brace to prevent foot drop and also aide in postural instability. Assistive devices such as canes, walkers, crutches, etc. can also help with weakness and/or balance impairment.34
- Protective footwear is of importance for anyone with sensory impairments for peripheral neuropathy to ensure no skin breakdown or wounds occur.
- Splinting and casting may also be of benefit to prevent or treat joint contractures occurring from weakness and immobilization in peripheral neuropathy.
At different disease stages
Coordination of care
The treatment team may include the treating physicians, pharmacologists, and physical and occupational therapists. If the neuropathy is due to an on the job exposure, human resources and occupational medicine may be involved as well. If there is pending litigation, the patient’s attorney will be part of the team.
Translation into Practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Drugs and toxins should always be considered in evaluation of peripheral neuropathy, and particularly in cases where there is no obvious explanation. These neuropathies can significantly affect quality of life.
Cutting Edge/ Emerging and Unique Concepts and Practice
Initially discovered in 1951, administration of oral alpha lipoic acid at 600 mg per day for 40 days has demonstrated decreases in patient’s subjective peripheral neuropathy symptoms including reductions in work disability, social life, and family life scoring for diabetic neuropathy.35, 36 Utilizing compounding pharmacies for topical agents such as ketamine, as well as anti-epileptics and TCA’s that are not tolerated orally due to side effects, have been found to be successful in some persons.37
Researchers continue to identify new biomarkers of CIPN and related proteins to better understand the pathogenesis and inform strategies for future CIPN treatment.38 One recent protein of interest in CIPN includes the neuronal calcium sensor 1 (NCS1 protein). The discovery that taxanes increase the binding of NCS1 has led researchers to turn towards Lithium therapy as NCS1 levels have been found to be elevated in patients with bipolar disorder. 39,40,41
Simple, non-pharmaceutical interventions continue to be investigated as well, providing unique and interdisciplinary approaches into play. One study conducted with 40 breast cancer patients has even explored the utilization of massage therapy, a cost effective and easy intervention, in preventing CIPN with positive outcomes.42 Other studies have continued to examine acupuncture in relief of CIPN. A more recent Systematic Review found acupuncture to be a safe treatment option, it did not find sufficient evidence to recommend it.43
Gaps in the Evidence-Based Knowledge
With an increase in both the number of cancer patients and the length of cancer survivorship, there is an urgent need to address potential prevention and novel treatments for CIPN. Examination of genetic factors associated with the development of toxic or chemotherapy induced neuropathies may lead to targeted treatments in the future. Previously studied agents such as vitamin E, calcium or magnesium infusions, melatonin, carbamazepine, erythropoietin, amifostine, and acetyl-L-carnitine have been studied as possible preventative interventions of CIPN. Despite this evolving evidence, there is no American Society of Clinical Oncology recognized recommended CIPN prevention.44
Preliminary evidence for novel neuropathic pain management has varied in options such as cannabinoids45, 46, lidocaine infusion47, ketamine infusions48, spinal cord stimulators4, and scrambler therapy.50,51 Future research is needed to further investigate these and other novel CIPN treatments as growing cancer population would undoubtedly benefit from this research
- Valentine WM. Toxic Peripheral Neuropathies: Agents and Mechanisms. Toxicologic Pathology. 2020;48(1):152-173.
- Kedar A, Cohen ME, Freeman AI. Peripheral neuropathy as a complication of cisdichlorodiammineplatinum (II) treatment: a case report. Cancer Treat Rep. 1978;62:819-21, 1978
- Alcohol Fact Sheet. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/alcohol Last updated September 21, 2018. Accessed 10/10/19.
- Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J. Peripheral Nervous System. 2008;13(27):27-46..
- Myers J, et al. Neurotoxicology and development: Human, environmental and social impacts. NeuroToxicology. 2014;45:217-219.
- Saper RB, Kales SN, Paquin J, et al. Heavy metal content of ayurvedic herbal medicine products. JAMA. 2004;292(23):2868-2873.
- Misra UK, Kalita J. Toxic neuropathies. Neurology India 2009;57:697-705.
- Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95 (Suppl 1): S144–50.
- Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Periph N Syst. 2001;6:14-20.
- Gaist D, Jeppesen U, Anderson M, et al. Statins and risk of polyneuropathy: a case controlled study. Neurology 58:1333-1337, 2002.
- Chapon F, Dupuy B, Gosset S, et al. Intoxication accidentale a la podophyllin: un cas avec etude du nerf peripherique. Rev Neurol. 1991;147:240-243.
- Ng TH, Chan YW, Yu YL, et al. Encephalopathy and neuropathy following ingestion of a Chinese herbal broth containing podophyllin. J Neurol Sci. 1991;101:107-113.
- Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother . 2001;35:1540-1547.
- Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs 24:655-667, 2010.
- Jain KK. Drug-induced peripheral neuropathies. In Jain KK, ed. Drug-Induced Neurological Disorders 2nd ed. Hogrefe and Huber, Seattle, WA, pp 263-294, 2001.
- Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249:9-17.
- Fraser AG, McQueen IN, Watt AH, et al. Peripheral neuropathy during long-term high-dose amiodarone therapy. J Neurol Neurosurg Psychiatry. 1985;48:576-578.
- Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf. 1998;19:481-494.
- Delforge M, Blade J, Dimopoulos MA, et al. Treatment related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol. 2010;11: 1086-1095.
- Rubens o, et al. Peipheral neuropathy in chronic occupational inorganic lead exposure: a clinical and electrophysiological study. BMJ. 2001;71(2):200-204.
- Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta analysis. Pain. 2004;155: 2461-2470.
- Swift TR, Gross JA, Ward LC, et al. Peripheral neuropathy in epileptic patients. Neurol. 1981;31:826-31.
- Argyriou AA, Polychronopolous P, Iconomou G, et al. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev. 200834:368-377.
- Richardson PG, Xie W, Mitsaides C, et al. Single agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy and molecular correlations with response and neuropathy. J Clin Oncol. 2009;27:3518-3525.
- Santoro L, Barbieri F, Nucciotti R, et al. Amiodarone-induced experimental acute neuropathy in rats. Muscle Nerve. 119215:788-795.
- Manji H. Toxic neuropathy. Current Opinion in Neurology. 2011;24:484-490.
- Albers JW, Chaudry V, Cavaletti G, et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev CD005228, 2011.
- Pachman DR, Qin R, Seisler D, et al. Comparison of oxaliplatin and paclitaxel-induced neuropathy. Support Care Cancer. 2016;24:5059-5068.
- Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology. 2003;61:1297–1300.
- Dyck PJ, Hughes RA, O’Brien PC. Quantitating overall neuropathic symptoms, impairments, and outcomes. Peripheral Neuropathy, 4th Edn. Dyck PJ, Thomas PK (Eds). Elsevier Saunders, Philadelphia, PA, pp 1031–1051, 2005.
- Arezzo JC, Litwak MS, Zotova EG. Correlation and dissociation of electrophysiology and histopathology in the assessment of toxic neuropathy. Toxicologic Pathology. 2011;39:46-51.
- Polydefkis M, Hauer P, Sheth S, et al. The time course of epidermal nerve fiber regeneration: studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606-1615.
- Marshall TF, Zipp GP, Battaglia F, et al. Chemotherapy-induced-peripheral neuropathy, gait and fall risk in older adults following cancer treatment. Journal of Cancer Research and Practice 4: 134-138, 2017.
- Gita Ramdharry. Chapter 26 – Peripheral nerve disease. Handbook of Clinical Neurology, Elsevier, Volume 159, 2018, Pages 403-415.
- Hershman DL, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in surivors of adult cancers: American Society of Clinical Oncology clinical practice guidelines. J Clin Oncol. 2014;32(18):1941-67.
- Kleckner IR, Kamen C, Gewandter JS, et al. Effects of Exercise during Chemotherapy on Chemotherapy-Inducted Peripheral Neuropathy: A Multicenter, Randomized Controlled Trial. Support Care Cancer. 2018;26: 1019-1028.
- Agathos E, Tentolouris A, Eleftheriadou I, et al. Effect of alpha lipoic acid on symptoms and quality of life in patients with painful diabetic neuropathy. J Int Med Res 2018;46:1779-1790.
- Hershman DL, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guidelines. J Clin Oncol. 2014;32(18):1941-67.
- Rodwin RL, Siddiq NZ, Ehrlich BE, Lustberg MB. Biomarkers of Chemotherapy-Induced Peripheral Neuropathy: Current Status and Future Directions. Front Pain Res (Lausanne). 2022;3:864910.
- Ibrahim EY, Ehrlich BE. Prevention of chemotherapy-induced peripheral neuropathy: A review of recent findings. Crit Rev Oncol Hematol. 2020;145:102831.
- 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.
- Izgu N, Metin ZG, Karadas C, Ozdemir L, Cetin N, Demirci U. Prevention of chemotherapy-induced peripheral neuropathy with classical massage in breast cancer patients receiving paclitaxel: An assessor-blinded randomized controlled trial. Eur J Oncol Nurs. 2019;40:36-43.
- Li K, Giustini D, and Seely D. A Systematic Review of Acupuncture for Chemotherapy-Induced Peripheral Neuropathy. Curr Oncol. 2019;26(2):e147-e154.
- Loprinzi CL, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO Guideline Update. J Clin Oncol. 2020;33(28):3325-3348.
- Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage. 2014 Jan;47(1):166-73.
- Blanton HL, et al. Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain. Drugs. 2019;79(9):969-995.
- Mouin DE, et al. Intravenous lidocaine in the management of chronic peripheral neuropathic pain: a randomized controlled trial. Can J Anaesth. 2019;66(7):820-827.
- Jonkman K, van de Donk T, Dahan A. Ketamine for cancer pain: what is the evidence? Curr Opin Support Palliat Care. 2017;11(2):88-92.
- Aman MM, et al. The American Society of Pain and Neuroscience (ASPN) Best Practices and Guidelines for the Interventional Management of Cancer-Associated Pain. J Pain Res. 2021 Jul 16;14:2139-2164.
- Loprinzi C, Le-Rademacher JG, Majithia N, et al: Scrambler therapy for chemotherapy neuropathy: A randomized phase II pilot trial. Support Care Cancer 28:1183-1197, 2020
- Smith TJ, Razzak AR, Blackford AL, et al: A pilot randomized sham-controlled trial of MC5-A Scrambler Therapy in the treatment of chronic chemotherapy-induced peripheral neuropathy (CIPN). J Palliat Care 35:53-58, 2020
Original Version of the Topic
Stephen Kishner, MD, Sarah E Clevenger, MD. Peripheral neuropathies associated with drugs and toxins. 9/2/2015.
Previous Revision(s) of the Topic
Kim Dan Do Barker, MD, Christopher J Vacek, MD, MS. Peripheral neuropathies associated with drugs and toxins. 11/19/2019.
Kim Dan Do Barker, MD
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Joseph Baker, MD
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Jasmina Solankee, MD
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