Peripheral Neuropathies Associated with Drugs and Toxins

Disease/Disorder

Definition

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. Toxic neuropathies are primarily characterized as length dependent, symmetric, sensory polyneuropathies with possible motor or autonomic involvement.¹

Etiology

The etiology of toxic neuropathies encompasses a broad spectrum of agents that can damage peripheral nerves.  Alcohol-induced neuropathy and chemotherapy-induced peripheral neuropathy (CIPN) are some of the most commonly implicated – while biological toxins, industrial chemicals, and heavy metals are less common but still notable. In high-income countries, drug and alcohol induced neuropathy are more common. In developing countries, occupational and environmental causes are more prevalent.² One thing to note is that 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.³ This includes a temporal relationship, some dose response effect, and stabilization or improvement after removal of the agent.

Classification

• Drugs associated with peripheral neuropathies²
  • Chemotherapeutic agents – cisplatin, oxaliplatin, taxanes, vinca alkaloids, bortezomib, suramin, misonidazole
  • TNF-alpha inhibitors (infliximab, etanercept)
  • Immune check-point inhibitors (Anti-PD1, Anti CTLA4)
  • Antiretroviral agents (zalcitabine, didanosine, stavudine)
  • Amiodarone ⁴
  • Thalidomide
  • Antibiotics (metronidazole, dapsone, fluoroquinolones, isoniazid, linezolid, nitrofurantoin)
  • Disulfiram
  • Pyridoxine excess
  • Colchicine
  • 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)
• Alcohol
• Nitrous oxide

Epidemiology

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. In the United States, chemotherapeutic agents are one of the most common drugs 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.⁵ Alcohol represents 10% of polyneuropathies. And approximately 40% of those with chronic alcohol use are estimated to experience neuropathy.²

Pathology

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.^6,7

• Dorsal root ganglion toxicity
  • Thalidomide
  • Cisplatin
  • Bortezomib
  • Pyridoxine excess
  • Isoniazid
  • Nitrofurantoin
  • Mercury
• Microtubular axon transport function abnormalities
  • Paclitaxel
  • Vinca alkaloids
• Voltage gated
• Sodium channel abnormalities
  • Cisplatin
  • Paclitaxel
  • Oxaliplatin
• Demyelination
  • Infliximab
  • Etanercept
  • Adalimumab
  • Suramin
  • Amiodarone
  • Perhexiline
  • Phenytoin

Disease course

Most symptoms have an insidious onset or occur very shortly after exposure with a few exceptions. Organophosphates and cisplatin may take many weeks post administration to develop symptoms.^8,9 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.¹⁰ Frequently it is difficult to attribute a subclinical neuropathy to prolonged, low-level toxic exposure. Neuropathy due to chronic alcohol use has a slowly progressive presentation. Chronic alcohol use, however, is associated with nutritional deficiencies, most notably thiamine deficiency which itself can cause secondary neuropathy.²

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 risk of falls and development of contractures. Autonomic impairments from neuropathy can also cause dizziness and falls.

Essentials of Assessment

History

• Positive or negative sensory findings including numbness, tingling, neuropathic pain, and stocking glove pattern sensory loss.
  • Paresthesia and neuropathic pain can be quite debilitating, significantly affecting one’s quality of life.
• 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)
• Other systemic manifestations associated with toxic neuropathies may include fatigue, anemia, renal failure, gastrointestinal symptoms, seizures, and cognitive changes.

Physical examination

• Impaired monofilament testing
• Impaired vibratory sensation and proprioception
• Impaired balance testing
• Coordination/dexterity deficits
• Impaired temperature sensation
• Depressed or absent distal symmetric tendon reflexes
• Distal motor weakness

Clinical functional assessment: mobility, self-care cognition/behavior/affective state

Grading Systems for Neuropathies¹¹

Multiple grading systems in assessing for CIPN exist.

• National Cancer Institute Common Toxicity Criteria (NCICTC)
  Most commonly used grading system
  5 grade scale¹¹
• 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

Laboratory studies

Standard workup of peripheral neuropathies includes hemoglobin A1C, TSH, vitamin B1, vitamin B6, vitamin B12, and SPEP/IFE. Heavy metal screening should be performed if a toxin is suspected. However, this is usually not helpful unless obtained immediately after an exposure.¹²

Supplemental assessment tools

Diagnostic Testing

Electrophysiology

The most common finding is a length dependent sensorimotor axonopathy with the nerve conduction studies (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 particularly in the distal muscles. A limitation of NCS is that they do not detect small fiber abnormalities.¹²

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.¹³
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

Recommended Treatments

There are three different components to treatment: prevention, rehabilitation of functional impairments, and symptomatic pain management.^14,15

• 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; topical ketamine
• Opiate analgesics and mixed opioids with serotonin-norepinephrine reuptake inhibition (tramadol and tapentadol)
• Alpha lipoic acid
• Home and outpatient rehabilitation: exercise has been shown to be helpful for various types of neuropathies.  Particularly, endurance training at moderate intensity (40–70% of heart rate reserve) and sensorimotor training are the most evidence-based exercise modalities.  This is thought to be due to the anti-inflammatory and pro-regenerative effects of endurance exercise after peripheral nerve injury.  Studies incorporating these forms of training have been shown to reduce neuropathic symptoms, improve balance control, and patient’s health-related quality of life.¹⁶
• Orthoses, splints and assistive devices: can aid impaired balance and gait impairment.
• Protective footwear and daily foot exams to diligently monitor any early skin breakdown and wound complications.
• 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

N/A

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

Development of axonal neuropathies have been found to be mediated through the protein sterile-α and Toll/interleukin 1 receptor motif containing protein 1 (SARM1). SARM1 is a metabolic sensor, and thought to be activated during times of metabolic stress. In preclinical trials, inhibition of the SARM1-mediated axon degeneration pathway has been associated with resistance to the development of neuropathy in three major categories of chemotherapy agents (DNA damaging – platinum based drugs; cytoskeletal modulating – taxanes, vinca alkaloids; and protein degradation – bortezomib, thalidomide).¹⁴

The use of biomarkers and neuroimaging are promising areas of advancement in better understanding the pathogenesis of drug and toxin induced neuropathies that will hopefully lead to early diagnosis, accurate prognosis, and targeted therapy. 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.¹⁷

Neuromuscular ultrasound (NMUS) is an established diagnostic tool that can be used in conjunction with NCS and EMG for peripheral neuropathies. NMUS can help differentiate axonal and demyelinating neuropathies. While a majority of CIPN demonstrate axonal loss, newer immunotherapies such as immune checkpoint inhibitors (anti-PD1, anti-LD-L1, anti-CTLA4) can be associated an immune-mediated neuropathy such as Guillain-Barre syndrome. In such cases, NMUS can help delineate the pattern and extent of nerve enlargement to aid in diagnosis.¹⁸

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.¹⁹ Intrathecal drug delivery systems and neuromodulation interventions such as spinal cord stimulation and peripheral nerve stimulation are well established therapies in chronic pain management.¹⁵ Future research is needed to better delineate their effectiveness in CIPN. Ongoing research efforts on non-pharmacologic interventions such as hand cooling and compression, acupuncture, and scrambler therapy have been promising but larger studies are needed in order to confirm efficacy in CIPN.¹⁵ There are also new emerging drugs such as suzetrigine, a newly FDA-approved non-opioid medication for pain that may have future applications in CIPN.¹⁴ Ongoing research is needed to further investigate these and other novel CIPN treatments as growing cancer population would undoubtedly benefit from this research.

References

1. Valentine WM. Toxic Peripheral Neuropathies: Agents and Mechanisms. Toxicologic Pathology. 2020;48(1):152-173.
2. Peters J, Staff NP. Update on Toxic Neuropathies. Curr Treat Options Neurol. 2022 May;24(5):203-216. doi: 10.1007/s11940-022-00716-5. Epub 2022 Apr 6. PMID: 36186669; PMCID: PMC9518699.
3. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health.  2005;95 (Suppl 1): S144–50.
4.  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.
5.  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.
6.  Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J. Peripheral Nervous System.  2008;13(27):27-46..
7. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol.  2002;249:9-17.
8. Santos NAGD, Ferreira RS, Santos ACD. Overview of cisplatin-induced neurotoxicity and ototoxicity, and the protective agents. Food Chem Toxicol. 2020 Feb;136:111079. doi: 10.1016/j.fct.2019.111079. Epub 2019 Dec 28. PMID: 31891754.
9. Viswanath, A., Barman, A., Sahoo, J. et al. Organophosphorus poisoning induced delayed neurotoxicity: a report of two cases. Spinal Cord Ser Cases 9, 54 (2023). https://doi.org/10.1038/s41394-023-00611-4
10. Albers JW, Chaudry V, Cavaletti G, et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev CD005228, 2011.
11. Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology. 2003;61:1297–1300.
12. Manji H. Toxic neuropathy. Current Opinion in Neurology. 2011;24:484-490.
13. 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.
14. Rhee JY, Paulino MT, Finnemore A, Tentor Z, Cashman C. Recent Advances in Diagnosis, Management, Treatment, and Prevention of Neuropathies in Cancer Patients. Curr Neurol Neurosci Rep. 2025 Jun 20;25(1):42. doi: 10.1007/s11910-025-01429-3. PMID: 40540116.
15. D’Souza RS, Alvarez GAM, Dombovy-Johnson M, Eller J, Abd-Elsayed A. Evidence-Based Treatment of Pain in Chemotherapy-Induced Peripheral Neuropathy. Curr Pain Headache Rep. 2023 May;27(5):99-116. doi: 10.1007/s11916-023-01107-4. Epub 2023 Apr 14. PMID: 37058254.
16. Streckmann F, Balke M, Cavaletti G, Toscanelli A, Bloch W, Décard BF, Lehmann HC, Faude O. Exercise and Neuropathy: Systematic Review with Meta-Analysis. Sports Med. 2022 May;52(5):1043-1065. doi: 10.1007/s40279-021-01596-6. Epub 2021 Dec 29. PMID: 34964950.
17. 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.
18. Hartinger S, Hammersen J, Leistner NA, Lawson McLean A, Risse C, Senft C, Schütze S, Heiling B, Schwab M, Mäurer I. The role of neuromuscular ultrasound in diagnostics of peripheral neuropathies induced by cytostatic agents or immunotherapies. Acta Neuropathol Commun. 2023 Nov 27;11(1):187. doi: 10.1186/s40478-023-01685-9. PMID: 38012771; PMCID: PMC10683078.
19. 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

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, Joseph Baker, MD, Jasmina Solankee, MD. Peripheral Neuropathies Associated with Drugs and Toxins. 11/30/2022.

Author Disclosure

Yoonhee Choi, MD
Nothing to Disclose

Kim Barker, MD
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Ryan Floresca, MD
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