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. 3 The immediate source of drug toxicity may not be evident. Many of these chemicals are organic solvents commonly used in occupational and recreational settings. A number of chemotherapeutic agents cause neurotoxicity.1 Thus, peripheral neurotoxicity can be a limiting factor in the use of many chemotherapy agents.2 Alcohol as the etiology 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.4 A 2014 Boston study found that 20% of locally available traditional Indian herbal medicine products contained harmful levels of lead, mercury and/or arsenic. 5
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.6 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 (einfliximab, etanercept)
- Antiretroviral agents (zalcitabine, didanosine, stavudine)7
- Cardiac medications (amiodarone, perhexiline, statins)8
- Antibiotics (metronidazole, dapsone, podophyllin9,10, fluoroquinolones11, isoniazid12, 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. 13 Again, 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.14
|Agent||Incidence of Peripheral Neuropathy|
|Amiodarone||6% incidence of neuropathy.17, 18|
|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.20|
|Chronic alcohol use||Neuropathy affects 25-66% of patients22|
|Cisplatin||30-65% incidence of symptomatic neuropathy.13 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.23|
|Oxaliplatin||10-20% with moderate doses, and 50% at high doses.15|
|Phenytoin||Neuropathy associated with chronic treatment (18%), particularly at higher levels.24 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.16|
|Thalidomide||Associated with neuropathy in 50% of cases but severe in less than 10%.21|
|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.19|
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.25
- 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.1,5
In CIPN, most symptoms plateau and show gradual improvement, especially after discontinuation, such as with paclitaxel. In contrast, oxaplatin neuropathy may worsen for up to three months after discontinuation.26
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.
2. 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 Neuropathies27,28
Multiple grading systems in assessing for CIPN exist.
- National Cancer Institute Common Toxicity Criteria (NCICTC)
Most commonly used grading system
5 grade scale28
- 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 include 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.25
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.25
|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|
2. Quantitative sensory testing (QST)
This may help evaluate vibratory and thermal impairments and define current perception threshold. QST can test small fiber neuropathies.
3. Histopathology and intradermal nerve fiber density assessment
Skin biopsies provide a detailed view of neuropathology.29,30
Punch biopsy assessment of nerve fiber density is considered a reliable technique to diagnose small fiber neuropathy.
3.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.1
- Dosage reduction or change in the drug
- Avoidance of the occupational toxin
- Neuropathic pain management
Anticonvulsants (gabapentin, pregabalin)
Tricyclic antidepressants (amitriptyline)
Serotonin-noradrenalin reuptake inhibitor (SNRI) drugs (duloxetine and venlafaxine)
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. 31 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. 32
- Orthotics, protective footwear, and assistive devices
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.
4. 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.33, 34 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, are successful in some persons.35
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Examination of potential genetic factors associated with the development of toxic or chemotherapy induced neuropathies may lead to targeted treatments in the future. Agents studied for the use in the prevention of CIPN include vitamin E, calcium or magnesium infusions, melatonin, carbamazepine, erythropoietin, amifostine, and acetyl-L-carnitine.
Currently, ongoing studies for novel neuropathic pain medications include cannabinoids,36 lidocaine infusions,37 ketamine infusions,38 and botulinum injections.39
- 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 13:27–46, 2008.
- Kedar A, Cohen ME, Freeman AI. Peripheral neuropathy as a complication of cisdichlorodiammineplatinum (II) treatment: a case report. Cancer Treat Rep. 62:819-21, 1978.
- Myers J, et al. Neurotoxicology and development: Human, environmental and social impacts. NeuroToxicology. 45:217-219, 2014.
- Saper RB, Kales SN, Paquin J, et al. Heavy metal content of ayurvedic herbal medicine products. JAMA 292:2868-73, 2004.
- Misra UK, Kalita J. Toxic neuropathies. Neurology India 57:697-705, 2009.
- Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health 95 (Suppl 1): S144–50, 2005.
- Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Periph N Syst 6:14-20, 2001.
- 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 147:240-243, 1991.
- Ng TH, Chan YW, Yu YL, et al. Encephalopathy and neuropathy following ingestion of a chinese herbal broth containing podophyllin. J Neurol Sci 101:107-113, 1991.
- Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother 35:1540-1547, 2001.
- 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.
- Seretny M, Currie GL, Sena ES, et al. Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta analysis. Pain 155: 2461-2470, 2014.
- Argyriou AA, Polychronopolous P, Iconomou G, et al. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev 34:368-377, 2008.
- Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 249:9-17, 2002.
- Fraser AG, McQueen IN, Watt AH, et al. Peripheral neuropathy during long-term high-dose amiodarone therapy. J Neurol Neurosurg Psychiatry 48:576-578, 1985.
- Santoro L, Barbieri F, Nucciotti R, et al. Amiodarone-induced experimental acute neuropathy in rats. Muscle Nerve 15:788-795, 1992.
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- 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 27: 3518-3525, 2009.
- Delforge M, Blade J, Dimopoulos MA, et al. Treatment related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11: 1086-1095, 2010.
- Rubens o, et al. Peipheral neuropathy in chronic occupational inorganic lead exposure: a clinical and electrophysiological study. BMJ. 2001;71(2):200-204.
- Swift TR, et al. Peripheral neuropathy in epileptic patients. Neurol. 1981;31:826-31.
- Manji H. Toxic neuropathy. Current Opinion in Neurology 24:484-490, 2011.
- 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. Comparisonand oxaliplatin and paclitaxel-induced neuropathy. Support Care Cancer 24: 5059-5068, 2016.
- Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology 61:1297–1300, 2003.
- 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 39:46-51, 2011.
- 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 127:1606-1615, 2004.
- 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.
- 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 26: 1019-1028, 2018.
- 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 46: 1779-1790, 2018.
- 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.
- 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.
- Park J, Park HJ. Botulinum Toxin for the Treatment of Neuropathic Pain. Toxins. 2017;9(9).
Original Version of the Topic
Stephen Kishner, MD, Sarah E Clevenger, MD. Peripheral neuropathies associated with drugs and toxins. 09/02/2015.
Kim Dan Do Barker, MD
Nothing to Disclose
Christopher J Vacek, MD, MS
Nothing to Disclose