Peripheral neuropathies associated with drugs and toxins

Author(s): Stephen Kishner, MD, Sarah E Clevenger, MD

Originally published:09/02/2015

Last updated:09/02/2015

1. DISEASE/DISORDER

Definition

An important complication of chemotherapy or other medication use, or exposure to toxins, is the development of a subacute or chronic peripheral neuropathy. This is primarily characterized by a distal symmetrical and primarily sensory polyneuropathy. There may also be motor or autonomic neuropathy involvement.

Etiology

Neurotoxic side effects are the second most common side effect to cancer treatment after hematological effects. 1 Thus peripheral neurotoxicity may be a limiting factor in the use of many chemotherapy agents. The first case of peripheral neuropathy associated with chemotherapy was secondary to cisplatin in 1978.2

More than 200 chemicals are known to be neurotoxic to humans. 3 Of these chemicals, many are organic solvents that can cause neuropathies. Solvents are commonly used in many occupational and recreational settings and must be considered in any unexplained neuropathy.

Drug toxicity may appear from unusual sources. For example, 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 Another example is recreational drugs that are spiked to increase potency. Arsenic has been added to opium to increase its potency.5

Chronic alcohol ingestion can be considered a toxin and has a well-recognized association with the development of a peripheral neuropathy.

It is often 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.

Classification

  1. 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
    • Thalidomide
    • Antibiotics (metronidazole, dapsone, podophyllin9,10, fluoroquinolones11, isoniazid12, nitrofurantoin)
    • Disulfiram
    • Pyridoxine excess
    • Colchicine
    • Phenytoin, Lithium
    • Chloroquine, hydroxychloroquine
  2. Organic solvents – aliphatic, aromatic, cyclic, and halogenated hydrocarbons, alcohols, ethers, esters, ketones, and glycols
  3. Heavy metals (arsenic, thallium, lead, mercury, gold)
  4. Alcohol

Epidemiology

Large-scale toxic exposures are rare; most are from small scale or individual exposures, or from suicidal or homicidal incidences. Only 24% of all peripheral neuropathies are thought to be secondary to drugs.13 A sizable proportion of neuropathies are undiagnosed as to etiology. Many medications and exposure to toxins may be important in finding a cause for these undiagnosed neuropathies.

Overall incidence of chemotherapy induced peripheral neuropathy (CIPN) is in the 30-40% range, but this is extremely variable. Important variables are duration of treatment, total dose, preexisting neuropathy, and comorbidities. Chemotherapeutic agents are more likely to cause peripheral neuropathy at higher dosages, and when used in combination. People with preexisting neuropathies are at significant risk for neuropathic deterioration after a potential neurotoxic exposure.

Agent Incidence of Peripheral Neuropathy
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.
Oxaliplatin 10-20% with moderate doses, and 50% at high doses.14
Paclitaxel 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.15
Amiodarone 6% incidence of neuropathy.16, 17
Zalcitabine and Stavudine 10% incidence of neuropathy.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.19
Vincristine Vinca alkaloids, such as vincristine, are associated with almost all people being treated developing a neuropathy, severe enough to limit treatment in 30% of cases.
Thalidomide Associated with neuropathy in 50% of cases but severe in less than 10%.20
Chronic alcohol use Neuropathy affects 25-66% of patients with chronic alcoholism.21

Pathology

Peripheral nerve axons are long and are susceptible to agents that interfere with axonal transport or energy metabolism. Toxic exposure causes axonal degeneration. This primarily affects the more distal nerve segments. This may continue proximally, even up to the corticospinal tracts, spinocerebellar tracts, and dorsal columns with certain agents.

The precise mechanism for the development of the neuropathy is often unclear. Cisplatin inhibits DNA synthesis, while taxanes and vinca alkaloids are antimicrotubule agents. There are different proposed neurotoxicity mechanisms depending on the drug.22

  1. Dorsal root ganglion toxicity
    • Thalidomide
    • Cisplatin
    • Bortezomib
    • Pyridoxine excess
    • Isoniazid
    • Nitrofurantoin
    • Mercury
  2. Micotubular axon transport function abnormalities
    • Paclitaxel
    • Vinca alkaloids
  3. Voltage gated
  4. Sodium channel abnormalities
    • Cisplatin
    • Paclitaxel
    • Oxaliplatin
  5. Demyelination
    • Infliximab
    • Etanercept
    • Adalimumab
    • Suramin
    • Amiodorone
    • Perhexiline
    • Phenytoin

Disease course

Most symptoms have an insidious onset, occur very shortly after exposure with a couple of exceptions. Organophosphates and cisplatin may take many weeks post administration to develop symptoms.1,5

Most symptoms plateau and show gradual improvement. However, cisplatin or oxaplatin neuropathy may progress for up to two months after discontinuation.

Some toxins produce other symptoms in addition to neuropathy, specifically central nervous system dysfunction.

Subclinical neuropathy may be seen from prolonged, low-level exposure. It is often difficult to relate the neuropathy to a toxic exposure in these cases.

Specific secondary or associated conditions and complications

N/A

2. ESSENTIALS OF ASSESSMENT

History

  1. Positive or negative sensory findings including numbness, tingling, neuropathic pain, and stocking glove pattern sensory loss.
  2. Distal motor weakness potentially leading to foot drop, gait abnormalities, hand weakness, and muscle atrophy. (e.g. Lead often resembles radial motor neuropathy with wrist drop)
  3. Autonomic dysfunction (e.g. orthostatic hypotension)
  4. Drugs causing toxic neuropathies can also lead to other systemic manifestations.
  5. Depending on the severity of the neuropathy there can be significant quality of life issues including problems with activities of daily living, balance, and fine motor skills.

Physical examination

  1. Decreased monofilament sensation
  2. Impaired vibratory sensation
  3. Loss of proprioception
  4. Loss of deep tendon reflexes symmetrically, starting distally.
  5. Distal motor weakness

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

Grading Systems for Neuropathies23,24

While there is no widely accepted grading system or assessment tool in use for CIPN, multiple grading systems exist.

  1. National Cancer Institute Common Toxicity Criteria (NCICTC)
    Most commonly used grading system
    5 grade scale24
  2. Total Neuropathy Score
    Primarily used in clinic research
    Has both electrophysiological and clinical components
  3. Chemotherapy Induced Neurotoxicity Questionnaire
  4. Neuropathy Symptom Score
  5. Neuropathy Impairment Score
  6. Patient Neurotoxicity Questionnaire

NCI-CTC Grading Criteria

Grade Sensory Motor
 0 None None
 1 Paresthesias with no objective sensory loss Subjective but no objective weakness
 2 Sensory loss with no ADL limitations Mild weakness
 3 Sensory loss with ADL limitations Moderate weakness
 4 Severe sensory loss interfering with function Flaccid paralysis

Laboratory studies

If a toxin is suspected, heavy metal screening should be performed. However, this is usually not helpful unless done immediately after an exposure. It may be beneficial with chronic low-grade exposures. Additional causes of peripheral neuropathies should also be assessed by checking hemoglobin A1C, fasting glucose, TSH, BUN, creatinine, and vitamin B12.

Supplemental assessment tools

Diagnostic Testing

1. Electrophysiology
A limitation to electrodiagnostic studies is that they are more sensitive but not specific.
The most common finding is of a distal motor sensory axonopathy. Thus sensory nerve, and compound motor action potentials can have a reduced amplitude or be absent.
There may be needle EMG abnormalities in a length dependent distribution that may include neurogenic findings such as reduced recruitment, large motor units, and abnormal spontaneous activity.

2. Quantitative sensory testing (QST)
This may help evaluate vibratory and thermal impairments, and current perception threshold.
Standard EMG and nerve conduction studies primarily test the largest fibers. QST on the other hand can test small fiber neuropathies.

3. Histopathology and intradermal nerve fiber density assessment
Skin biopsies may provide a detailed view of neuropathology.25,26
Punch biopsy assessment of nerve fiber density is considered a reliable technique to diagnose small fiber neuropathy.

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

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

1. Dosage reduction or change in the drug involved
2. Avoidance of the occupational toxin
3. Neuropathic pain management
Anticonvulsants (gabapentin, pregabalin)
Tricyclic antidepressants (amitriptyline)
Serotonin-noradrenalin reuptake inhibitor (SNRI) drugs (duloxetine and venlafaxine)
Topical capsaicin, lidocaine
Opiate analgesics
4. Rehabilitation including physical therapy and occupational therapy
5. Orthotics, protective footwear, and assistive devices

At different disease stages

N/A

Coordination of care

The treatment team may include the treating physicians including the oncologist if the neuropathy is due to chemotherapeutics, pharmacologists, and physical and occupational therapists. If the neuropathy is due to a on the job exposure human resources may be involved as well. If there is pending litigation, the patient’s attorney will also 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 unexplained peripheral neuropathy. These neuropathies can significantly affect quality of life.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Understanding the genetic factors that are associated with the development of toxic or chemotherapy induced neuropathies may lead to beneficial treatments in the future. Ongoing research attempts to reveal the factors that predispose someone to these neuropathies.

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Multiple trials of different chemoprotective agents, such as vitamin E, used to reduce or prevent chemotherapy-induced neuropathy have not showed conclusive results. However, one study, unfortunately with a high dropout rate, showed a significant decrease in cisplatin neuropathy with 400mg/day of vitamin E (Alpha-tocopherol) of 5.9% versus 41.7% in the placebo group.27 Other agents studied for the use in the prevention of CIPN include calcium or magnesium infusions, melatonin, carbamazepine, erythropoietin, amifostine and acetyl-L-carnitine.

REFERENCES

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  2. 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.
  3. Myers J, et al. Neurotoxicology and development: Human, environmental and social impacts. NeuroToxicology. 45:217-219, 2014.
  4. Saper RB, Kales SN, Paquin J, et al. Heavy metal content of ayurvedic herbal medicine products. JAMA 292:2868-73, 2004.
  5. Misra UK, Kalita J. Toxic neuropathies. Neurology India 57:697-705, 2009.
  6. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health 95 (Suppl 1): S144–50, 2005.
  7. Dalakas MC. Peripheral neuropathy and antiretroviral drugs. J Periph N Syst 6:14-20, 2001.
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  9. 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.
  10. 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.
  11. Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother 35:1540-1547, 2001.
  12. Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs 24:655-667, 2010.
  13. 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.
  14. Argyriou AA, Polychronopolous P, Iconomou G, et al. A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev 34:368-377, 2008.
  15. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol 249:9-17, 2002.
  16. 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.
  17. Santoro L, Barbieri F, Nucciotti R, et al. Amiodarone-induced experimental acute neuropathy in rats. Muscle Nerve 15:788-795, 1992.
  18. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 19:481-494, 1998.
  19. 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.
  20. Delforge M, Blade J, Dimopoulos MA, et al. Treatment related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 11: 1086-1095, 2010.
  21. Manji H. Toxic neuropathy. Current Opinion in Neurology 24:484-490, 2011.
  22. Albers JW, Chaudry V, Cavaletti G, et al. Interventions for preventing neuropathy caused by cisplatin and related compounds. Cochrane Database Syst Rev CD005228, 2011.
  23. Cavaletti G, Bogliun G, Marzorati L, et al. Grading of chemotherapy-induced peripheral neurotoxicity using the Total Neuropathy Scale. Neurology 61:1297–1300, 2003.
  24. 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.
  25. 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.
  26. 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.
  27. Pace A, Giannarelli D, Savarese A, et al. Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology 74:762-768, 2010.

Author Disclosure

Stephen Kishner, MD
Nothing to Disclose

Sarah E Clevenger, MD
Nothing to Disclose

 

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