Peripheral neuropathies associated with drugs and toxins

Author(s): Kim Dan Do Barker, MD, Christopher J Vacek, MD, MS

Originally published:09/02/2015

Last updated:11/19/2019

1. DISEASE/DISORDER

Definition

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.

Etiology

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.

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 such as arsenic, thallium, lead, mercury, gold via environmental exposure (e.g. occupation, living conditions, or consumption)
  4. Alcohol

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. 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

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.25

  1. Dorsal root ganglion toxicity
    • Thalidomide
    • Cisplatin
    • Bortezomib
    • Pyridoxine excess
    • Isoniazid
    • Nitrofurantoin
    • Mercury
  2. Microtubular 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 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

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 toxicity often resembles radial motor neuropathy with wrist drop and weak finger extension)
  3. Autonomic dysfunction (e.g. orthostatic hypotension)
  4. Drugs causing toxic neuropathies can lead to other systemic manifestations such as fatigue, anemia, renal failure, gastrointestinal symptoms, seizures, and cognitive changes.
  5. 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.

Physical examination

  1. Impaired monofilament testing
  2. Impaired vibratory sensation and proprioception
  3. Impaired balance testing
  4. Coordination/dexterity deficits
  5. Impaired ability to discern temperature differences
  6. Depressed or absent distal symmetric tendon reflexes
  7. 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.

  1. National Cancer Institute Common Toxicity Criteria (NCICTC)
    Most commonly used grading system
    5 grade scale28
  2. Total Neuropathy Score
    Primarily used in clinic research with 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 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

Laboratory studies

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

Diagnostic Testing

1. Electrophysiology
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

Recommended Treatments

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
  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)
    Capsaicin, lidocaine
    Opiate analgesics and mixed opioids with serotonin-norepinephrine reuptake inhibition (tramadol and tapentadol)
  4. 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
  5. Orthotics, protective footwear, and assistive devices

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.

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

REFERENCES

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Original Version of the Topic

Stephen Kishner, MD, Sarah E Clevenger, MD. Peripheral neuropathies associated with drugs and toxins. 09/02/2015.

Author Disclosure

Kim Dan Do Barker, MD
Nothing to Disclose

Christopher J Vacek, MD, MS
Nothing to Disclose

 

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