Loading

Review Article Open Access
Volume 6 | Issue 2 | DOI: https://doi.org/10.33696/Neurol.6.112

Drug-Induced Peripheral Neuropathy: Focus on Newer Offending Agents

  • 1Faculté de médecine de Tunis, Gouvernorat de Tunis, Tunis, Tunisia
+ Affiliations - Affiliations

*Corresponding Author

Yasmine S. Mahjoubi, m.yasmin7951@gmail.com

Received Date: September 27, 2024

Accepted Date: December 12, 2024

Abstract

Peripheral neuropathy (PN) is a common neurological disorder resulting from peripheral nerve damage, significantly contributing to morbidity and adversely affecting patients’ quality of life. Drug-induced peripheral neuropathy (DIPN) accounts for 2-4% of cases and typically manifesting as distal, symmetrical sensory polyneuropathy. The growing diversity of medications complicates DIPN diagnosis, often leading to underreporting and mismanagement due to overlapping symptoms with other conditions. This systematic review analyzed DIPN literature up to September 15, 2024, emphasizing both established and emerging neurotoxic drugs. A focused search prioritized recent studies and case reports on new agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). Traditional chemotherapeutics and other recognized drug classes were summarized, while TKIs and ICIs were analyzed in detail, highlighting their neurotoxic risks. Statistical data on the incidence rates of TKI- and ICI-related neuropathy are not yet uniformly collected or thoroughly analyzed in the literature. Current evidence suggests that incidence rates for neuropathy vary by drug and cancer type, estimated at 10% for TKIs and 14% for ICIs. Increased vigilance is recommended for healthcare providers when prescribing medications associated with PN, particularly newer agents. Regular monitoring and reporting of suspected cases to pharmacovigilance systems are essential for improving patient outcomes and enhancing the understanding of DIPN mechanisms. Further research is necessary to explore neuroprotective strategies and genetic susceptibility factors, enabling personalized treatment appraoches.

Keywords

Drug induced neuropathy, Peripheral neuropathy, Neuropathy with systemic drugs, Chemotherapy-induced neuropathy, Platinum drugs, Taxanes, Vinca alkaloïds, Tyrosine kinase inhibitors, Immune checkpoint inhibitors

Background 

Peripheral neuropathy (PN) is one of the most common neurological diseases, with an estimated prevalence of 2.4% in the general population and increasing to 8% in the elderly [1]. PN results from damage to peripheral nerves [2-5]. Although fatal outcomes due to PN are rare, it significantly contributes to morbidity, with pain symptoms affecting 10%–30% of patients and falls and fractures occurring in 18%–25% of adults, adversely affecting patients’ quality of life [5-7]. The severity of PN varies depending on the type and distribution of the affected nerves [5]. PN has numerous causes, including diabetes, human immunodeficiency virus (HIV) infection, alcohol abuse, and certain medications [3,8].

Drug-induced peripheral neuropathy (DIPN) is relatively uncommon, accounting for only 2–4% of cases referred to neurology clinics [9-11]. However, broader epidemiological studies estimate that drugs may contribute to up to 24% of all peripheral neuropathies. This discrepancy highlights the under-recognition of DIPN, likely due to the challenges associated with its diagnosis [12]. The majority of DIPN cases present as distal, symmetrical, predominantly sensory polyneuropathy, with dying-back axonal degeneration being the most frequent type of neuropathy linked to medications. Certain drugs, however, can also affect other components of the peripheral nerve, such as myelin, autonomic nerves, and nerve roots [9,13,14]. DIPN can cause severe symptoms and limit the use of medications in about 30% of cases [12].

The number of medications continues to grow rapidly, with over 200 drugs reported to cause neuropathy to date, although objective evidence is lacking for several [15,16]. A significant challenge in managing DIPN is its underestimation, as subclinical or unsuspected cases often go undiagnosed. Studies suggest that subclinical cases may account for 60 to 90% of all DIPN [12]. Additionally, many cases are managed internally and not referred to neurologists, leading to underreporting. Furthermore, mild neuropathic symptoms are frequently overshadowed by more serious underlying conditions, notably malignancies and HIV infection [11,15].

Diagnosing DIPN is particularly challenging due to the lack of a definitive test to identify the causative medication. The difficulty is compounded when neuropathy develops gradually, with symptoms appearing months or even years after the initiation or dosage adjustment of the drug [15]. Recognizing these drug-related cases is essential, as it may prevent unnecessary, costly or invasive investigations. Moreover, early intervention, including timely discontinuation of the offending drug, can help limit toxicity and potentially lead to complete resolution of symptoms in 50%–70% of cases when identified early [11,15-18].

This review aims to provide a comprehensive overview of the literature on drug-induced peripheral neuropathy, with a particular focus on emerging medications that are newly implicated as triggers.

Methodology 

We conducted a systematic review of the literature using PubMed to identify articles on drug-induced peripheral neuropathy published up to September 15, 2024. The search strategy employed the following key terms: "neuropathy", "peripheral neuropathy", "drug-induced", "neurotoxicity" and "axonal neuropathy".

Based on the initial search results, additional searches were performed using terms such as ‘chemotherapy’, ‘proteasome inhibitors’, ‘anti-tumour necrosis factor-alpha’, ‘statins’, ‘targeted therapy’, ‘tyrosine kinase inhibitors’, ‘immunotherapy’, ‘immune checkpoint inhibitors’, ‘interferon’, ‘antibiotics’, and ‘fluoroquinolones’.

Inclusion criteria

  • Articles published in English that focused on original studies, reviews, case series and case reports were included.
  • Preference was given to articles published within the last ten years for current insights.
  • Studies on established drug classes, such as chemotherapeutic agents, cardiovascular drugs, and antimicrobials, were summarized.
  • Newer agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors, were discussed in detail.

Exclusion criteria

  • Articles lacking original data were excluded.
  • Search terms for ‘Guillain-Barré syndrome’ and ‘optic neuropathy’ were omitted. 
  • Articles focusing only on Guillain-Barré syndrome or optic neuropathy were excluded, unless these conditions were directly linked to the drugs of interest (tyrosine kinase inhibitors and immune checkpoint inhibitors).

To facilitate the presentation and interpretation of data, findings are organized into the following tables :

  • Table 1: Summarizes key characteristics of well-known drug classes that induce peripheral neuropathy such as incidence, risk factors, type of neuropathy, primary symptoms, management options, clinical outcomes, and potential mechanisms.
  • Table 2: Provides a comprehensive list of drugs identified in the literature as potential causes of peripheral neuropathy, forming an up-to-date reference for clinicians and researchers.
  • Table 3: Focuses on cases of neuropathy linked to tyrosine kinase inhibitors (TKIs), highlighting agent-specific variations.
  • Table 4: Details cases of neuropathy linked to immune checkpoint inhibitors (ICIs), emphasizing variations among different agents.

Results and Discussion

Pathogenesis of drug-induced peripheral neuropathy

The exact etiology of DIPN remains largely unknown; however, several potential mechanisms have been proposed [3,7,10,11,19-21] (Figure 1):

Direct mechanisms

  • Disruption of axonal transport: leading to axonal degeneration

Indirect mechanisms

  • Oxidative stress and mitochondrial dysfunction: Caused by inhibiting DNA polymerase gamma or blocking mitochondrial protein synthesis.
  • Vitamin deficiencies: Vitamin B1 (Thiamine), B6 (Pyridoxine), B12 (Cobalamin), and B9 (Folate).
  • Drug-induced peripheral nerve vasculitis.
  • Alteration of ion channel activity: which disrupts normal nerve function. 
  • Immune-mediated processes and neuroinflammation: that involve inflammatory responses affecting nerve tissue.
  • Interference with microtubules: altering axon structure and function.

Culprit drugs

Chemotherapeutic drugs: PN is a common adverse effect of various chemotherapeutic agents, causing significant pain and discomfort in cancer patients. Approximately 68% of patients undergoing chemotherapy experience PN within the first month of treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a well-documented toxicity that frequently necessitates dose reduction or discontinuation of the offending agent, often resulting in the use of less effective alternatives [11,19,22].

PN is associated with six major groups of chemotherapeutic agents. The highest incidence has been identified with platinum-based drugs (70–92%), vinca alkaloïds, particularly vincristine (96%), taxanes (up to 76%), thalidomide (23–70%), proteasome inhibitors like bortezomib and epothilones such as ixabepilone (64%) [10,11,19,23] (Table 1).

Table 1. Key characteristics and features of peripheral neuropathy associated with major drug classes.

Drug

Incidence

Risk factors

Dosage

Time of onset

Type of neuropathy/main symptoms

Management and outcome

Mechanism

Platinum compound: Oxaliplatin [11,19,20]

90%

- Exposure to cool temperature

- Cumulative dose

- Low body weight

- Body surface area >2

- Young age

- Persistent neuropathy in a past cycle

- Recent surgery

60 mg/m2

- Few days

- Cold hypersensitivity: jaw tightness, cramps, perioral and limb paresthesias

- Tetanic spasms, fasciculations, muscular contractions

- Decline between treatment cycles

- Resolution within hours or days

- Channelopathy: alteration of ion channel activity in particular calcium homeostasis

- Excessive neuronal excitation

- Mitochondrial dysfunction and oxidative stress 

- Neurodegeneration

 

70%

>540 mg/m2

 

- Chronic sensory neuropathy: tactile allodynia and numbness, paresthesias, hypoesthesias and dysesthesias of the hands and feet

- Changes in proprioception (>780 mg/m2)

- Complete resolution within 6–8 months in 40% of patients

Cisplatin [19]

92%

- Cumulative doses

- Long time of exposure

540–600 mg/m2)

- From the 1st to the 12th cycle of therapy

- Acute: tingling, numbness, mechanical and thermal hyperalgesia

- Coasting phenomenon*

- Changes to calcium homeostasis and cell signaling

- Mitochondrial dysfunction

- Changes in voltage-dependent Na+ channels resulting in oxidative stress

5–20%

12 months

- Chronic neuropathy

 

- Damage to dorsal root sensory neurons mediated by irreversible cross-linking to DNA and neuronal apoptosis

Taxanes: Paclitaxel [10,19,20]

30%

70-95%

- Increased frequency

- Cumulative dose

300 mg/m2

 

 

 

- Resolution within 6 months

- Ion channel dysfunction

- Demyelination and axonal degeneration

- Immune-mediated processes

- Mitochondrial dysfunction

Docetaxel [10,19,21]

Up to 50%

- Increased frequency

- Cumulative dose

100 mg/m2 

 

 

Improvement or complete resolution within 6 months

 

Vinca alkaloids: Vincristine [10,11,19,28]

96% of patients

with incidence rates ranging from 0% to 37% for grade 3 or 4

- Older age

- Higher single dose and cumulative drug concentration

- Concurrent administration with azoles antifungals

>4 mg/m2

Several weeks

- Sensory, motor and autonomic components

- Decreased touch, vibration, and temperature sensations

- Reduced or absent ankle reflexes

- Initially in the distal lower extremities and progresses proximally

- Coasting phenomenon*

- Complete recovery

- Disruption of calcium homeostasis

- Immune-mediated processes and neuroinflammation

- Membrane remodeling of peripheral neurons

- Loss of large myelinated fibers

- Polymerization dysfunction within axonal microtubules

Anti-myeloma treatment: Thalidomide [10,11]

23-70% (with up to one-third grade 3–4)

- High doses

- Duration of exposure

>200 mg/ d

 

- Painful sensory length-dependent axonal neuropathy: numbness, paresthesias, cramps

- Mild motor dysfunction

- Resolution

- Nuclear factor-dependent dysregulation of neurotrophins

- Antiangiogenic activities

 

Bortezomib [10,11]

37%-64% (with 13% grade 3 or 4)

- Cumulative dose

- Longer treatment duration

- Combination therapy with thalidomide

30 mg/m2

5th cycle

Length dependent sensory neuropathy of small c-fiber: significant burning pain, distal paresthesia, numbness

- Motor involvement (severe cases)

- Autonomic neuropathy (15% of cases): diarrhea, constipation, orthostatic hypotension

- Resolution in 85% within a median of 98 days

- Nuclear factor-dependent dysregulation of neurotrophins

- Promotion of mitochondrial calcium release and interference with microtubule stabilization

- Activation of ATF3 in DRG and neurodegeneration

Epothilones: Ixabepilone [10,16]

15%-64%

- High dosage

- Duration of infusion

- Cumulative dose

>40 mg/m2

4 cycles

Sensory neuropathy

- Dose reduction is effective

- Mostly reversible

- Microtubule dysfunction 

Arsenic Trioxide [10]

10.3%

 

10 mg/d

 

- Chronic sensorimotor polyneuropathy

- Mild and reversible

- Acute axonal damage with demyelination

- Thiamine deficiency

Statins [10,11,21,31]

21%

(OR of 1.19 to 4.6)

- Duration of treatment (>2 years)

 

1- 5 years

 

- Sensory neuropathy: decreased vibration perception

 

- May persist for months or years after statin withdrawal

but often reversible

 

- Alteration of membrane function

- Hypersensitivity and immune-mediated processes

- Disruption of ubiquinone synthesis and change in neurons’ energy consumption

Amiodarone [10,11,21]

6-10%

(2.38 per 1000 person-years)

- Increased dose

- Duration of therapy

>200 mg (at maintenance dose of 600 mg/d)

> 1month

- Subacute or chronic symmetrical sensorimotor neuropathy which progress to involve proximal muscles resulting in quadriplegia

- Acute resembling GBS (rare)

- Resolution

or persistent disability if severe axonal loss

- Oxidative stress and impaired lysosomal degradation within Schwann cells

- Lipophilic nature and accumulation in tissues

- Demyelination and axonal degeneration by accumulation of amiodarone and its metabolite desethylamiodarone

Isoniazid [10,27]

2-44%

- Increased dose

- Alcohol dependence

- Malnutrition

-diabetes

- HIV infection

- Elderly and pregnant

16-25 mg/kg/day

3-5 weeks

Sensory

-Supplementation with pyridoxine

- Resolution within weeks to months

- Interference with vitamin B6 synthesis

Ethambutol [10,27]

1-18%

- Increased dose

- Eldery

- Prolonged duration of treatment

- Hypertension

- Renal failure

- Diabetes

- Concurrent optic neuritis

- Tobacco and alcohol 

> 15 mg/kg/day

>2 months

Optic: bilateral vision loss

Mostly reversible

- Zinc chelation affecting mitochondrial metal-containing enzymes

- Excitotoxic pathway activation

- Mitochondrial dysfunction

Linezolid [10,11,27]

13-20%

- Prolonged treatment

- Increased doses

 

>1 month

- Sensory

- Optic

Irreversible

- Protein inhibition

- Mitochondrial toxicity

Fluoroquinolones [3,4,44]

Increased relative incidence of neuropathy of 1.47

- Additional day of exposure

 

4 days

 

- Mono and polyneuropathy:

burning sensation, pain

 

 

Metronidazole [10, 21]

10-85%

- Prolonged treatment

- Increased dose

 

4-11 months

Motor, sensory, autonomic and optic neuropathy

Recovery

binding to neuronal RNA and axonal degeneration

Azoles antifungals [10,28]

11.7%

Voriconazole (9-30%)

Itraconazole (17%)

Posaconazole (2.5%)

 - Increased doses

- Diabetes

 

150-350 mg

3 months

- Bilateral symmetrical

sensory axonal, and typically small fibers affected the earliest: tingling, numbness, decreased position and vibratory sensation,

- Motor neuropathy reported with voriconazole: weakness

- Complete recovery within few weeks

- Irreversible in minority

- Caused by the azole group

- Mitochondrial destruction

Antiretroviral Drugs [10,11]

 

8-10%

(Zalcitabin: 30-100%
Didanosine: 23%
Stavudine: 31%
Lamivudine: rare

- Advanced HIV disease

- Older age

- Metabolic impairements

- Pre-existing neuropathy

- Underlying malignancy

- Low CD4 count <50 cells/mm3

- Increased doses

- Combination therapy

- Alcohol use

Zalcitabine: 2.25 mg/day

Didanosine: 400 mg/day

Stavudine:

30-40 mg

Lamivudine: 300 mg/day

1 week to 6 months

Distal axonal sensory small fiber neuropathy: burning, shooting pain, allodynia, numbness, altered thermal sensitivity, uncomfortable walking distal weakness, decreased ankle jerk reflex

Difficult management

-Inhibition of
γ-DNA polymerase leading to mitochondrial dysfunction

Tumor Necrosis Factor alpha inhibitors [10,11,32,80]

0.003%

- Increased dose

- Prolonged duration of treatment

 

6 weeks -2 years (mean of 8 months)

- GBS

- MFS

- CIDP

- Multifocal motor neuropathy

- Mononeuropathy multiplex

- Axonal sensorimotor polyneuropathy

Significant response to IVIg, plasmapheresis or corticosteroids and dose reduction in some patients

- Improvement over few months of drug cessation

- Spontaneous relapse can occur

- Inhibition of the proinflammatory role of TNF-a

- T cell and humoral immune attack on peripheral myelin

- Vasculitis-induced nerve ischemia

- Inhibition of axon signaling

Interferons [10, 80]

Rare

Concomitant autoimmune disease

 

 

- Axonal and demyelinating neuropathy

autoimmune polyradiculopathy

- Chronic inflammatory demyelinating polyneuropathy

- Focal neuropathy at interferon β injection sites in the radial nerve distribution

- Plasmapheresis or IVIg

- Recovery

- Immune-mediated myelin degradation

- Vessel occlusion leading to nerve ischemia

- Induction of anti-GM1 antibodies

Leflunomide [10,16]

5-10%

- Older age

- Diabetes

- Previous use of neurotoxic drugs

- Alcoholism

 

3 to 6 months

Distal axonal sensorimotor polyneuropathy

Slow recovery

- Neurologic vasculitis

- Epineural perivascular inflammation

Levodopa [10,31]

20-55% (30.2%)

- Increased dose

- High serum Hcy

- Low vitamin B12

- LCIG administration
- Low BMI

700 mg/day
(higher risk > 1500 mg/day)

>3 years

Axonal sensory neuropathy: mildly symptomatic or even asymptomatic, slowly progressive

Vitamin supplementation in particular vitamin B12

 

-Accumulation of serum homocysteine and cobalamin-related metabolites

- Free radical accumulation

Anti-epileptic drugs [30]

16.7% with different agents

12%-14% (TPM)

Combined therapy

Toxic and non toxic doses (PTH)

Short and long term treatment (PTH)

- Axonal sensory: stocking hypesthesia, reduced achilles reflexes

- Demyelinating and axonal (TPM): transient parasthesia in the face, mouth and extremities, parathesia in both lower limbs, decreased ankle jerks

 

- PHT: direct toxic effect or blockage of sodium channels

- TPM: inhibition of carbonic anhydrase isoenzymes

 

*Symptoms may persist for several months despite drug cessation and can progressively worsen over time; DRG: Dorsal Root Ganglia; OR: Odds Ratio; GBS: Guillain–Barre Syndrome; HIV: Human Immunodeficiency Virus; MFS: Miller Fisher Syndrome; CIDP: Chronic Inflammatory Demyelinating Polyneuropathy; ATF3: Activating Transcription Factor 3; IVIg: Intravenous Immunoglobulin; TNF: Tumor Necrosis Factor; Hcy: Homocysteine; LCIG: Levodopa-Carbidopa Intestinal Gel Infusion; BMI: Body Mass Index; PTH: Phenytoin; TPM: Topiramate.


CIPN may present acutely, either during or shortly after infusion, particularly with agents like oxaliplatin and paclitaxel. More commonly, it manifests as a delayed effect following high cumulative doses [19]. CIPN is predominantly sensory and initially targets long axons. It typically presents with progressive symptoms such as numbness, tingling, and paresthesias in the distal limbs, along with impaired vibration and altered touch sensations. Pain is common, affecting up to 80% of patients [23]. In severe cases, loss of sensory perception can occur, while motor impairment is less frequent. Autonomic symptoms are primarily associated with vinca alkaloids [23].

Platinum-based compounds: Among platinum compounds, carboplatin is generally less neurotoxic than cisplatin and oxaliplatin, but can still cause severe neurotoxicity at standard doses [21]. Platinum-based agents often exhibit long-term manifestations of neuropathy, including the development of chronic neuropathy due to drug accumulation in the dorsal root ganglion. They are also associated with the "coasting" phenomenon, where neuropathy may continue to progress for several months after therapy cessation. Additionally, symptoms may occasionally emerge up to three weeks after treatment has ended [10,11,19] (Table 1).

Vinca alkaloids: Among vinca alkaloids, vincristine is associated with the highest incidence of neurotoxicity, although vinorelbine and vinblastine have also been reported to cause PN. Unique to this class, vinca alkaloid-induced PN can present with unusual manifestations including autonomic dysfunction in up to one-third of patients, as well as less commonly occurring mononeuropathies and cranial nerve palsies [10,11,19]. These drugs affect microtubule dynamics, leading to alterations in the neuronal cytoskeleton and axonal transport. Vincristine, with its highest affinity for tubulin, produces the most severe neuropathy. In contrast, neuropathy associated with other vinca alkaloids is often less severe [21]. Vinorelbine, in particular, causes mild, distal axonal sensorimotor neuropathy, frequently involving deep tendon reflexes (reported in 94% of cases) and paraesthesia in approximately half of cases [21] (Table 1).

Taxanes: Paclitaxel is more frequently associated with PN compared to docetaxel; however, docetaxel tends to induce more severe neuropathy. Both taxanes disrupt microtubule dynamics and alter axonal transport, with neuropathy being more prevalent in dose-dense regimens. Approximately 71% of patients receiving taxanes develop delayed neuropathic symptoms, although some may also experience acute painful neuropathy, which typically peaks a few days after infusion [10,11,19] (Table 1).

Proteasome inhibitors: Similar to other types of antineoplastic agents, proteasome inhibitors are associated with PN, which is a significant dose-limiting toxicity that can curtail their effectiveness. To reduce the toxic profile of bortezomib, the first proteasome inhibitor approved for clinical use, a new generation of structurally distinct proteasome inhibitors has been developed and is increasingly used in clinical settings. Second-generation proteasome inhibitors, such as carfilzomib and ixazomib, demonstrate a significantly lower incidence of PN compared to bortezomib. Notably, ixazomib exhibits the lowest incidence of PN among these agents, and when it occurs, it is generally mild, with most affected patients having reported prior exposure to bortezomib [24,25,26] (Table 1).

Epothilones: Epothilones are utilized in the treatment of advanced breast cancer and include both natural agents and the semisynthetic analogue, ixabepilone. These agents bind to tubulin at distinct sites, akin to vinca alkaloids and taxanes. PN associated with ixabepilone is primarily characterized by mild to moderate sensory neuropathy, which improves after drug withdrawal. More severe cases are rare when ixabepilone is used in monotherapy but occurs in 10% to 15% of patients receiving combination therapy or those previously treated with taxanes or capecitabine. The reported reversibility of epothilone-induced neuropathy is notable, especially in contrast to experiences with other microtubule-targeting agents [16,21] (Table 1).

Other antineoplastic drugs: Arsenic trioxide, used in the treatment of acute leukaemia, has also been associated with PN. Many newer microtubule-binding agents, including eribulin and cabazitaxel, are linked to PN. Cabazitaxel has also been associated with optic neuropathy. Overall, patients treated with these newer agents experience a lower frequency and severity of neuropathy compared to those receiving older treatments. Additionally, brentuximab, an antibody-drug conjugate approved for lymphoma treatment, exhibits a vinca-like mechanism of action on axonal transport, leading to dose-dependant and reversible PN upon drug interruption [21,24] (Table 1).

Antimicrobials

Antibiotics: The antibiotics most commonly associated with PN are metronidazole, linezolid, and dapsone. However, neuropathy has also been described in patients taking chloramphenicol, chloroquine, ethambutol, fluoroquinolones, isoniazid, nitrofurantoin, and sulfasalazine. The mechanism behind antibiotic-induced neuropathy is primarily believed to involve axonal injury resulting from disruptions in DNA repair, cellular metabolism, and mitochondrial function. Antibiotic-induced PN most commonly presents as sensorimotor neuropathies; however, autonomic neuropathy has been observed with metronidazole, while dapsone is linked to pure motor neuropathy. Optic neuropathy is most frequently associated with linezolid and ethambutol, though individual case reports have noted optic neuropathy with other antibiotics including ciprofloxacin, levofloxacin, chloramphenicol, metronidazole, sulfonamides, isoniazid, and streptomycin. Prolonged exposure to antibiotics is a significant risk factor for developing PN. In most patients, recovery occurs within weeks to months after discontinuation of the antibiotics, although “coasting” phenomenon has been described in a few cases [27] (Table 1).

Azole antifungals: The reported incidence of PN in patients treated with azoles varies widely in the literature. PN is most commonly documented when azoles are administered concurrently with vinca alkaloids in patients with hematologic malignancies or with calcineurin inhibitors in transplant recipients. Nevertheless, PN has also been observed following the administration of fluconazole, itraconazole, voriconazole, and posaconazole in the absence of other neuropathy-inducing medications or underlying conditions [28] (Table 1).

Antiretroviral drugs: The incidence of PN with antiretroviral drugs varies by agent and is often cited as a frequent reason for discontinuing therapy. Among these agents, lamivudine appears to have a low incidence of PN compared to others. The clinical symptoms, physical examination findings, and neurophysiological studies associated with this toxic neuropathy due to antiretroviral drugs resemble those seen in distal sensory neuropathy caused by human immunodeficiency virus (HIV) [10,11] (Table 1).

Cardiovascular drugs

Cardiovascular drugs are generally well tolerated and infrequently lead to neurological complications. However, both statins and antiarrhythmics have been associated with a potential risk of developing PN [21].

Statins: Previous studies indicate that while the overall prevalence of PN is low, it is up to four times higher among patients using statins. Statin-related PN can occasionally manifest in rare forms, such as Guillain-Barré syndrome and small fiber neuropathy. Typically, this type of neuropathy resolves after discontinuation of the statin. However, symptoms have been reported to recur either after re-challenge with the same statin or after switching to a different one. Statins interfere with cholesterol production, which is crucial for maintaining the function and integrity of cell membranes, particularly in the peripheral nervous system. By altering cholesterol levels, these drugs may compromise membrane stability. Additionally, statins inhibit ubiquinone (Coenzyme Q10), a key component in mitochondrial respiration, potentially impacting neuronal energy metabolism and contributing to the development of PN [11,13,21].

Antiarrhythmic drugs: PN has been reported with various antiarrhythmic drugs, often considered a class effect across this drug group, particularly resembling the well documented amiodarone-induced neuropathy. However, data on the relative risk of PN in patients treated with antiarrhythmics remain limited. A 2018 retrospective study found a low PN incidence of, ranging from 1.08 per 1,000 patient-years with flecainide to 2.38 per 1,000 patient-years with amiodarone. Amiodarone, in particular, has PN as one of its most frequently reported neurological adverse effects, with several case reports detailing its occurrence. Conversely, fewer than three cases of PN associated with flecainide have been reported in the literature. Amiodarone-induced PN can occur with doses as low as 200 mg/day or within a month of treatment, although the risk increases with higher cumulative doses or prolonged use [11,29] (Table 1).

Nervous system agents

Anti-epileptic drugs: Peripheral neuropathy is a rare but significant adverse effect of anti-epileptic drugs (AEDs). Identified risk factors for AED-induced PN include high doses, elevated serum concentrations, and prolonged treatment duration. Among AEDs, phenytoin (PHT) is most frequently associated with PN, as demonstrated by both clinical and experimental studies. PN can develop during both short-term (hours to weeks) and long-term (≥ 5 years) PHT therapy, regardless of whether the adminisetred doses are therapeutic or toxic [(30)] (Table 2).

Table 2. Drugs reported in literature to cause pripheral neuropathy.

Chemotherapeutic drugs

Cardiovascular drugs

Antimicrobials

Nervous system drugs

Immunosuppressive drugs

Other agents

Cisplatin

Amiodarone

Isoniazid

Phenytoin

Etanercept

Chloroquine

Oxaliplatin

Donedarone

Ethambutol

Carbamazepine

Infliximab

Colchicine

Carboplatin

Flecaïne

Linezolid

Phenobarbital

Adalimumab

Allopurinol

Paclitaxel

Procaïnamide

Dapsone

Sodium valproate

Certolizumab

Sulphasalasine

Docetaxel

Disopyramide

Nitrofurantoin

Levetiracetam

Leflunomide

Dichloroacetate

Thalidomide

Propafenone

Metronidazole

Gabapentin

Tacrolimus

Cimetidine

Lenalidomide

Hydralazine

Co-trimoxazole

Lacosamide

Cyclosporin

Clofibrate

Vincristine

Sotalol

Eryhtromycin

Topiramate

Interferon alpha

Zimeldine

Vinblastine

Atorvastatin

Azithromycin

Nitrous oxide

 

Etretinate

Vinorelbine

Simvastatin

Clindamycin

Levodopa

 

Penacillamine

Vindesine

Pravastatin

Streptomycin

Chlorprothixene

 

 

Bortezomib

Enalapril

Amoxicillin

Glutethemide

 

 

Ixabepilone

Perhexiline

Chloramphenicol

Phenelzine

 

 

Etoposide

Almitrine

Griseofulvin

Disulfiram

 

 

5-Fluorouracil

 

Levofloxacin

Amitriptyline

 

 

Cytarabine

 

Ciprofloxacin

Gangliosides

 

 

Gemcitabine

 

Norfloxacin

Gluthethimide

 

 

Ifosfamide

 

Moxifloxacin

Litium

 

 

5-azacytidine

 

Ofloxacin

 

 

 

Suramin

 

Sulfonamides

 

 

 

Misoidazole

 

Voriconazole

 

 

 

Teniposide

 

Fluconazole

 

 

 

Hexamethylmelamine

 

Itraconazole

 

 

 

Misonidazole

 

Posaconazole

 

 

 

 

 

Clioquinol

 

 

 

 

 

Mefloquine

 

 

 

 

 

Zalcitabine

 

 

 

 

 

Didanosine

 

 

 

 

 

Stavudine

 

 

 

 

 

Lamivudine

 

 

 


Levodopa: Several studies have demonstrated a significant association between PN and dopamine-replacement therapies. Up to 55% of patients treated with oral levodopa and 75% of those receiving l-dopa/carbidopa intestinal gel (LCIG) infusions may develop PN symptoms. A 2019 systematic review reported a PN prevalence of 30.2% in Parkinson's disease patients on oral l-dopa, increasing to 42.1% in those treated with LCIG. Oral l-dopa-related PN typically presents as a slowly progressive axonal neuropathy, primarily affecting sensory fibers. In contrast, LCIG-induced PN often involves both motor and sensory components, with most cases presenting as axonal neuropathy, though 9.2% show demyelinating features. While PN associated with oral l-dopa tends to follow a chronic course, 35.7% of cases linked to LCIG have an acute or subacute onset, suggesting potential immune-mediated inflammatory mechanisms, possibly triggered by the PEG-J tube or the gel formulation. Other factors, such as neurodegeneration, toxic exposures, or nutritional deficiencies, may also contribute to the development of acute PN in LCIG-treated patients. Neurophysiological findings often indicate axonal patterns, and the frequent co-occurrence of vitamin B12 deficiency further supports this. Notably, vitamin B12 deficiency-induced PN can share clinical features with LCIG-associated PN [31].

Immunosupressive drugs

Various classes of immunosuppressive drugs, such as tumor necrosis factor-alpha (TNF-α) inhibitors, interferons, calcineurin inhibitors, and leflunomide, have been linked to the development of PN [10].

Tumor necrosis alpha inhibitors: TNF-α inhibitors have been associated with a range of neurological complications, including central nervous system demyelination, optic neuritis, and various forms of neuropathy. Evidence on the risk of PN with TNF-α inhibitors primarily comes from case reports and series, although several reviews have confirmed these associations. PN has been reported with infliximab, adalimumab, and etanercept, with fewer cases linked to certolizumab. Notably, no neuropathies have been observed with the newer golimumab. Typically, PN develops shortly after the initiation of anti-TNF-α therapy and often improves with treatment withdrawal. Management strategies include corticosteroid use, dose reduction of the anti-TNF-α agent with low-dose corticosteroids, or complete drug discontinuation. However, some patients experience relapses months after treatment cessation, underscoring variability in clinical outcomes [9,11,32].

Calcineurin inhibitors: Calcineurin inhibitors (CNIs), such as tacrolimus and cyclosporine, are known to cause neurotoxicity, particularly PN [28]. Risk factors for CNI-induced neurotoxicity include elevated plasma concentrations, co-administration of azole antifungals, diabetes, and intravenous administration. Additional risk factors for cyclosporine-treated patients include advanced liver failure, hypertension, hypocholesterolemia, and hypomagnesemia [28]. The incidence of neurotoxicity is slightly higher with tacrolimus than cyclosporine, with PN affecting approximately 3 in 1,000 tacrolimus-treated patients [33]. PN typically presents as multifocal demyelinating sensorimotor polyneuropathy within 2 to 10 weeks of therapy initiation, and symptoms often improve or resolve after discontinuation [34]. CNI-induced PN is thought to involve both calcineurin inhibition and an immune-mediated component [35]. Management options include dose reduction or switching to an alternative CNI. For instance, switching from tacrolimus to cyclosporine may alleviate tacrolimus-induced neurotoxicity, while switching from cyclosporine to sirolimus has been reported to relieve cyclosporine-induced neurotoxicity. The distinct chemical structures of cyclosporine and tacrolimus, despite their shared immunosuppressive mechanisms, likely contribute to the more efficient clearance of tacrolimus and its metabolites [35]. In contrast, sirolimus, which operates through a different mechanism of action, is generally not linked to neurotoxicity and has been shown to mitigate the neurotoxic effects of both cyclosporine and tacrolimus [33].

Interferons : Case studies have suggested a link between interferon therapy and the development of axonal sensory neuropathy, with rare reports of inflammatory demyelinating polyneuropathies. While the exact mechanism remains unclear, interference with neuronal DNA, RNA synthesis, and protein metabolism has been proposed. More likely, interferons elevate pro-inflammatory cytokine levels, potentially triggering autoimmune responses in genetically predisposed individuals. This immune response, driven by molecular mimicry, leads to the mistaken attack on the body’s nerve tissue, which may result in acute inflammatory neuropathy [36,37] (Table 1).

Leflunomide: Leflunomide-induced PN has been documented in the literature, typically manifesting around three months after treatment initiation, with an onset range of 45 to 120 days [38,39]. Studies suggest that patients who discontinue leflunomide soon after symptom onset are more likely to experience improvement or full recovery compared to those who continue the drug for more than one month [40]. Carulli et al. hypothesized that leflunomide-induced PN may be related to neurologic vasculitis triggered by the drug [38] (Table 1).

Tyrosine kinase inhibitors: PN is a common and often debilitating adverse effect observed during anti-tumor therapies, including both chemotherapy and targeted therapies. While CIPN has been well documented, the rise of targeted therapies, particularly tyrosine kinase inhibitors (TKIs), has brought attention to a new spectrum of drug induced neurotoxicities [41] (Figure 2).

Neurological complications associated with TKIs are relatively rare, but various neuromuscular adverse effects have been reported, mainly neuropathy [42]. PN remains an uncommon adverse effect of TKIs, with incidences rarely exceeding 10% [43]. Case reports have linked several TKIs to PN, including brigatinib, crizotinib, encorafenib, imatinib, ivosidenib, ixazomib, lorlatinib, ponatinib, vemurafenib, and sorafenib [23]. A study on dasatinib reported a 5% incidence of PN, with severe cases occurring in only 0.05% [44]. Imatinib, known for inducing optic neuropathy, targets platelet derived growth factor (PDGF) receptors, and its neurotoxicity may stem from inhibiting these neuroprotective receptors on pericytes, affecting the vascular endothelium, retinal ganglion cells, and optic nerve. Although imatinib generally does not cross the blood-ocular barrier, damage to pericytes may allow its passage [44,45]. Sorafenib, another TKI, has been shown to either induce PN or exacerbate taxane-induced neuropathies when used in combination therapy. Sorafenib-induced PN causes significant neuropathic pain that is often resistant to standard analgesics and may necessitate treatment discontinuation. This neuropathy is linked to vascular endothelial growth factor (VEGF) inhibition, which interferes with VEGF’s neuroprotective role on sensory neurons, limiting management options to dose reduction or drug withdrawal [23]. Other TKIs have also been implicated in neurotoxicity. Crizotinib has been associated with optic neuropathy. Sunitinib has been reported in approximately 20 cases of optic neuropathy and has also been linked to Guillain-Barre syndrome in the literature [24,46,47]. Bevacizumab led to severe optic neuropathy in 1.2% of patients, necessitating immediate drug discontinuation [46]. Ceritinib treatment has been linked to neuropathy in 17% of patients. Sensory PN was noted as an adverse effect in phase II trials of cediranib [24,48]. In phase II trial of dovitinib, two patients developed significant neuropathy after the first cycle, requiring dose reduction [49]. Additionally, a possible link between ruxolitinib and PN has been suggested in the literature [50]. Momelotinib has been associated with PN in 46% of patients in a phase II trial [51], and lorlatinib-induced PN occured in 43.7% of cases, with a median onset of 77 days [52]. Tandutinib, in experimental studies, caused reversible muscle weakness and electrophysiologic changes consistent with PN [47]. Nintedanib has also been associated with the development of neuropathies [47].

Among patients receiving VEGFR-TKI monotherapy, about 6% experienced neuropathy [53]. Among BRAF and MEK inhibitors, PN is specifically mentioned in the summary of product characteristics for vemurafenib, encorafenib and binimetinib. However, PN is not explicitly listed as known adverse effect for other inhibitors within the same class such as cobimetinib, trametinib and dabrafenib [54]. Regorafenib and encorafenib were linked to PN in 20.1% of cases in the FAERS database [55]. Another recent study indicated that the combination encorafenib and binimetinib increased the risk of PN, with a median onset of around five months, primarily manifesting as axonal sensory neuropathy affecting the lower limbs [54].

According to our literature review, TKI-induced neuropathy predominantly occurs in elderly patients, with a mean age of 56 years and a male predominance (M/F sex ratio = 1.6). A single case of optic neuropathy has been reported in a 14-year-old child [56]. Most cases involved imatinib and dasatinib followed by ibrutinib. Imatinib, the first TKI approved for chronic myeloid leukemia, was later complemented by nilotinib and dasatinib as alternative first-line treatments [57]. Notably, no cases of neuropathy associated with nilotinib were identified, and patients who developed PN on imatinib or dasatinib successfully transitioned to nilotinib [42,43,58,59]. Additionally, one case reported no recurrence of symptoms after switching from imatinib to bosutinib, and no PN cases linked to bosutinib were found [44]. Both axonal and demyelinating nerve injuries have been reported, presenting as sensory or motor symptoms, with optic neuropathy frequently observed. The median onst of symptoms was 3.5 months, ranging from 4 days for motor neuropathy caused by nintedanib [47] to 10 years for sensory neuropathy related to imatinib [43]. Although late-onset neurotoxicity is rare, a delay of up to one year after TKI therapy initiation was observed in several cases involving imatinib [43,58,60,61], dasatinib [44] and ibrutinib [22]. Partial or complete recovery occurred in nearly all cases, and rechallenge with the offending TKI was frequent, often leading to symptom recurrence, although some cases did not experience a relapse upon rechallenge (Table 3).

Table 3. Main characteristics of well-documented neuropathy cases associated with tyrosine kinase inhibitors in the literature.

Author, year

Gender/Age

TKI agent/ Dosage

Time of onset

Type of neuropathy

Management

Outcome

Rechallenge

Babu, 2007 [81]

M/50

Imatinib

 400 mg/d

25 days

Optic neuropathy

Discontinuation

Oral prednisolone

Improvement (6 weeks)

None

Breccia, 2008 [82]

F/38

Imatinib 400 mg/d

51 days

Optic neuropathy

Discontinuation

Topical steroids

Recovery

(6 weeks)

None

Kwon, 2008 [56]

F/14

Imatinib

500 mg/d

2 months

Optic neuropathy

Discontinuation

Improvement (3 weeks)

Negative

Chakupurakal, 2011 [61]

M/58

Imatinib

5.5 years

Sensorimotor neuropathy

Discontinuation

Recovery

(6 months)

Positive

Yung, 2011 [83]

M/59

Sunitinib

50 mg/d

18 weeks

Optic neuropathy

Discontinuation

Improvement (2 months)

None

DeLuca, 2012 [84]

M/66

Imatinib

400 mg/d

4 months

Optic neuropathy

Discontinuation

Improvement (few weeks)

Negative with dose reduction

Kunadu, 2013 [47]

F/59

Nintedanib

3 weeks

Motor neuropathy

Discontinuation

Recovery

(few weeks)

None

Niro, 2015 [85]

M/70

Vemurafenib + cobimetinib

7 months

Optic neuropathy

Discontinuation

Partial Improvement

None

Monge, 2015 [86]

M/36

Dasatinib 100 mg/d

2.5 months

Optic neuropathy

Discontinuation

Oral prednisone

Improvement

(2 months)

Switch to nilotinib

with no recurrence

Chun, 2015 [87]

F/69

Crizotinib

3 months

Optic neuropathy

Discontinuation

Stabilization

Positive

Napolitano, 2017 [58]

M/62

Imatinib

400 mg/d

1 year

Optic neuropathy

Discontinuation

Recovery

(2 months)

Switch to nilotinib with no recurrence

Ishida, 2017[14]

F/46

Dasatinib 100 mg/d

6 months

Demyelinating peripheral neuropathy

Discontinuation

intravenous immunoglobulin

Recovery

(1 week)

 

Positive

Kavanagh, 2018 [43]

F/41

Imatinib

400 mg/d

10 years

Sensory neuropathy

Discontinuation

Improvement (6 weeks)

Positive

Switch to nilotinib with no recurrence

Suponeva, 2018 [88]

M/65

Ibrutinib 420 mg/d

5 months

Sensorimotor polyneuropathy

Dose reduction

Improvement

None

Shaikh, 2019 [89]

NS

Ibrutinib

NS

Peripheral neuropathy

Discontinuation

Improvement

None

Rafei, 2019 [44]

M/70

Dasatinib

20 mg/d

7 years

Axonal neuropathy

Discontinuation

intravenous immunoglobulin

Minimal improvement

None

M/70

Dasatinib 100 mg/d

 

3 months

Optic neuropathy

Discontinuation

steroids

Partial Recovery

Switch to imatinib with recurrence

Imatinib 400 mg/d

2 weeks

Discontinuation

steroids

Partial Recovery

Switch to bosutinib with no recurrence

Gun, 2020 [60]

F/59

Imatinib

400 mg/d

2 years

Optic neuropathy

Discontinuation

intravenous methylprednisolone

Recovery

(3 days)

Negative

Comert, 2020 [90]

M/63

Ibrutinib 420 mg/d

10 months

Sensory polyneuropathy

Discontinuation

Recovery

(4 weeks)

Positive but less severe

Inoue, 2020 [59]

F/54

Dasatinib 100 mg/d

 2 months

demyelinating peripheral neuropathy

Discontinuation

Recovery

(2 weeks)

Switch to nilotinib with no recurrence

Na, 2021 [83]

M/60

Sunitinib 37.5 mg

1 month

Optic neuropathy

Discontinuation

intravenous methylprednisolone

Improvement

None

Monga, 2021 [45]

F/41

Imatinib

400 mg/d

1 month

Optic neuropathy

Discontinuation

Recovery

(3 months)

None

F/54

Imatinib

400 mg/d

6 months

Optic neuropathy

Discontinuation

Stabilization

(1 year)

None

Kunadu, 2021 [47]

M/39

Nintedanib 300 mg/d

4 days

Motor polyneuropathy

Discontinuation

Recovery

(2 weeks)

None

Tiwari, 2023 [22]

M/70

Ibrutinib 420 mg/daily

28 months

Sensorimotor neuropathy

Discontinuation

Improvement (1 month)

None

Cellini, 2023 [91]

M/75

Ibrutinib 420 mg/d

9 months

Demyelinating polyneuropathy

Discontinuation

intravenous steroids

Recovery

(1 year)

None

Heard, 2024 [92]

M/73

Imatinib

NS

Axonal neuropathy

Discontinuation

methylprednisolone

Improvement (6 weeks)

None

TKI: Tyrosine Kinase Inhibitor; NS: Not Specified


The underlying mechanisms of TKI-induced neuropathy are not fully understood, but studies suggest that toxic metabolite accumulation in mitochondria and the endoplasmic reticulum, which plays a role in TKI-induced cardiotoxicity, may similarly contribute to neurotoxicity [61]. In some cases, an immune-mediated process has been proposed, as seen in dasatinib-induced PN, where patients responded well to intravenous immunoglobulin therapy, suggesting the involvement of auto-antibodies targeting Schwann cells or nerve myelin [14].

Immune checkpoint inhibitors: The advent of oncological immunotherapy has undoubtedly revolutionized cancer treatment, offering long-lasting tumor responses and improved survival outcomes. However, it has not spared patients from potential adverse effects, including PN. This immunotherapy-induced neuropathy is now recognized alongside the well-known toxic neuropathies caused by traditional chemotherapies [2] (Figure 2). Although PN associated with immune checkpoint inhibitors (ICI) are less common than those caused by chemotherapeutics [41], they still pose a significant risk, with reported incidence rates ranging from 3.8 to 12%, and severe reactions occurring in about 1% of patients [62]. Among ICI-induced neurotoxicities, PN is one of the most commonly observed, comprising almost half of all cases in some studies [63] and emerging as the second most reported neurological complication in the European pharmacovigilance database [2]. Recent data suggest the frequency of ICI-related PN is increasing, ranging from 1 to 6% in monotherapy and up to 14% in combination therapies [63,64].

The clinical presentation of ICI-induced PN can be highly variable, manifesting with symptoms such as paresthesia, hyporeflexia, neuropathic pain, muscle weakness, and involvement of cranial nerves [63]. In contrast to CIPN which tends to be symmetric and progressive sensory neuropathy, ICI-related PN is typically asymmetric, with acute onset and notable motor involvement [63]. The management of ICI-induced neuropathy largely depends on its severity. For mild (grade 1) cases, treatment can be continued with close monitoring. Moderate (grade 2) cases require temporary discontinuation of ICI with a possible rechallenge after symptom recovery. Severe (grades 3 or 4) neuropathies warrant permanent drug discontinuation, with corticosteroid therapy being the primary choice. Other treatments, such as plasma exchange or immunoglobulin therapy, may be considered in more resistant cases [63,65]. Most patients exhibit favorable outcomes, but fatal events have occurred in about 20% of those with severe neurotoxicities [63].

A prior analysis of ICI safety reports identified more than 700 cases of PN linked to ICI treatment. The majority of these reports involved nivolumab (35.9%), followed by pembrolizumab (26.3%) and ipilimumab (14.8%). Other ICIs were reported less frequently (<10%), with cemiplimab being the least reported, accounting for only 0.1% of cases [66]. Published case reports primarily incriminated nivolumab, followed by ipilimumab and durvalumab (Table 4). Notably, only one case of optic neuropathy linked to cemiplimab has been documented in the literature [67]. The majority of reports involved elderly patients, with a predominance of males, which aligns with our literature review, where the mean age was 62 years, and 10 out of 12 patients were male (Table 4). In the safety reports analysis, 22.2% of ICI-related PNs resulted in unfavorable outcomes. Similarly, two patients from published case reports showed no improvement even after discontinuation of ICIs. Both demyelinating and axonal injuries were observed in this dataset, with demyelinating PNs being more commonly reported. These findings are consistent with published case reports which describe both types of injuries. Interestingly, this safety reports analysis revealed a higher frequency of atezolizumab-induced PN compared to other ICIs [2,68,69]. Our literature review identified two cases of atezolizumab-induced PN, along with one case of optic neuropathy [67,70,71].

Table 4. Key features of Published neuropathy cases linked to immune checkpoint inhibitors.

Author, year

Gender/Age

ICI agent/Dosage

Number of last cycle before neuropathy onset

Time of onset after ICI initiation

Type of neuropathy

Management

Outcome

Rechallenge

Wilson, 2016 [93]

M/53

Ipilimumab 3 mg/kg every 3 weeks

NS

4 months

Optic neuropathy

Discontinuation

steroids

Stabilization

None

Thaipisuttikul, 2017 [94]

M/57

Ipilimumab

NS

36 days

sensorimotor polyneuropathy

Discontinuation steroids

 

Improvement

None

M/62

Ipilimumab

NS

1 month

polyneuropathy

Discontinuation

Steroids and mycophenolate

Recovery

(4 months)

None

Aoki, 2020 [95]

F/85

Pembrolizumab (200 mg) every 3 weeks

5th cycle

3 weeks

Demyelinating neuropathy

Discontinuation

steroids

Improvement (5 months)

None

Kambayashi, 2020 [96]

M/64

Ipilimumab

nivolumab

4th cycle

12 weeks

motor axonal neuropathy

 

steroids

Gradual improvement

None

Bilic, 2021 [97]

M/70

avelumab

4th dose

NS

demyelinating polyneuropathy

Discontinuation

No improvement

None

Yamanaka, 2021 [70]

M/76

atezolizumab

3rd cycle

NS

Demyelinating polyneuropathy

Discontinuation

Steroids

IVIg

Recovery

None

Cohen, 2021 [71]

M/64

atezolizumab

16th cycle

1 year

sensorimotor neuropathy 

Discontinuation

IVIg

Rapid improvement

None

Perez, 2021[98]

M/22

nivolumab

1st dose

1 month

Demyelinating polyneuropathy

Discontinuation

Steroids

IVIg

Recovery (3 months)

None

Scurfield, 2023 [99]

M/62

durvalumab

NS

4 months

Mononeuopathy multiplex

Discontinuation

Recovery (5 months)

None

McCormak, 2023 [100]

F/71

pembrolizumab

NS

1.5 years

Peripheral neuropathy

Discontinuation

steroids

Recovery (1 month)

None

Bonilla, 2024 [63]

M/74

durvalumab

6th cycle

6 months

Mixed axonal polyneuropathy

Discontinuation

steroids

 

Recovery (72 hours)

Negative

Pietris, 2023 [67]

M/82

atezolizumab

NS

NS

Optic neuropathy

steroids

NS

None

F/67

pembrolizumab

NS

NS

Optic neuropathy

Steroids, plasmapheresis,

immunoglobulin

 

 

None

M/67

ipilimumab

NS

NS

Optic neuropathy

steroids

 

None

F/27

ipilimumab

NS

NS

Optic neuropathy

Steroids

Plasma exchange

 

None

M/65

durvalumab

NS

NS

Optic neuropathy

steroids

 

None

M/64

nivolumab

NS

NS

Optic neuropathy

None

 

None

F/65

Cemiplimab

NS

NS

Optic neuropathy

steroids

 

None

Park, 2023 [101]

F/32

Nivolumab (3 mg/kg) every 2 weeks

NS

7 months

Demeyelinating polyneuropathy

steroids

Improvement

None

ICI: Immune Checkpoint Inhibitor; NS: Not Specified; IVIg: Intravenous Immunoglobulin


The exact mechanism by which ICIs cause neuropathy remains unclear. While T-cells are thought to play a key role in ICI-mediated toxicity, the wide range of immune-related adverse events suggests that other immune cells and cytokines may also contribute to these reactions through multiple mechanisms. Additionally, the abnormal immune activation triggered by this immunotherapy can result in various complications, including demyelination and axonal damage [2].

Management of Drug-Induced Peripheral Neuropathy

A comprehensive approach to managing peripheral neuropathy includes early recognition, pharmacologic interventions, physical therapy, and environmental modifications.

Although effective therapies supported by high-quality evidence are lacking, pharmacological management should primarily address the symptoms of PN, such as neuropathic pain and paresthesia. Medications used for neuropathic pain include amitriptyline, duloxetine, venlafaxine, gabapentin, pregabalin, and opioids. Duloxetine, at doses of 30 to 60 mg daily, has been found to be more effective than a placebo in reducing chemotherapy-induced neuropathic pain. It is the only medication with sufficient evidence supporting its use as the first-line treatment for patients with neuropathic pain. The evidence for other medications is less robust [72]. For PN-associated paresthesia, B complex vitamins (B1, B6, B12), folic acid, and niacinamide may be considered. Recent pain research has shifted towards addressing neuroinflammation as a strategy for managing chronic neuropathic pain. Notably, toll-like receptor-4 (TLR-4) has emerged as a key player in immune system activation, and ongoing research suggests its potential role in alleviating chemotherapy-induced neuropathic pain [73].

Another preventive and therapeutic strategy for alleviating neurotoxicity in patients receiving platinum-based chemotherapy is supplementation with vitamins, minerals and antioxidants. Evidence suggests that vitamin B12 may help prevent or reduce the severity of CIPN, although further studies are needed. Historically, peripheral neuropathy induced by isoniazid has been preventable with pyridoxine (vitamin B6) [74]. Vitamin B3 has shown protective effects in animal studies [75]. Vitamin E has been extensively studied as a preventive and therapeutic agent for the toxic effects of platinum-based chemotherapy. Retinoic acid (a metabolite of vitamin A) has also been explored in cisplatin-induced neuropathy in both animal and human studies. Additionally, thiamine pyrophosphate and coenzyme Q10 have been studied for their potential neuroprotective effects [76]. Vitamin D insufficiency has been suggested as a risk factor for CIPN induced by oxaliplatin, bortezomib, and thalidomide. A previous analysis found that vitamin D supplementation helped prevent CIPN [77].

Non-pharmacological treatment options include physical exercise, acupuncture, auricular plaster therapy and cryotherapy. Acupuncture has proven to be safe and effective. Physical exercise can be started early, even when potentially neurotoxic treatmens are initiated, helping reduce the incidence of PN and alleviating symptoms when they occur [78,79].

Strenghts

In this literature review, we provided a comprehensive overview of drugs linked to peripheral neuropathy, drawing from review articles, clinical trials, retrospective studies, and case reports. Our aim was to compile both medications historically known to induce peripheral neuropathy and those newly associated with this condition. While previous reviews have often studied older and newer triggers separately, our review integrates both, offering an up-to-date resource that can serve as reference for physicians when assessing a medication’s role in the devlopment of peripheral neuropathy. We have studied almost all aspects of PN from triggering agents to clinical impacts, possible mechanisms and management options. Additionally, we included a review of case reports on peripheral neuropathy induced by tyrosine kinas inhibitors and immune checkpoint inhibitors, providing valuable insights into the characteristics of this emerging adverse reaction. Furthermore, we presented an up-to-date registry of all drugs reported to cause peripheral neuropathy, enhancing the clinical utility of our review.

Conclusion

Based on our review findings, we recommend increased vigilance among healthcare providers when prescribing medications known or suspected to induce PN, particularly newer therapies such as TKIs and ICIs. Regular monitoring for early symptoms of neuropathy is crucial for timely intervention and management. Further research is warranted to explore the underlying mechanisms of neuropathy associated with these agents, as understanding these pathways could lead to better prevention strategies and treatment options. Research into neuroprotective agents needs to be strengthened and better articulated. Furthermore, successful neuroprotective agents should be incorporated into management guidelines, providing clinicians with effective strategies that improve patients’ quality of life. Clinicians should also report any suspected cases to pharmacovigilance systems to contribute to a more robust and up-to-date registry of offending drugs. Research studies identifiying genetic factors that may increase patient susceptibility to peripheral neuropathy should be enhanced, allowing for more personalized treatment approaches.

References

1. Hammi C, Yeung B. Neuropathy. 2022 Oct 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

2. Ruggiero R, Balzano N, Di Napoli R, Fraenza F, Pentella C, Riccardi C, et al. Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years. Front Immunol. 2023 Mar 16;14:1134436.

3. Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA Neurol. 2019 Jul 1;76(7):827-33.

4. Ali AK. Peripheral neuropathy and Guillain-Barré syndrome risks associated with exposure to systemic fluoroquinolones: a pharmacovigilance analysis. Ann Epidemiol. 2014 Apr;24(4):279-85.

5. Barrell K, Smith AG. Peripheral Neuropathy. Med Clin North Am. 2019 Mar;103(2):383-97.

6. Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep. 2019 Aug 27;19(10):86.

7. Hammad MA, Syed Sulaiman SA, Alghamdi S, Mangi AA, Aziz NA, Mohamed Noor DA. Statins-related peripheral neuropathy among diabetic patients. Diabetes Metab Syndr. 2020 Jul-Aug;14(4):341-6.

8. Merheb D, Dib G, Zerdan MB, Nakib CE, Alame S, Assi HI. Drug-induced peripheral neuropathy: diagnosis and management. Current Cancer Drug Targets. 2022 Jan 1;22(1):49-76.

9. Stübgen JP. Drug-induced dysimmune demyelinating neuropathies. J Neurol Sci. 2011 Aug 15;307(1-2):1-8.

10. Jones MR, Urits I, Wolf J, Corrigan D, Colburn L, Peterson E, et al. Drug-induced peripheral neuropathy: a narrative review. Curr Clin Pharmacol. 2020 Apr 1;15(1):38-48.

11. Manji H. Drug-induced neuropathies. Handb Clin Neurol. 2013;115:729-42.

12. Peripheral Neuropathies Associated with Drugs and Toxins | PM&R KnowledgeNow [Internet]. 2017 [cited on 5 Dec 2024]. Available from: https://now.aapmr.org/peripheral-neuropathies-associated-with-drugs-and-toxins/

13. Emad M, Arjmand H, Farpour HR, Kardeh B. Lipid-lowering drugs (statins) and peripheral neuropathy. Electronic Physician. 2018 Mar;10(3):6527-33.

14. Ishida T, Akagawa N, Miyata T, Tominaga N, Iizuka T, Higashihara M, et al. Dasatinib-associated reversible demyelinating peripheral polyneuropathy in a case of chronic myeloid leukemia. Int J Hematol. 2018 Mar;107(3):373-7.

15. Weimer LH. Medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep. 2003 Jan;3(1):86-92.

16. Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep. 2009 Jan;9(1):69-75.

17. Wang C, Chen S, Jiang W. Treatment for chemotherapy-induced peripheral neuropathy: A systematic review of randomized control trials. Frontiers in Pharmacology. 2022 Dec 23;13:1080888.

18. 1743-Anti-cancer drug induced peripheral neuropathy | eviQ [Internet]. [cited on 5 Dec 2024]. Available from: https://www.eviq.org.au/clinical-resources/side-effect-and-toxicity-management/neurological-and-sensory/1743-anti-cancer-drug-induced-peripheral-neuropath

19. Starobova H, Vetter I. Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. Front Mol Neurosci. 2017 May 31;10:174.

20. Yamamoto S, Egashira N. Drug Repositioning for the Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy: A Mechanism- and Screening-Based Strategy. Front Pharmacol. 2021 Jan 14;11:607780.

21. Vilholm OJ, Christensen AA, Zedan AH, Itani M. Drug-induced peripheral neuropathy. Basic Clin Pharmacol Toxicol. 2014 Aug;115(2):185-92.

22. Tiwari D, Panda* D, Sharma A, Kishan D. Ibrutinib induced sensorimotor neuropathy: A novel side effect. Indian J Pathol Oncol.10(2):174-6.

23. Laforgia M, Laface C, Calabrò C, Ferraiuolo S, Ungaro V, Tricarico D, et al. Peripheral neuropathy under oncologic therapies: a literature review on pathogenetic mechanisms. International Journal of Molecular Sciences. 2021 Feb 17;22(4):1980.

24. Zukas AM, Schiff D. Neurological complications of new chemotherapy agents. Neuro-oncology. 2018 Jan 10;20(1):24-36.

25. Alé A, Bruna J, Navarro X, Udina E. Neurotoxicity induced by antineoplastic proteasome inhibitors. Neurotoxicology. 2014 Jul;43:28-35.

26. Velasco R, Alberti P, Bruna J, Psimaras D, Argyriou AA. Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: From pathogenesis to treatment. J Peripher Nerv Syst. 2019 Oct;24 Suppl 2:S52-62.

27. Bhattacharyya S, Darby R, Berkowitz AL. Antibiotic-induced neurotoxicity. Curr Infect Dis Rep. 2014 Dec;16(12):448.

28. Benitez LL, Carver PL. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs. 2019 Jun;79(8):833-53.

29. Wu C, Tcherny-Lessenot S, Dai W, Wang Y, Kechemir H, Gandhi S, et al. Assessing the risk for peripheral neuropathy in patients treated with dronedarone compared with that in other antiarrhythmics. Clinical Therapeutics. 2018 Mar 1;40(3):450-5.

30. Hamed SA. Topiramate induced peripheral neuropathy: A case report and review of literature. World J Clin Cases. 2017 Dec 16;5(12):446-52.

31. Romagnolo A, Merola A, Artusi CA, Rizzone MG, Zibetti M, Lopiano L. Levodopa-induced neuropathy: a systematic review. Mov Disord Clin Pract. 2019 Feb;6(2):96-103.

32. Etminan M, Sodhi M, Samii A, Carleton BC, Kezouh A, Antonio Avina-Zubieta J. Tumor necrosis factor inhibitors and risk of peripheral neuropathy in patients with rheumatic diseases. Semin Arthritis Rheum. 2019 Jun;48(6):1083-6.

33. Bilodeau M, Hassoun Z, Brunet D. Demyelinating sensorimotor polyneuropathy associated with the use of sirolimus: a case report. Transplantation Proceedings 2008 Jun ;40(5):1545‑7.

34. Wu G, Weng FL, Balaraman V. Tacrolimus-induced encephalopathy and polyneuropathy in a renal transplant recipient. Case Reports. 2013 Dec 5;2013:bcr2013201099.

35. Sayin R, Soyoral YU, Erkoc R. Polyneuropathy due to cyclosporine A in patients with renal transplantation: a case report. Ren Fail. 2011;33(5):528-30.

36. Khiani V, Kelly T, Shibli A, Jensen D, Mohanty SR. Acute inflammatory demyelinating polyneuropathy associated with pegylated interferon α 2a therapy for chronic hepatitis C virus infection. World Journal of Gastroenterology: WJG. 2008 Jan 1;14(2):318-21.

37. Visovsky C. Chemotherapy-induced peripheral neuropathy. Cancer Invest. 2003 Jun;21(3):439-51.

38. Martin K, Bentaberry F, Dumoulin C, Miremont-Salamé G, Haramburu F, Dehais J, et al. Peripheral neuropathy associated with leflunomide: is there a risk patient profile? Pharmacoepidemiol Drug Saf. 2007 Jan;16(1):74-8.

39. Bharadwaj A, Haroon N. Peripheral neuropathy in patients on leflunomide. Rheumatology (Oxford). 2004 Jul;43(7):934.

40. Kho LK, Kermode AG. Leflunomide-induced peripheral neuropathy. J Clin Neurosci. 2007 Feb;14(2):179-81.

41. Si Z, Zhang S, Yang X, Ding N, Xiang M, Zhu Q, et al. The association between the incidence risk of peripheral neuropathy and PD-1/PD-L1 inhibitors in the treatment for solid tumor patients: a systematic review and meta-analysis. Frontiers in Oncology. 2019 Sep 4;9:866.

42. Mehra N, Varmeziar A, Chen X, Kronick O, Fisher R, Kota V, et al. Cross-domain text mining to predict adverse events from tyrosine kinase inhibitors for chronic myeloid leukemia. Cancers. 2022 Sep 26;14(19):4686.

43. Kavanagh S, Bril V, Lipton JH. Peripheral neuropathy associated with imatinib therapy for chronic myeloid leukemia. Blood Research. 2018 Jun 1;53(2):172-4.

44. Rafei H, Jabbour EJ, Kantarjian H, Sinicrope KD, Kamiya-Matsuoka C, Mehta RS, et al. Neurotoxic events associated with BCR-ABL1 tyrosine kinase inhibitors: a case series. Leuk Lymphoma. 2019 Dec;60(13):3292-5.

45. Monga S. Imatinib Related Toxic Optic Neuropathy: Case Report. Neuro Ophthalmol Vis Neurosci. 2021;6(1):4‑7.

46. Fortes BH, Tailor PD, Dalvin LA. Ocular toxicity of targeted anticancer agents. Drugs. 2021 May;81(7):771-823.

47. Kunadu A, Alqalyoobi S, Frere RC, Obi ON. Acute motor neuropathy with quadriparesis following treatment with triple tyrosine kinase inhibitor, nintedanib. Respiratory Medicine Case Reports. 2021 Jan 1;34:101472.

48. Bender D, Sill MW, Lankes HA, Reyes HD, Darus CJ, Delmore JE et al. A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: an NRG oncology/gynecologic oncology group study. Gynecologic Oncology. 2015 Sep 1;138(3):507-12.

49. Ma WW, Xie H, Fetterly G, Pitzonka L, Whitworth A, LeVea C, et al. A phase Ib study of the FGFR/VEGFR inhibitor dovitinib with gemcitabine and capecitabine in advanced solid tumor and pancreatic cancer patients. American Journal of Clinical Oncology. 2019 Feb 1;42(2):184-9.

50. Ruxolitinib and peripheral neuropathy: causal link? React Wkly. 2017 Sep 1;1668(1):5.

51. Duenas-Perez AB, Mead AJ. Clinical potential of pacritinib in the treatment of myelofibrosis. Therapeutic Advances in Hematology. 2015 Aug;6(4):186-201.

52. Bauer TM, Felip E, Solomon BJ, Thurm H, Peltz G, Chioda MD, et al. Clinical management of adverse events associated with lorlatinib. The Oncologist. 2019 Aug 1;24(8):1103-10.

53. Roy B, Das A, Ashish K, Bandyopadhyay D, Maiti A, Chakraborty S, et al. Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis. Neurology. 2019 Jul 9;93(2):e143-8.

54. Picca A, Birzu C, Berzero G, Sanchez‐Pena P, Gaboriau L, Vidil F, et al. Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: a pharmacovigilance study. British Journal of Clinical Pharmacology. 2022 Nov;88(11):4941-9.

55. Barbieri MA, Russo G, Sorbara EE, Cicala G, Franchina T, Santarpia M, et al. Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System. Frontiers in Oncology. 2023 Oct 31;13:1268672.

56. Kwon SI, Lee DH, Kim YJ. Optic disc edema as a possible complication of Imatinib mesylate (Gleevec). Japanese Journal of Ophthalmology. 2008 Jul;52:331-3.

57. Cheng F, Li Q, Cui Z, Hong M, Li W, Zhang Y. Dose optimization strategy of the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib for chronic myeloid leukemia: From clinical trials to real-life settings. Frontiers in Oncology. 2023 Apr 5;13:1146108.

58. Napolitano M, Santoro M, Mancuso S, Carlisi M, Raso S, Tarantino G, et al. Late onset of unilateral optic disk edema secondary to treatment with imatinib mesylate. Clinical Case Reports. 2017 Oct;5(10):1573-5.

59. Inoue H, Taji H, Yamada K, Iriyama C, Saito T, Kato H, et al. Dasatinib-induced Reversible Demyelinating Peripheral Neuropathy and Successful Conversion to Nilotinib in Chronic Myelogenous Leukemia. Intern Med. 2020 Oct 1;59(19):2419-21.

60. Gün RD, Koçkar A, Altunrende B, Şengül EA. Bilateral Optic Neuropathy in a Patient with Imatinib Usage. Turkiye Klinikleri J Case Rep. 2020;28(1):9-12.

61. Chakupurakal G, Etti RJ, Murray JA. Peripheral neuropathy as an adverse effect of imatinib therapy. Journal of Clinical Pathology. 2011 May 1;64(5):456.

62. Liu W, Chen B, Liu Y, Luo Z, Sun B, Ma F. Durvalumab-induced demyelinating lesions in a patient with extensive-stage small-cell lung cancer: A case report. Frontiers in Pharmacology. 2022 Jan 3;12:799728.

63. Bonilla CE, Ávila V. Immune‐Related Peripheral Neuropathy Associated with Immune Checkpoint Inhibitors: Case Report and Review of Literature. Case Reports in Oncological Medicine. 2024;2024(1):8212943.

64. Frey C, Etminan M. Immune-Related Adverse Events Associated with Atezolizumab: Insights from Real-World Pharmacovigilance Data. Antibodies. 2024 Jul 15;13(3):56.

65. Goedee HS, Attarian S, Kuntzer T, Van den Bergh P, Rajabally YA. Iatrogenic immune-mediated neuropathies: diagnostic, epidemiological and mechanistic uncertainties for causality and implications for clinical practice. Journal of Neurology, Neurosurgery & Psychiatry. 2021 Sep 1;92(9):975-82.

66. Ruggiero R, Balzano N, Di Napoli R, Fraenza F, Pentella C, Riccardi C, et al. Do peripheral neuropathies differ among immune checkpoint inhibitors? Reports from the European post-marketing surveillance database in the past 10 years. Frontiers in Immunology. 2023 Mar 16;14:1134436.

67. Pietris J, Santhosh S, Ferdinando Cirocco G, Lam A, Bacchi S, Tan Y, et al. Immune Checkpoint Inhibitors and Optic Neuropathy: A Systematic Review. Seminars in Ophthalmology. 2023 Aug 18;38(6):547-58.

68. Abrahao A, Tenorio PHM, Rodrigues M, Freitas LZ, Nascimento OJ. Peripheral Neuropathies in Checkpoint Inhibitor Therapy: An In-depth Investigation through Pharmacovigilance Data-driven Analysis. Ann Med Clin Oncol. 2023;5:153.

69. Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B, et al. Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. Journal for immunotherapy of Cancer. 2019 Dec;7:1-9.

70. Yamanaka N, Oishi M, Shimizu F, Koga M, Kanda T. [Atezolizumab-induced Guillain-Barré syndrome-like acute demyelinating polyneuropathy responsive to steroid therapy: a case report]. Rinsho Shinkeigaku. 2021 Oct 28;61(10):653-57. Japanese.

71. MDA Clinical & Scientific Conference 2025 [Internet]. [cited on 23 Sept 2024]. Paranodal Neuropathy associated with Atezolizumab/Enfortumab in a patient with metastatic carcinoma. Available from: https://www.mdaconference.org/abstract-library/paranodal-neuropathy-associated-with-atezolizumab-enfortumab-in-a-patient-with-metastatic-carcinoma/

72. Abramson JS, Stuver R, Herrera A, Patterson E, Wen YP, Moskowitz A. Management of Peripheral Neuropathy Associated with Brentuximab Vedotin in the Frontline Treatment of Classical Hodgkin Lymphoma. Critical Reviews in Oncology/Hematology. 2024 Sep 6:104499.

73. Babu N, Gadepalli A, Akhilesh, Sharma D, Singh AK, Chouhan D, et al. TLR-4: a promising target for chemotherapy-induced peripheral neuropathy. Mol Biol Rep. 2024 Oct 28;51(1):1099.

74. Badrinath M, Chen P, John S. Isoniazid toxicity. InStatPearls [Internet]. StatPearls Publishing; 2024 Feb 28.

75. Schloss J, Colosimo M. B vitamin complex and chemotherapy-induced peripheral neuropathy. Current Oncology Reports. 2017 Dec;19(12):76.

76. Stankovic JS, Selakovic D, Mihailovic V, Rosic G. Antioxidant supplementation in the treatment of neurotoxicity induced by platinum-based chemotherapeutics—a review. International Journal of Molecular Sciences. 2020 Oct 20;21(20):7753.

77. Chen CS, Zirpoli G, Barlow WE, Budd GT, McKiver B, Pusztai L, et al. Vitamin D insufficiency as a risk factor for paclitaxel-induced peripheral neuropathy in SWOG S0221. Journal of the National Comprehensive Cancer Network. 2023 Nov 1;21(11):1172-80.

78. Cimbro E, Dessì M, Ziranu P, Madeddu C, Atzori F, Lai E, et al. Early taxane exposure and neurotoxicity in breast cancer patients. Supportive Care in Cancer. 2024 Oct;32(10):709.

79. Zhang J, Yang H, Lu Y. Management of neurotoxic reactions induced by antibody-drug conjugates. Asia-Pacific Journal of Oncology Nursing. 2024 Sep 14:100595.

80. Toyooka K, Fujimura H. Iatrogenic neuropathies. Curr Opin Neurol. 2009 Oct;22(5):475-9.

81. Govind Babu K, Attili VS, Bapsy PP, Anupama G. Imatinib-induced optic neuritis in a patient of chronic myeloid leukemia. Int Ophthalmol. 2007 Feb;27(1):43-4.

82. Breccia M, Gentilini F, Cannelai L, Latagliata R, Carmosino I, Frustaci A, et al. Ocular side effects in chronic myeloid leukemia patients treated with imatinib. Leuk Res. 2008 Jul;32(7):1022-5.

83. Na S, Kim T. Optic neuritis associated with sunitinib. Neurol Sci. 2021 Mar;42(3):1165-7.

84. DeLuca C, Shenouda-Awad N, Haskes C, Wrzesinski S. Imatinib mesylate (Gleevec) induced unilateral optic disc edema. Optom Vis Sci. 2012 Oct;89(10):e16-22.

85. Niro A, Strippoli S, Alessio G, Sborgia L, Recchimurzo N, Guida M. Ocular Toxicity in Metastatic Melanoma Patients Treated With Mitogen-Activated Protein Kinase Kinase Inhibitors: A Case Series. Am J Ophthalmol. 2015 Nov;160(5):959-67.e1.

86. Monge KS, Gálvez-Ruiz A, Alvárez-Carrón A, Quijada C, Matheu A. Optic neuropathy secondary to dasatinib in the treatment of a chronic myeloid leukemia case. Saudi J Ophthalmol. 2015 Jul-Sep;29(3):227-31.

87. Chun SG, Iyengar P, Gerber DE, Hogan RN, Timmerman RD. Optic neuropathy and blindness associated with crizotinib for non-small-cell lung cancer with EML4-ALK translocation. J Clin Oncol. 2015 Feb 10;33(5):e25-6.

88. Suponeva NA, Grishina DA, Piradov MA. Ibrutinib-induced chronic demyelinating polyneuropathy in a 65-year-old man with chronic lymphoid leucosis: A clinical case. Romanian Journal of Neurology. 2018 Jan 1;17(1):41-9.

89. Shaikh H, Khattab A, Faisal MS, Chilkulwar A, Albrethsen M, Sadashiv S, et al. Case series of unique adverse events related to the use of ibrutinib in patients with B-cell malignancies-A single institution experience and a review of literature. J Oncol Pharm Pract. 2019 Jul;25(5):1265-70.

90. Cömert P, Albayrak M, Yıldız A, Şahin O, Öztürk HB, Reis Aras M. Ibrutinib-induced polyneuropathy: A case report. J Oncol Pharm Pract. 2020 Sep;26(6):1501-04.

91. Cellini A, Visentin A, Salvalaggio A, Cacciavillani M, Ferrari S, Briani C. Demyelinating Polyradiculoneuropathy in Chronic Lymphocytic Leukemia: A Case Report on BTKis versus Venetoclax-Rituximab. Hemato. 2023 Dec 27;5(1):19-25.

92. Heard SJ, Heard R, Forsyth C, Reynolds M. 2684 Two forms of neuropathy associated with imatinib therapy: a case report. BMJ Neurol Open. 2024 Feb 01;5(Suppl 1).

93. Wilson MA, Guld K, Galetta S, Walsh RD, Kharlip J, Tamhankar M, et al. Acute visual loss after ipilimumab treatment for metastatic melanoma. J Immunother Cancer. 2016 Oct 18;4:66.

94. Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with ipilimumab: a report of 2 cases. J Immunother. 2015 Feb-Mar;38(2):77-9.

95. Aoki S, Yasui M, Tajirika H, Terao H, Funahashi M, Ohta J. Pembrolizumab-Induced Severe Neuropathy in a Patient with Metastatic Urothelial Carcinoma after Achieving Complete Response: Guillain-Barré Syndrome-Like Onset. Case Rep Oncol. 2020 Dec 17;13(3):1490-4.

96. Kambayashi Y, Fujimura T, Kuroda H, Otsuka A, Irie H, Aiba S. Severe Demyelinating Neuropathy in an Advanced Melanoma Patient Treated with Nivolumab plus Ipilimumab Combined Therapy. Case Rep Oncol. 2020 Apr 30;13(1):474-7.

97. Bilić H, Sitaš B, Hančević M, Habek M, Simetić L, Bilić E. Severe Demyelinating Polyneuropathy and Cranial Neuropathy During Avelumab Treatment of Metastatic Merkel Cell Carcinoma. Clin Neuropharmacol. 2021 Sep-Oct 01;44(5):193-5.

98. Perez M, Lancaster E. Nivolumab-induced Immune-mediated Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report (1673). Neurology. 2021 Apr 13;96(15_supplement):1673.

99. Scurfield A, Kelly A, Desai N, Dhanjal S. A Case of Mononeuopathy Multiplex in the Setting of Durvalumab Therapy (P13-8.002). Neurology. 2023;100 (17_supplement_2).

100. McCormack SM, Hamad A. Pembrolizumab-Induced Myasthenia Gravis and Peripheral Neuropathy: A Case Series. Cureus. 2023 Sep 6;15(9):e44799.

101. Park C, Kim KT. Demyelinating polyneuropathy combined with brachial plexopathy after nivolumab therapy for hodgkin lymphoma: a case report. BMC Neurol. 2023 Mar 30;23(1):130.

Author Information X