Update on Toxic Neuropathies

Abstract

Purpose of Review

Toxic neuropathies are an important preventable and treatable form of peripheral neuropathy. While many forms of toxic neuropathies have been recognized for decades, an updated review is provided to increase vigilant in this area of neurology. A literature review was conducted to gather recent information about toxic neuropathies, which included the causes, clinical findings, and treatment options in these conditions.

Recent Findings

Toxic neuropathies continue to cause significant morbidity throughout the world and the causative agents, particularly with regards to medications, do not appear to be diminishing. A wide variety of causes of toxic neuropathies exist, which include alcohol, industrial chemicals, biotoxins, and medications. Unfortunately, no breakthrough treatments have been developed and prevention and symptom management remain the standard of care.

Summary

A detailed medication, occupational and hobby exposure history is critical to identifying toxic neuropathies. Increased research is warranted to identify mechanisms of neurotoxic susceptibility and potential common pathomechanistic pathways for treatment across diverse toxic neuropathies.

Introduction

Neuropathies due to toxins are an important preventable cause of peripheral neuropathy throughout the world. Typical causes of toxic neuropathies include alcohol, drug therapies, biological toxins, industrial toxins, metabolic causes, and heavy metals. In high income countries, drug and alcohol induced neuropathy are more common, while in developing countries occupational and environmental causes prevail (1, 2). Symptom onset may be acute or delayed and can involve motor, sensory or autonomic nerves. While many toxic neuropathies are dose dependent and can reverse over time, some may persist and impact the quality of life drastically.

One of the major challenges with diagnosing toxic neuropathies is that there often is not a single test that provides the answer. Furthermore, toxic neuropathies have overlapping neurological signs and symptoms, often with complicating systemic illness (Table 1). The most relevant diagnostic tool is often a detailed drug, occupational, and hobby exposure history. This review summarizes toxic neuropathies based on the newest findings. For each of the substances the clinical features are stated, as well as possible treatments.

Table 1:

Symptoms outside peripheral nervous system that may occur with toxic neuropathies

Domain	Toxin	Comment
Neuropsychiatric	Lead
	Arsenic
	Mercury
	Disulfiram
Cerebellum	Mercury
Skin	Lead
	Arsenic	Alopecia Melanosis
	Thallium	Alopecia
	Silver	Blue discoloration
Nails	Arsenic	Mees lines
	Thallium	Mees lines
Intestines	Lead
	Arsenic
	Thallium
Liver	Arsenic
Kidney	Mercury
	Diethylene glycol
Anemia	Lead
Pancytopenia	Arsenic

Alcohol

Alcohol is a common cause of neuropathy and represents about 10% of polyneuropathies (3). It has been estimated that approximately 40% of people with chronic alcohol abuse experience signs and symptoms of peripheral neuropathy (3). Alcohol has direct neurotoxic effects, but chronic alcohol consumption is also often accompanied with nutritional deficiencies, the most recognized of which is thiamine. It is thought that the clinical characteristics of neuropathy help differentiate whether it is due to alcohol abuse versus thiamine deficiency. Neuropathy due to thiamine deficiency is most often characterized by a an acutely progressive motor dominant neuropathy that evolves in a distal symmetric fashion (4, 5). On the other hand, alcohol related peripheral neuropathy leads to slowly progressive, sensory predominant neuropathy with impaired decreased sensation, pain or burning dysesthesias (4). Pain, ataxia and paresthesia in the lower extremities are also a common presentation. Alcohol-related peripheral neuropathy is primarily axonal, length-dependent, and strongly affects the small peripheral nerve fibers (3, 4, 6). Diagnosis can be made with physical examination, patient history (CAGE Questionnaire) and blood tests that should include thiamine, folate, niacin, vitamins E and A, as well as vitamins B6 and B12.

A recent systematic review highlighted important aspects of the management of alcohol related peripheral neuropathy (3). Importantly, there is evidence that alcohol abstinence and a normal diet can improve sensory symptoms (7), albeit without complete resolution. In a randomized blind placebo-controlled study, supplementation of vitamins demonstrated improvement of symptoms as well (3, 8).

Biological toxins

There are several biotoxins that affect the peripheral nervous system. The ciguatera toxin blocks sodium channels and causes perioral paresthesia, metallic, dysesthesias and hot/cold reversals (9, 10). The toxin can be found in reef-dwelling fish (such as barracuda and grouper). Electrophysiological studies tend to be normal (11). Another biological toxin that causes paralysis comes from Mollusks that are contaminated with dinoflagellate-produced saxitoxin or brevetoxin B. Circumoral dysesthesias and numbness can be caused by tetrodotoxins, which is produced in the ovaries of the puffer fish, a common sushi item. Higher intakes of the sodium channel blocking toxin may lead to flaccid weakness of the extremities and death due to respiratory muscle weakness (9). Strength can be regained after a few days. Early peripheral nerve excitability may show no recordable responses (12).

A syndrome that can be misdiagnosed as Guillan-Barré syndrome is caused by toxins in Buckthorn fruits. The plant that is endemic in the southwest United States and Mexico produces a distal, symmetric, ascending flaccid paralysis of the limbs with a mixed demyelination (9, 13).

Tick bites from Dermacentor andersoni, Dermacentor variabilis, or Ixodes holocyclus can cause a tick paralysis syndrome. Ataxia may be followed by an ascending symmetrical flaccid paralysis (9). A conduction block may be seen in nerve conduction studies (14). Despite the strong symptoms, full recovery is achieved when the tick is removed.

Industrial toxins

Exposure to several industrial agents results in neuropathy and central nervous system dysfunction. While occupational exposures to the following agents is rare in Western countries, reports continue to arise in developing countries.

Acrylamide

Acrylamide is used in the production of plastic, paper, tapes, dyes and food packaging (15). While it is even present in baked potatoes, coffee and bakery products, the acrylamide levels are considered non-toxic (16). Clinical reports of acrylamide neurotoxicity have come from occupational exposure, including mining, tunnel construction, and acrylamide production plants. Acrylamide causes a sensorimotor peripheral neuropathy, but also has central nervous system effects, including drowsiness and cerebellar ataxia (17). When the exposure to acrylamide is removed, neurotoxicity is reversible in mild cases.

Allyl chloride

Allyl chloride exposure occurs in manufacturing and can lead to a distal symmetrical sensorimotor neuropathy (18). Patients can present with numbness and weakness. Nerve conduction studies may show reduced conduction velocity and reduced sensory and motor potential amplitudes. When the exposure is removed, there is typically good recovery (19).

Carbon disulfide

Carbon disulfide is a solvent used widely in manufacturing (especially rayon) and fumigation with exposure typically occurring in the workplace. Inhalation is the primary route of intoxication where it leads to an axonal sensorimotor neuropathy and central nervous system dysfunction (neuropsychiatric symptoms and parkinsonism) (20). Patients often have poor recovery, which may relate to longstanding exposures in reported cases.

Ethylene oxide

Ethylene oxide can be inhaled in industrial workplaces, although its use as a medical equipment sterilizer has also caused neurotoxicity. The length dependent sensorimotor peripheral neuropathy has a good recovery (2).

Diethylene glycol

Diethylene glycol, used in antifreeze, leads to acute kidney injury, but also delayed neurological symptoms, such as decreased reflexes, ataxia and limb weakness 2–7 days after DEG ingestions (21, 22). Sensorimotor axonopathy and unexcitable motor and sensory responses have been reported. The lower extremities are most commonly affected, although facial neuropathies may also occur (23). Most patients experience neurological improvement (23).

Hexacarbons

Hexacarbons are used in spray cans in the automotive industry to clean breaks and engine parts (24). N-Hexane leads to a distal symmetrical peripheral neuropathy with axonal degeneration (25, 26). The neuropathy does reverse in mild cases and might persist in severe cases (27, 28).

Organophosphates

Organophosphates are used as pesticides, plastic softeners and hydraulic fluids (29, 30). Organophosphate poisoning (OP) causes acute, intermediate and delayed neuropathy (31). The typical delayed neuropathy is a distal axonal degeneration and demyelination of the central and peripheral axons and causes progressive muscle weakness, ataxia and paralysis (32). Organophosphate induced delayed neuropathy can be severe and irreversible (33).

Metabolic causes

Uremic neuropathy is a complication of chronic kidney disease. When the renal filtration is dysfunctional, urea accumulates. It affects 90% of dialysis patients and up to 70% of pre-dialysis patients (34–36). A distal symmetric sensorimotor neuropathy occurs that starts distally from the lower limbs and can spread to upper extremities (37). Paresthesia, increased pain and cramps may be early signs (37). It is thought that concomitant diabetes mellitus results in a more severe uremic neuropathy with weakness. Effective dialysis is a treatment to halt progression and normalize nerve excitability (38), while renal transplant is the most promising therapy and can revert symptoms completely (34).

Heavy metals

Heavy metal intoxication can occur with essential heavy metals (iron, zinc, copper, manganese) which support metabolic functions and are only toxic in higher concentrations and non-essential heavy metals (arsenic, lead, thallium, mercury) which are toxic even in low concentrations (39, 40). These heavy metals are not metabolized, accumulate and lead to peripheral neuropathy (41). While industrial production and occupational exposure to heavy metals is now tightly regulated in most countries, ingestion still may be seen in the setting of nutraceuticals (42) or traditional medicines (43), and residual industrial sources are ubiquitous (2).

Subacute intoxication with high concentrations of lead is possible (44). Chronic lead exposure leads sensory and autonomic dysfunctions (45, 46). The presenting features of lead intoxication include extensor weaknesses (wrist and foot drops) and slight sensory deficits (45, 47–50). Concomitant features of lead poisoning are lead lines on gingivae (Burton lines), encephalopathy and erythrocyte basophilic stippling, abdominal colic and sideroblastic anemia. While systemic symptoms may reverse, neurological damage can persist (51).

Arsenic poisoning occurs primarily from ingestion of contaminated water and food exposed to polluted water (52, 53). Subacute intoxication can lead to demyelinating peripheral neuropathy and may be confused for Guillain-Barre syndrome (54–57). Common symptoms in case of chronic toxicity include numbness and tingling (58, 59). Skin lesions, pancytopenia, diarrhea and abdominal pain might also occur (60, 61). Nerve conduction studies may be normal in chronic cases (62), while subacute axonal neuropathy presents with a slower conduction velocity (54). Detoxification can be supported with folate and methylcobalamin, but complete recovery is possible without specific chelating therapy (54).

Acute mercury intoxication due to inhalation leads to pneumonitis (63). Chronic exposure due to dental fillings, food (fish) and industrial exposure can lead to stomatitis, fatigue, and weight loss (64, 65). About 50% of patients develop peripheral neuropathy as a long-term consequence with symptoms such as weakness, paresthesia, numbness, diminished reflexes and sensory loss (66, 67). Assessing mercury intoxication can be a difficult task, as blood, hair and urine levels only display recent exposure (65, 68, 69). Neurological symptoms from mercury poising are often irreversible.

Thallium is present in some pesticides and has been used with homicidal intent. Thallium can lead to polyneuropathy with memory impairment and mental disturbances, as well as seizures (70–72). Acute thallium poisoning may present with hyperalgesia, abdominalgia, hepatic damage and alopecia (73). Due to their similar neurologic symptoms, patients may be misdiagnosed with Guillain-Barré syndrome (73). Blood and urine levels may be used to diagnose thallium intoxication (73). Prussian Blue and hemoperfusion are therapeutic options to detoxify thallium (73). Peripheral neuropathy can persist over years.

Rare cases of polyneuropathy have been reported due to ingestion of colloidal silver, which was taken in the intent to kill pathogens. Apart from the sensory predominant neuropathy, patients may present with argyria, a bluish discoloration of the skin (74). No effective treatment to detoxify silver is available yet (75).

Chelation is often used as a treatment to reduce the burden of heavy metals. Dimercapto-Propanseulphonate (DMPS) or Dimercaptosuccinic acid (DMSA) can be used as chelating agents to detoxify arsenic, lead and mercury (76–79). Lead can also be detoxified with Dimercaprol and EDTA. Antioxidants such as Vitamin E, C, Zinc and selenium, as well as alpha lipoic acid can be added to reduce oxidative stress and to improved therapeutic efficacy (80–83). Other therapeutic alternatives are plasmapheresis in emergency conditions to chelate mercury (79, 84).

Drugs

Drug-induced peripheral neuropathies are among the most common forms of toxic neuropathies. While the risk of neuropathy for many drugs is dose- and time-dependent (especially chemotherapeutics), other drugs cause neuropathy in an idiosyncratic fashion. It has been hypothesized that the differential susceptibility to drug-induced neuropathies is likely due to genetic factors or concomitant mild underlying neuropathies from other causes (85).

Antimicrobials

There is a 10% prevalence of peripheral neuropathy in patients who are treated for tuberculosis (86). Ethambutol can lead to sensory predominant axonal neuropathy, as well as retrobulbar optic neuropathy (87). Pyridoxine supplementation can prevent the sensory neuropathy with a glove and stocking distribution that isoniazid can cause. Patients with drug resistant tuberculosis (resistance to isoniazid and rifampicin, along with resistance to a fluoroquinolone) have a higher prevalence of peripheral neuropathy of 13 to 17% (88), partly because linezolid is added to their treatment. Linezolid can induce thrombocytopenia, optic neuropathy, lactic acidosis and peripheral neuropathy (89). There are reports that nearly one in three patients who receive linezolid develop neuropathy (90). The neurologic damage is mostly irreversible. Another antimicrobial class that can be used in tuberculosis patients and is associated with neuropathy is fluoroquinolones (91, 92), albeit with a very rare occurrence (85, 92). The presenting symptoms can be numbness and pain (92, 93). It is not yet clear if the symptoms are reversible (94).

Dapsone can cause a motor predominant axonal neuropathy that may present with weakness and abnormal deep tendon reflexes. The symptoms may mimic mononeuritis multiplex, but are reversible upon discontinuation of the drug (95). Other side effects of dapsone affect the hematologic system, the gastrointestinal system, and the skin (96).

Metronidazole is a widely used antibiotic that is usually well tolerated, apart from gastrointestinal disturbances (97). Rare side effects are convulsive seizures and peripheral neuropathy (98). The sensory predominant axonal neuropathy is typically characterized with numbness, diminished sensation and pain in the lower extremities (97). Less often, diminished reflexes, muscle weakness and abnormal nerve conduction occurs (99). After discontinuation most patients experience a reversal of symptoms (97).

Antiretrovirals

HIV can directly cause neuropathy through dysregulation of macrophages (100). However, anti-retro-viral-therapy (ART) can also cause distal symmetric polyneuropathy (101). Stavudine, didanosine and zalcitabine have all been linked to neuropathy (102). A recent systematic review reported that 31% of patients with HIV develop peripheral neuropathy (103). The distal symmetrical polyneuropathy is characterized by pain, numbness, a burning sensation, decreased vibration sense and ankle tendon reflexes (104). In recent literature, voluntary exercise has been described as an effective strategy to alleviate symptoms (105).

Chemotherapeutic agents

Several drug classes of chemotherapy cause neuropathy with high incidence in a dose-dependent fashion. There has been extensive research in chemotherapy-induced peripheral neuropathy (CIPN) in order to prevent this dreaded complication that results in dose reductions of medications that are used to treat cancers (106).

Platinum based compounds (cisplatin, carboplatin, oxaliplatin) have the highest occurrence of CIPN (107) and can cause both a sensory neuronopathy and length-dependent sensory neuropathy. Platinum-induced neuropathies are known to worsen after removal of the medication, a phenomenon known as “coasting.” The pathomechanism of platinum-induced neuropathy is thought to be DNA-adduct formation and neuronal apoptosis, with concomitant mitochondrial damage (which may mediate the coasting phenomenon). Due to the severe damage from platinum compounds, it can take years for the symptoms to improve and complete resolution is often not be achieved (108). Oxaliplatin is unique as it can also cause acute neuropathic symptoms around the time of infusion, which manifests as cold hypersensitivity (109).

Patients who are treated with taxanes (docetaxel, paclitaxel) can experience length-dependent distal sensory neuropathy (110). Taxanes stabilize microtubules and disrupt axonal transport mechanisms in neurons. In case of paclitaxel, there is an acute pain syndrome that may occur around the time of infusion, but it is unclear whether this is neuropathic or myalgiform (109). Pain, tingling, cold-sensitivity and numbness in a stocking and glove distribution are typical symptoms of taxane neuropathies (111). Motor deficits and autonomic dysfunction is also possible (112). The symptoms can persist for years (113–115).

Vincristine (a vinca alkaloid, which destabilize microtubules) leads to a peripheral motor and sensory neuropathy (116). Numbness, paresthesia, impaired balance, weakened tendon reflexes and altered gait might be presenting symptoms (117). In addition, autonomic dysfunction and cranial nerve palsies, central nerve system toxicities and systemic side effects such as alopecia, SIADH and myelosuppression can develop (116, 118, 119). Symptoms can reverse, but loss of deep tendon reflexes and decreased motor functions may persist in children (106).

Proteasome inhibitors, like bortezomib can also induce peripheral neuropathy. The distal symmetrical length-dependent axonal sensorimotor neuropathy can resolve when the dose is reduced or the drug is stopped (120, 121). The mild to severe neuropathic pain and occasional mild motor weakness usually starts in the distal lower extremities (120, 121). Rarely, an immune mediated polyradiculoneuropathy develops following bortezomib exposure (122).

Thalidomide can cause a predominantly sensory, axonal and length dependent neuropathy that affects large and small fibers (123, 124). Other symptoms are sedation, constipation and thromboembolism (125). Sensory nerve amplitudes can be reduced, as well as motor nerve conductions (123). Symptoms usually reverse when treatment is ceased (125).

Immune Checkpoint inhibitors (Anti-PD1, Anti-PD-L1, Anti CTLA4) activate T-Cells and improve the patients’ immune response against certain cancers. Side effects such as inflammation of the gastrointestinal, dermatologic, endocrine or pulmonary organs can occur (126). Neurologic toxicity can involve the central, peripheral and autonomic nervous system (127). Patients who experience peripheral neuropathy from immune checkpoint inhibitors present with pain, paresthesia and weakness (126, 128). The acute or chronic symptom onset can be accompanied by cranial neuropathies (facial nerve palsy or trigeminal neuralgia) and inflammatory polyradiculopathies (such as Guillian-Barre Syndrome) (129, 130).

Miscellaneous Pharmaceuticals

Nitrous oxide is a widely used anesthetic drug. It also has euphoric and hallucinogenic effects which has led to recreational uses and abuse (131). Side effects range from psychological disorders, emotional disorders, subacute combined degeneration to demyelinating polyneuropathy (132–135). Due to the functional B12 deficiency that nitrous oxide causes, the signs and symptoms reflect subacute combined degeneration (upper motor neurons sings may be present) (131). The neuronal damage may be permanent (131).

Phenytoin has been used since the 1940s as an anticonvulsive agent. Its blockage of sodium channels has also been used to treat neuropathy topically (136, 137). If neuropathy occurs as a side effect, it has been reported to be mostly a subclinical phenomenon (no clinical signs, but polyneuropathy on electro physiological assessment) (138). If a mild sensorimotor axonal neuropathy develops, the symptoms reverse upon discontinuation of the drug (138).

Vitamin B6 is a water soluble vitamin that is abundant in many food sources (139). It plays an important role in neuronal signaling through the synthesis of neurotransmitters (140). Despite the fact that its deficiency is rare, Vitamin B6 supplementation is common among the general population (139). Excessive Vitamin B6 intake (>100 mg/day) may result in neuropathy (141). Early symptoms range from paresthesia in toes, to sensory ataxia, loss of balance and difficulty handling small objects (139). Once B6 supplementation is stopped, symptoms could progress before gradually resolving, except for distal sensory perception (139).

Conclusion

The peripheral nervous system is susceptible to damage from a broad spectrum of toxins. The damage can occur at the level of the neuron (sensory, motor, autonomic) or Schwann cell, and may be reversible or permanent. Other than in the setting of CIPN, where there is a clear correlation of drug ingestion and neuropathic symptoms, it can often be difficult to confidently ascribe causality for any given toxin. There may not be a specific test that identifies the toxin and therefore the detailed exposure history and timeline is critical. Sometimes, merely including toxic neuropathies on the differential and taking a detailed history quickly leads to the correct diagnosis.

Despite the longstanding recognition of toxic neuropathies, they continue to be a clinical problem. Neurotoxic industrial exposures may shift to less regulated countries, and neurotoxic medications have not been replaced by newer, less toxic formulations. Therefore, continued clinical and public health vigilance will be required. Furthermore, there will need to be continued mechanistic studies of toxic neuropathies to help develop novel therapeutics for these conditions. A detailed understanding of genetic susceptibility may reveal those at risk for neurotoxicity when the drug cannot be otherwise avoided. Finally, uncovering common final mechanisms of neuronal damage may provide strategies for neuroprotection across diverse neurotoxins.