This chapter reviews neuropathies associated with various drugs and other environmental exposures (Table 20-1). Toxic neuropathies due to chemotherapeutic agents are discussed in Chapter 19. The associated neuropathy for most of these is an axonal, length-dependent predominantly sensory neuropathy. The history of exposure and sometimes the involvement of other organ systems help to suggest the correct diagnosis. Although we mention features that have been reported on nerve biopsy, this is not typically part of the workup as in most cases the abnormalities are nonspecific.

METRONIDAZOLE

Clinical Features

Metronidazole is used to treat a variety of protozoan infections and Crohn disease.^1–8 Metronidazole is a member of the nitroimidazole group and has been associated with hyperalgesia and hypesthesia in a length-dependent pattern. Autonomic dysfunction may develop as well. Motor strength is typically normal. The cumulative dose at which neuropathy occurs is wide, ranging from 3.6 to 228 g. Although there is no clear dose effect, neuropathy appears to occur more frequently in patients receiving greater than 1.5 g daily of metronidazole for 30 or more days The neuropathic symptoms usually improve upon discontinuation of the drug, but there can be a coasting effect such that the symptoms may continue to worsen for several weeks. Some patients are left with residual sensory symptoms.

Laboratory Features

Nerve conduction studies (NCS) may be normal, as typical of a small fiber neuropathy, or reveal reduced amplitudes or absent sensory nerve action potentials (SNAPs) in the legs worse than in the arms. Motor conduction studies are usually normal.

Histopathology

Nerve biopsies are not routinely performed for this but have demonstrated loss of myelinated nerve fibers.

Pathogenesis

The pathogenic basis of the neuropathy is not known. Some have found that metronidazole binds to DNA and/or RNA, which could lead to breaks and impair transcription or translation to normal proteins.^7,8 Others have speculated that toxicity may arise from the production of nitro radical anions that bind and disrupt normal protein/enzyme function.⁸ Furthermore, the histological abnormalities in metronidazole-treated rodents and abnormalities on brain MRI scans in patients with metronidazole-associated encephalopathy resemble thiamine (vitamin B1) deficiency. It has been postulated that there may be enzymatic conversion of metronidazole to an analog of thiamine, which may act as a B1 antagonist.⁹

MISONIDAZOLE

Clinical Features

Misonidazole is used as an adjuvant agent in the treatment of various malignancies.^10–13 As with metronidazole, misonidazole is a member of the nitroimidazole group. Some patients have developed painful paresthesias and sometimes distal weakness in a length-dependent pattern after approximately 3–5 weeks of therapeutic drug administration (total dose greater than 18 g). Vibratory and temperature perception are usually reduced, but muscle stretch reflexes are preserved. The neuropathy usually improves following discontinuation of the drug.

Laboratory Features

Sensory NCS reveal reduced amplitudes or unobtainable responses in the legs more than the arms. Motor conduction studies are typically normal.

Histopathology

A reduction in the large myelinated fibers with axonal degeneration and segmental demyelination and remyelination has been found on sural nerve biopsies. Accumulation of neurofilaments with axonal swellings can be found on electron microscopy (EM).

Pathogenesis

The pathogenic basis of the neuropathy is not known, but may be similar to metronidazole.

CHLOROQUINE

Clinical Features

Chloroquine is used in the treatment of malaria, sarcoidosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis (RA). Chloroquine is associated with a toxic myopathy characterized by slowly progressive, painless, proximal weakness and atrophy, which is worse in the legs than in the arms (discussed in Chapter 35).^14–16 A neuropathy can also develop with or without the myopathy, leading to sensory loss, distal weakness, and reduced muscle stretch reflexes. The “neuromyopathy” usually appears in patients taking 500 mg/d for a year or more but has been reported with doses as low as 200 mg/d. The signs and symptoms of the neuropathy and myopathy are usually reversible following discontinuation of chloroquine.

Laboratory Features

Serum creatine kinase (CK) levels are usually elevated due to the superimposed myopathy. NCS reveal mild slowing of motor and sensory nerve conduction velocities (NCVs) with a mild to moderate reduction in the amplitudes. NCS may be normal in patients with only the myopathy. Electromyography (EMG) demonstrates myopathic motor unit action potentials (MUAPs), increased insertional activity in the form of positive sharp waves, fibrillation potentials, and occasionally myotonic potentials, particularly in the proximal muscles. Neurogenic MUAPs and reduced recruitment are found in more distal muscles.

Histopathology

Nerve biopsies demonstrate autophagic vacuoles and inclusions within Schwann cells (Fig. 20-1). Vacuoles may also be evident in muscle biopsies.

Pathogenesis

The pathogenic basis of the neuropathy is not known but may be related to the amphiphilic properties of the drug. Chloroquine contains both hydrophobic and hydrophilic regions that allow chloroquine to interact with the anionic phospholipids of cell membranes and organelles. This drug–lipid complex may be resistant to digestion by lysosomal enzymes, leading to the formation of autophagic vacuoles filled with myeloid debris that may, in turn, cause degeneration of nerves and muscle fibers.

HYDROXYCHLOROQUINE

Hydroxychloroquine is structurally similar to chloroquine and, not surprisingly, has also been associated with a toxic neuromyopathy.¹⁷ Weakness and histological abnormalities are usually not as severe as seen in chloroquine myopathy. Vacuoles are typically absent on biopsy, but EM still may demonstrate abnormal accumulation of myeloid and curvilinear bodies.

AMIODARONE

Clinical Features

Amiodarone is an antiarrhythmic medication that is also associated with a neuromyopathy similar to chloroquine^18–23 Severe proximal and distal weakness can develop in the legs worse than in the arms, combined with distal sensory loss, tingling, and burning pain. In addition, amiodarone is also associated with tremor, thyroid dysfunction, keratitis, pigmentary skin changes, hepatitis, pulmonary fibrosis, and parotid gland hypertrophy. The neuromyopathy typically appears after patients have taken the medication for 2–3 years. Physical examination demonstrates arm and leg weakness, reduced sensation to all modalities, and diminished muscle stretch reflexes. The neuromyopathy usually improves following discontinuation of the drug.

Laboratory Features

Sensory NCS reveal markedly reduced amplitudes and, when obtainable, mild to moderately slow conduction velocities and prolonged distal latencies.^19,21,22 Motor NCS may also be abnormal, but usually not to the same degree as seen in sensory studies. EMG demonstrates fibrillation potentials, positive sharp waves, and occasionally myotonic discharges with a mixture of myopathic and neurogenic-appearing MUAPs.

Histopathology

Muscle biopsies demonstrate neurogenic atrophy, particularly in distal muscles, and autophagic vacuoles with myeloid and dense inclusions on EM. Sural nerve biopsies demonstrate a combination of segmental demyelination and axonal loss. EM reveals lamellar or dense inclusions in Schwann cells, pericytes, and endothelial cells. The inclusions in muscle and nerve biopsies have persisted as long as 2 years following discontinuation of the medication.

Pathogenesis

The pathogenesis is presumably similar to other amphiphilic medications (e.g., chloroquine).

COLCHICINE

Clinical Features

Colchicine is used primarily to treat patients with gout and is also associated with a toxic neuropathy and myopathy.^24–26 Affected individuals usually present with proximal weakness along with numbness and tingling in the distal extremities. Reduced sensation to touch, vibration, position sense, and diminished muscle stretch reflexes are found on examination.

Laboratory Features

Motor and sensory NCS demonstrate reduced amplitudes.^24–26 The distal motor and sensory latencies can be normal or slightly prolonged and conduction velocities are normal or mildly slow. EMG demonstrates fibrillation potentials and positive sharp waves along with short-duration, low-amplitude MUAPs in the proximal limb muscles and long-duration, large-amplitude MUAPs distally.

Histopathology

Muscle biopsies reveal a vacuolar myopathy, while sensory nerve biopsies demonstrate axonal degeneration.

Pathogenesis

Colchicine inhibits the polymerization of tubulin into microtubules. The disruption of the microtubules probably leads to defective intracellular movement of important proteins, nutrients, and waste products in muscles and nerves.²⁵

PODOPHYLLIN

Clinical Features

Podophyllin is a topical agent used to treat condylomata acuminata. Systemic side effects include pancytopenia and liver and renal dysfunction. Podophyllin is also potentially toxic to both the central and the peripheral nervous systems (PNS), leading to psychosis, altered consciousness, and polyneuropathy.^27,28 The neuropathy is characterized by slowly progressive sensory loss, paresthesias, muscle weakness, and diminished muscle stretch reflexes in a length-dependent pattern. Autonomic neuropathy with nausea, vomiting, gastrointestinal paresis, urinary retention, orthostatic hypotension, and tachycardia may also occur. The signs and symptoms of this toxic neuropathy can progress for a couple of months even after stopping the medication. The neuropathy gradually improves with discontinuation of the podophyllin, but it can take several months to over a year and residual deficits may remain.

Laboratory Features

Cerebrospinal fluid (CSF) protein levels can be elevated. Laboratory evaluation may also demonstrate pancytopenia, liver function abnormalities, and renal insufficiency. Sensory NCS reveal absent SNAPs or their reduced amplitudes. Motor NCS are less affected but can demonstrate reduced amplitudes.

Histopathology

Nerve biopsies demonstrate axonal degeneration.

Pathogenesis

Podophyllin binds to microtubules similar to colchicine and probably inhibits axoplasmic flow leading to axonal degeneration.²⁹

THALIDOMIDE

Clinical Features

Thalidomide is an immunomodulating agent used to treat multiple myeloma, graft-versus-host disease, leprosy, and other autoimmune disorders.^30–36 Thalidomide is associated with severe teratogenic effects as well as peripheral neuropathy, which can be dose limiting. Most patients who develop the neuropathy have received a cumulative dose of at least 20 g of thalidomide.³⁴ Less than 10% of patients receiving less than 20 g of thalidomide develop polyneuropathy. Patients complain of numbness, painful tingling, burning discomfort in the feet and hands, and less commonly muscle weakness and atrophy. Even after stopping the drug for 4–6 years, as many as 50% of patients continue to have significant symptoms. Physical examination demonstrates a reduction in vibration and position sense, hypo- or areflexia, and occasionally proximal and distal weakness.

Laboratory Features

NCS demonstrate reduced amplitudes or complete absence of the SNAPs with preserved conduction velocities when obtainable.^30–36 Motor NCS are usually normal.

Histopathology

Nerve biopsies reveal a loss of large-diameter myelinated fibers and axonal degeneration.³⁵ Degeneration of dorsal root ganglion cells has been appreciated on autopsies.

Pathogenesis

The pathogenic basis of the neuropathy is not known.

DISULFIRAM

Clinical Features

Disulfiram (antabuse) is used to treat alcoholism. It is metabolized to carbon disulfide, which is a neurotoxin and can have adverse effects on both the PNS and the central nervous system (CNS).^37–44 A neuropathy with distal weakness (e.g., foot drop) and sensory loss may develop as early as 10 days to as long as 18 months after starting the drug.

Laboratory Features

NCS are suggestive of an axonal sensorimotor polyneuropathy with reduced amplitudes or absent SNAPs and CMAPs with normal or only moderately slow conduction velocities.^37,40,41 Needle EMG reveals fibrillation potentials and positive sharp waves in distal muscles along with decreased recruitment of neurogenic-appearing MUAPs.

Histopathology

Sural nerve biopsy has demonstrated axonal degeneration and segmental demyelination with a loss of predominately large-diameter fibers, although small-diameter fibers can be affected as well.^37–40 On EM, swollen axonal due to the accumulation of neurofilamentous debris within the myelinated and unmyelinated axons may be appreciated.

Pathogenesis

The neuropathy may be secondary to carbon disulfide, which is a metabolite of disulfiram. A similar axonal neuropathy characterized by accumulation of neurofilaments occurs with carbon disulfide toxicity.

DAPSONE

Clinical Features

Dapsone is used primarily for the treatment of leprosy and for various dermatologic conditions. A primarily motor neuropathy can develop as early as 5 days to as long as 5 years after starting the drug.^45–49 Weakness initially involves the hands and feet and over time progresses to affect more proximal muscles. Occasionally, patients complain of sensory symptoms without weakness.

Laboratory Features

Motor and sensory NCS usually demonstrate reduced amplitudes with normal or only slightly slow conduction velocities.^45–49 The NCS usually improve after the dapsone is discontinued.

Histopathology

Biopsy of the motor nerve terminal at the extensor brevis muscle has demonstrated axonal atrophy and Wallerian degeneration of the distal motor nerve terminals.⁴⁹ Sural nerve biopsy may reveal a loss of myelinated nerve fibers.

Pathogenesis

The pathogenic basis of the neuropathy is not known.

LEFLUNOMIDE

Clinical Features

Leflunomide is used for the treatment of RA. It is a prodrug for an active metabolite that reversibly inhibits dihydroorotate dehydrogenase. This enzyme catalyzes the rate-limiting step in the de novo synthesis of pyrimidines that are necessary for lymphocyte production. There have been several reports of patients treated with leflunomide who developed distal numbness and paresthesia.^50–55 The median duration of treatment at the onset of neuropathy was 7.5 months (range 3 weeks to 29 months) in one large study.⁵²

Laboratory Features

NCS may demonstrate features of a primarily axonal, sensorimotor polyneuropathy.^50–55 More commonly, the NCS are normal and do not correlate with symptoms, which suggests that leflunomide may cause a small fiber neuropathy.⁵⁴ In this regard, a study of leflunomide treatment in patients with RA revealed abnormal cold detection on quantitative sensory testing compared to controls; vibratory thresholds were normal.⁵⁵

Histopathology

There are no reports of nerve biopsies.

Pathogenesis

The pathogenic basis for the neuropathy is not known.

Treatment

The neuropathy usually improves after withdrawal of the medication.

NITROFURANTOIN

Clinical Features

Nitrofurantoin is an antibiotic most often used to treat urinary tract infections and may cause an acute and severe sensorimotor polyneuropathy ^56–60 or a non–length-dependent small fiber neuropathy/ganglionopathy.⁶¹ Patients may develop numbness, painful paresthesia, and sometimes quadriparesis. Elderly and those with baseline renal insufficiency are most at risk. Physical examination most often reveals decrease of all sensory modalities (except in cases of small fiber neuronopathy) in the distal regions of the upper and lower limbs. Muscle stretch reflexes are reduced or absent. Most patients slowly improve following discontinuation of the drug.

Laboratory Features

NCS may demonstrate reduced amplitudes or absent SNAPs and CMAPs suggestive of an axonopathy^58,59 or may be normal in cases of a small fiber neuropathy/ganglionopathy.⁶¹

Histopathology

Sural nerve biopsy may reveal loss of large myelinated fibers with signs of active Wallerian degeneration.⁵⁸ An autopsy study has shown degeneration of the spinal roots, dorsal more severely affected than ventral roots, and chromatolysis of the anterior horn cells.⁵⁷ Skin biopsies in patients with small fiber sensory neuropathy/ganglionopathy have shown distinctive morphologic changes with clustered terminal nerve swellings without a reduction in density.⁶¹

Pathogenesis

The pathogenic basis of the neuropathy is not known.

PYRIDOXINE (VITAMIN B6) TOXICITY

Clinical Features

Pyridoxine is an essential vitamin that serves as a coenzyme for transamination and decarboxylation. The recommended daily allowance in adults is 2–4 mg. However, at high doses (116 mg/d) patients can develop a severe sensory neuropathy with dysesthesia and sensory ataxia.^62–66 Some patients also complain of a Lhermitte’s sign. There is one report of a patient taking 9.6 g pyridoxine per day who developed weakness as well.⁶⁷ Neurological examination reveals marked impaired vibratory perception and proprioception. Sensory loss can begin and be more severe in the upper than in the lower limbs. Muscle strength is usually normal, although there may be loss of fine motor control. Gait is wide based and unsteady secondary to the sensory ataxia. Muscle stretch reflexes are reduced or absent.

Laboratory Features

NCS usually reveal absent or markedly reduced SNAP amplitudes with relatively preserved CMAPs,^62–66 although one case with severe weakness reported reduced CMAP amplitudes and moderately slowing of CVs.⁶⁷

Histopathology

Nerve biopsies have shown loss of axons of all fiber diameters.^65,66 Reduced numbers of dorsal root ganglion cells and subsequent degeneration of both the peripheral and the central sensory tracts have been appreciated in animal models.